CODEINE/PARACETAMOL 30 MG / 500 MG FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Codeine/Paracetamol 30mg/500mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 30mg Codeine Phosphate Hemihydrate and 500mg Paracetamol

Excipient with known effect: Each film-coated tablet contains 0.98 mg lecithin soya (E322).

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Film-coated tablets

Codeine/Paracetamol film-coated tablets are white, oval, 8.5 × 17mm, biconvex tablets, marked ’5 3’ on one side with a score line.

The score 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 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

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: Two tablets not more frequently than every 4 to 6 hours, up to a maximum of 8 tablets in any 24 hour period.

Elderly: As adults, however a reduced dose may be required. See warnings.

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

Children aged 12 to 15 years: One tablet every 6 hours when necessary to a maximum of 4 tablets in 24 hours.

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.

Paediatric population

Children 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

Codeine/Paracetamol film-coated tablets are for oral use.

4.3 Contraindications

Hypersensitivity to paracetamol or codeine which is rare.

Hypersensitivity to the active substances, soya or peanut or to any of the other 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

-Following biliary tract surgery

-Breast-feeding (see section 4.6).

Monoamine oxidase inhibitor therapy, concurrent or within 14 days.

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 patients for whom it is known they are CYP2D6 ultra-rapid metabolisers.

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 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 partially metabolised by CYP2D6. 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 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 nausea, vomiting, constipation, lack of appetite, somnolence, shallow breathing, small pupils and confusion. 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:

The leaflet will state in the “pregnancy and breast-feeding” subsection of the section 2 “Before taking your medicine”:

Codeine/Paracetamol is contraindicated in breast-feeding

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.

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

Concomitant use of Codeine/Paracetamol 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/Paracetamol 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 m (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).

Care should be observed in administering the product to any patient whose condition may be exacerbated by opioids, particularly the elderly, who may be sensitive to their central and gastro-intestinal effects, those on concurrent CNS depressant drugs, those with prostatic hypertrophy and those with inflammatory or obstructive bowel disorders. Care should also be observed if prolonged therapy is contemplated.

Codeine/Paracetamol should be used upon medical advice in 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.

Caution is advised in patients with underlying sensitivity to aspirin and/or to nonsteroidal anti-inflammatory drugs (NSAIDs).

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 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 pain killer 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.

Important information about the ingredients of Codeine/Paracetamol Codeine/Paracetamol contains Lecithin soya

If you are allergic to peanut or soya, do not use this medicinal product.

Codeine/Paracetamol Tablets contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‚sodium-free‘.

4.5 Interaction with other medicinal products and other forms of interaction

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.

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).

Alcohol and opioids

The concomitant use of alcohol and opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. Concomitant use with alcohol is not recommended (see section 4.4).

CYP2D6 inhibitors:

Codeine is metabolised by the liver enzyme CYP2D6 to its active metabolite morphine. Medicines that inhibit CYP2D6 activity may reduce the analgesic effect of codeine.

Patients taking codeine and moderate to strong CYP2D6 inhibitors (such as quinidine, fluoxetine, paroxetine, bupropion, cinacalcet, methadone) should be adequately monitored for reduced efficacy and withdrawal signs and symptoms. If necessary, an adjustment of the treatment should be considered.

CYP3A4 inducers:

Medicines that induce CYP3A4 activity may reduce the analgesic effect of codeine. Patients taking codeine and rifampicin should be adequately monitored for reduced efficacy and withdrawal signs and symptoms. If necessary, an adjustment of the treatment should be considered.

4.6 Fertility, pregnancy and lactation

Pregnancy

Careful consideration should be given before prescribing the product for pregnant patients.

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.

Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy 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, use of Codeine/Paracetamol should be avoided during the third trimester of pregnancy and during labour.

Breastfeeding

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

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

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

Codeine can produce typical opioid effects including constipation, nausea, vomiting, dizziness, light-headedness, confusion, drowsiness and urinary retention. The frequency and severity are determined by dosage, duration of treatment and individual sensitivity. Tolerance and dependence can occur, especially with prolonged high dosage of codeine.

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 frequency of undesirable effects is classified 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).

Undesirable effects

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.

Codeine

The effects of Codeine 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 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

Management 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 4 hours after ingestion, or 8 hours if a sustained release preparation has been taken.

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:

is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St. John's Wort or other drugs that induce liver enzymes, or

regularly consumes ethanol in excess of recommended amounts, or

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. Increased levels of hepatic transaminases, lactate dehydrogenase and bilirubin may occur, and the INR may increase. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, gastrointestinal bleeding, disseminated intravascular coagulation 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, pancreatitis and pancytopenia have been reported.

Management

Immediate treatment is essential in the management of Paracetamol overdose. Despite lack of significant early symptoms, patients should be referred to hospital urgently for immediate 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 concentrations 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 NPIS or a liver unit.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Codeine, combinations excl. Psycholeptics. ATC Code: N02AA59

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 p 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

Following oral administration of two tablets (i.e. a dose of paracetamol 1000mg and codeine phosphate 60mg) the mean maximum plasma concentrations of paracetamol and codeine were 15.96pg/ml and 212.4ng/ml respectively.

The mean times to maximum plasma concentrations were 0.88 hours for paracetamol and 1.05 hours for codeine.

The mean AUC for the 9 hours following administration was 49.05pg./ml per hour for paracetamol and 885.0ng/ml per hour for codeine.

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

Codeine is mainly metabolized by glucuronidation to codeine-6-glucuronide. Minor routes of metabolism include O- demethylation leading to morphine, N-demethylation to norcodeine and after both O- and N-demethylation formation of normorphine. Morphine and norcodeine are further transformed in glucuroconjugates. Unchanged codeine and its metabolites are mainly excreted by urinary route within 48h (84.4±15.9%).

The O-demethylation of codeine to morphine is catalyzed by the cytochrome P450 isozyme 2D6 (CYP2D6) which shows genetic polymorphism that may affect the efficacy and toxicity of codeine.

Genetic polymorphism in CYP2D6 leads to ultra-rapid, extensive and poor metaboliser phenotypes.

5.3 Preclinical safety data

There are no non-clinical data of relevance which are additional to that already included in other sections of the SPC.

Paracetamol

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

Tablet core:

Povidone K29/32

Magnesium stearate

Silica colloidal anhydrous

Talc

Sodium croscarmellose

Copovidone (25.2–30.8)

Cellulose microcrystalline

Tablet coating:

Hydroxypropylated starch (E1440)

Talc

Mannitol

Lecithin soya (E322)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

White PVC/Aluminium blisters

or white PVC/Aluminium/PE/pa­per child resistant blisters

or white HDPE tablet container with a white LDPE cap

or white HDPE tablet container with a white PP child-resistant screw cap.

Pack Sizes:

PVC/Aluminium or PVC/Aluminium/PE/pa­per blisters: 8, 10, 16, 20, 24, 30, 40, 50 and 100 film-coated tablets

Tablet containers: 50 and 100 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

Instructions for use of child resistant blisters:

1. The tablet should not be pushed directly out of the pocket

2. One blister cell has to be separated from the strip at the perforations

3. The backing has to be carefully peeled off to open the pocket

7 MARKETING AUTHORISATION HOLDER

Torrent Pharma (UK) Ltd.

Unit 4, Charlwood Court,

County Oak Way,

Crawley,

West Sussex.

RH11 7XA,

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 36687/0140

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 02/07/2015

Date of latest renewal: