CO-DYDRAMOL TABLETS BP 10/500 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Co-Dydramol Tablets BP 10/500mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10mg Dihydrocodeine Tartrate and 500mg Paracetamol.

For the full list of excipients, see section 6.1.

White uncoated tablets.

White, circular, flat bevelled-edge uncoated tablets impressed with “C” and “CT” on either side of a central division line on one face. Nominal diameter 12.5mm.

4.1 Therapeutic indications

Analgesic for the relief of mild to moderate pain.

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

It is recommended that this product should be taken during or after meals.

Adults and children over 16 years:

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

Elderly:

As for adults, however a reduced dose maybe required if renal or hepatic function is impaired.

Paediatric Population:

Children 12–15 years:

One tablet every 4–6 hours when necessary to a maximum of 4 tablets in 24 hours.

Children under 12 years:

Not recommended.

For oral administration.

4.3 Contraindications

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

Diarrhoea caused by poisoning until the toxic material has been eliminated, or diarrhoea associated with pseudomembraneous colitis

respiratory depression

obstructive airways disease

liver disease

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 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-Dydramol Tablets.

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.

Co-Dydramol Tablets should be used with caution in patients with:

hepatic function impairment (avoid if severe) and those with non-cirrhotic alcoholic liver disease. The hazards of overdose are greater in those with alcoholic liver disease.

Prolonged use may cause hepatic necrosis. Patients should be advised not to exceed the recommended dose and not to take other paracetamol-containing products concurrently.

renal function impairment.

hypothyroidism (risk of depression and prolonged CNS depression is increased). Dosage should be reduced.

inflammatory bowel disease – risk of toxic megacolon.

asthma attacks. Opioids should not be administered during an asthma attack and it should be administered with due care to persons liable to such attack.

convulsions – may be induced or exacerbated.

drug abuse, dependence (including alcoholism), enhanced instability, suicidal ideation or attempts – predisposed to drug abuse.

head injuries or conditions where intracranial pressure is raised.

gall bladder disease or gall stones – opioids may cause biliary contraction.

gastro-intestinal surgery – use with caution after recent GI surgery as opioids may alter GI motility.

prostatic hypertrophy or recent urinary tract surgery.

adrenocortical insufficiency, eg Addison’s Disease.

hypotension and shock.

myasthenia gravis.

phaeochromocytoma – opioids may stimulate catecholamine release by inducing the release of endogenous histamine.

Where analgesics are used long-term (>3 months) with administration every two days or more frequently, headache may develop or worsen. Headache induced by overuse of analgesics (MOH medication-overuse headache) should not be treated by dose increase. In such cases, the use of analgesics should be discontinued in consultation with the doctor.

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

Concomitant use of co-dydramol 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-dydramol 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).

Alcohol should be avoided. When dihydrocodeine is prescribed for chronic use, care should be taken to avoid unnecessary increase in dosage.

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

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

Contains paracetamol. Do not take anything else containing paracetamol while taking this medicine. Talk to a doctor at once if you take too much of this medicine even if you feel well. Do not take for longer than directed by your prescriber as taking dihydrocodeine regularly for a long time can lead to addiction.

Leaflet Warning (in ‘What you need to know before you take Co-dydramol Tablets’):

Do not take for longer than directed by your prescriber.

This medicine contains paracetamol. Do not take anything else containing paracetamol while taking this medicine.

Taking a painkiller for headaches too often or for too long can make them worse.

Opioids can cause addiction and you may get withdrawal symptoms if you stop taking it suddenly.

4.5 Interaction with other medicinal products and other forms of interaction

Paracetamol can interact with the following:

Drugs which alter gastric emptying time (e.g. cimetidine, ethyl alcohol, oral steroid contraceptives). These drugs reduce or delay peak paracetamol blood levels.

Metoclopramide or domperidone increases the speed of absorption of paracetamol.

Colestyramine reduces paracetamol absorption.

Drugs which interfere with the metabolism of paracetamol by competition with metabolic pathways or substrates e.g. anticonvulsants (phenytoin), hepatic enzyme inducers, alcohol, barbiturates, tricyclic antidepressants. A poor diet (low protein) may also have a similar effect on the risk of serious paracetamol toxicity to hepatic enzyme inducers. Patients who have taken barbiturates, tricyclic antidepressants and alcohol may show diminished ability to metabolise large doses of paracetamol, the plasma half-life of which may be prolonged.

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.

Alcohol can increase the hepatotoxicity of paracetamol overdosage and may have contributed to the acute pancreatitis reported in one patient who had taken an overdosage of paracetamol.

Dihydrocodeine can interact with the following:

CNS depressants – enhanced sedative and/or hypotensive effect with alcohol, anaesthetics, hypnotics, anxiolytics, antipsychotics, hydroxyzine, tricyclic antidepressants.

Antibacterials, e.g. ciprofloxacin, – avoid premedication with opioids as reduced plasma ciprofloxacin concentration.

Monoamine Oxidase Inhibitors (MAOIs) or have taken these within the last 2 weeks – use only with extreme caution.

Cyclizine.

Mexiletine – delayed absorption.

Metoclopramide and domperidone – antagonise GI effects.

Cisapride – possible antagonism of GI effects.

Dopaminergics (e.g. selegiline) – possible risk of hyperpyrexia and CNS toxicity. This risk is greater with pethidine but with other opioids the risk is uncertain.

Ulcer healing drugs – cimetidine inhibits the metabolism of opioid analgesics.

Anticholinergics (e.g. atropine) – risk of severe constipation which may lead to paralytic illness, and/or urinary retention.

Antidiarrhoeal drugs (e.g. loperamide, kaolin) – increased risk of severe constipation.

Antihypertensive drugs (e.g. guanethidine, diuretics) – enhanced hypotensive effect.

Opioid antagonists (e.g. buprenorphine, naltrexone, naloxone).

Neuromuscular blocking agents – additive respiratory depressant effects.

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

Pregnancy

Paracetamol:

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. 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.

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.

As with all medicines, use should be avoided during the first trimester.

Breast-feeding

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

4.7 Effects on ability to drive and use machines

Opioid analgesics can impair mental function and can cause blurred vision and dizziness. Patients should make sure they are not affected before driving or operating machinery.

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

The frequencies of adverse events are ranked according to the following:

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)

Unknown (cannot be estimated from the available data).

At the recommended dosage, paracetamol may cause the following side effects:

1 Pancreatitis is more likely to occur at above normal doses

2 Reported after prolonged administration

Chronic hepatic necrosis has been reported in a patient who took daily therapeutic doses of paracetamol for about a year, and liver damage has been reported after daily ingestion of excessive amounts for shorter periods.

A review of a group of patients with chronic active hepatitis failed to reveal differences in the abnormalities of liver function in those who were long-term users of paracetamol, nor was the control of their disease improved after paracetamol withdrawal.

Adverse effects of opioid treatment which have been reported include:

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. Tolerance diminishes rapidly after withdrawal so a previously tolerated dose may prove fatal.

Regularly prolonged use of dihydrocodeine 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: website: 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.

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).

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 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, gastrointestinal bleeding 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.

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). 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 serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

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.

Acute overdosage with dihydrocodeine can be manifested by somnolence progressing to stupor or coma, miotic pupils, rhabdomyolysis, non-cardiac pulmonary oedema, bradycardia, hypotension and respiratory depression or apnoea.

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.

In the case of massive overdosage, administer naloxone intravenously (0.4 to 2 mg for an adult and 0.01 mg/kg body weight for children) if the patient is in a coma or respiratory depression is present. Repeat the dose at 2 minute intervals if there is no response, or by an infusion. An infusion of 60% of the initial dose per hour is a useful starting point. A solution of 10 mg made up in 50 ml dextrose will produce 200 micrograms/ml for infusion using an IV pump (dose adjusted to the clinical response). Infusions are not a substitute for frequent review of the patient's clinical state. Intramuscular naloxone is an alternative in the event that IV access is not possible.

As the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. Naloxone is a competitive antagonist and large doses (4 mg) may be required in seriously poisoned patients. For less severe overdosage, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to dihydrocodeine overdosage. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on dihydrocodeine. In such cases, an abrupt or complete reversal of opioid effects may precipitate pain and an acute withdrawal syndrome.

Consider activated charcoal (50 g for adults, 10–15 g for children), if an adult presents within 1 hour of ingestion of more than 420mg or a child more than 3mg/kg.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anilides, ATC code: N02BE71

Paracetamol has analgesic and antipyretic effects. It is only a weak inhibitor of prostaglandin biosynthesis, although there is some evidence to suggest that it may be more effective against enzymes in the CNS than those in the periphery. This fact may partly account for its ability to reduce fever (a central action) and to induce analgesia.

Dihydrocodeine tartrate is an opioid analgesic.

Dihydrocodeine is a centrally acting analgesic which produces its effects by its action at opioid binding sites within the CNS.

5.2 Pharmacokinetic properties

Dihydrocodeine is absorbed from the gastrointestinal tract. Dihydrocodeine is metabolised in the liver and excreted almost entirely by the kidney, mainly as conjugates with glucoric acid.

Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 0.5–2hours after ingestion.

Paracetamol is distributed into most body tissues. It crosses the placenta and is present in breast milk. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations. Paracetamol is metabolised predominantly in the liver and excreted in the urine mainly as the glucoronide and sulfate conjugates. Less than 5% is excreted as unchanged paracetamol. A minor hydroxylated 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 tissue damage. The elimination half-life varies from about 1–3 hours.

The pharmacokinetics of dihydrocodeine may be similar to those of codeine.

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

Also contains: pregelatinised maize starch, maize starch, colloidal silicon dioxide, stearic acid, water.

6.2 Incompatibilities

None known

6.3 Shelf life

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/recon­stitution

Not applicable.

Shelf-life after first opening

Not applicable.

6.4 Special precautions for storage

Store below 25°C in a dry place. Protect from light.

6.5 Nature and contents of container

Child-resistant blister pack: (i) 250^m white rigid PVC (ii) 9^m soft aluminium / 35g/m2 glassine paper. Compliant with BS8404.

Pack sizes: 30, 100.

PE tablet container with a child-resistant PP closure. Compliant with ISO8317.

Pack sizes: 30, 100.

PP tablet container with or without polyfoam wad or polyethylene ullage filler and a PE closure for supply to nursing homes.

Pack sizes: 500, 1000.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Not applicable.

7. MARKETING AUTHORISATION HOLDER

Accord-UK Ltd

(Trading style: Accord)

Whiddon Valley

Barnstaple

Devon

EX32 8NS

8 MARKETING AUTHORISATION NUMBER(S)

PL 00142/0384

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26/01/1994 / 11/03/2009