SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Co-Dydramol Tablets BP 500/10mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains:

Paracetamol BP 500mg.

Dihydrocodeine Tartrate BP 10mg.

3. PHARMACEUTICAL FORM

Compressed tablet.

4. CLINICAL PARTICULARS

4.1. Therapeutic Indications

For the relief of mild to moderate pain and as an antipyretic. Co-dydramol tablets may also be used as an antitussive.

4.2 Posology and method of administration

Posology

Adults

One to two tablets every four to six hours.

Maximum of eight tablets daily.

Paediatric population

Not recommended for children under 12 years of age. Elderly

One to two tablets every four to six hours.

Maximum of eight tablets daily.

Reduce dosage if renal or hepatic function is impaired. Method of administration For oral administration.

Do not exceed the recommended dose.

Do not take with any other paracetamol-containing products. Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

4.3 Contraindications

Hypersensitivity to dihydrocodeine, paracetamol, other opioids and/or any of the other constituents.

Respiratory depression and obstructive airways disease.

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

4.4 Special warnings and precautions for use

Co-dydramol 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 of co-dydramol may cause hepatic necrosis.

•    renal function impairment

•    hypothyroidism (risk of depression and prolonged CNS depression is increased)

•    inflammatory bowel disease - risk of toxic megacolon

•    dihydrocodeine may bring about histamine release, therefore it should be given with caution to patients with allergic disorders and should not be given during an asthmatic 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, e.g. 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.

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

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 dihydrocodeine is considered essential then great care should be taken in patients taking MAOIs, or within 14 days of stopping MAOIs (see section 4.5).

Dosage should be reduced in the elderly, in hypothyroidism, in renal insufficiency and in chronic hepatic disease.

Patients should be advised not to exceed the recommended dose and not to 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 directed by your prescriber

•    Taking dihydrocodeine 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.

•    Talk to a doctor at once if you take too much of this medicine even if you feel well. This is because too much paracetamol can cause delayed, serious liver damage.

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 dihydrocodeine regularly for a long time can lead to addiction.

Keep out of the sight and reach of children.

Paracetamol Label Warnings:

Contains paracetamol

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

Do not take anything else containing paracetamol while taking this medicine. If no package leaflet:

Talk to a doctor at once if you take too much of this medicine even if you feel well. This is because too much paracetamol can cause delayed, serious liver damage.

Or if package leaflet present:

Talk to a doctor at once if you take too much of this medicine, even if you feel well.

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

•    MAOIs - use only with extreme caution. MAOIs taken with pethidine have been associated with severe CNS excitation or depression (including hypertension or hypotension). Although this has not been documented with dihydrocodeine, it is possible that a similar interaction may occur and therefore the use of dihydrocodeine should be avoided while the patient is taking MAOIs and for 2 weeks after MAOIs discontinuation

•    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

4.6 Fertility, pregnancy and lactation

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage. However, paracetamol should be avoided in pregnancy unless considered essential by the physician.

Risk benefit must be considered because opioid analgesics cross the placenta. Studies in animals have shown opioids to cause delayed ossification in mice and increased resorption in rats.

Regular use during pregnancy may cause physical dependence in the fetus, leading to withdrawal symptoms in the neonate. Dihydrocodeine has been used for many years without apparent ill effects.

During labour opioids enter the fetal circulation and may cause respiratory depression in the neonate.

Administration should be avoided during the late stages of labour and during the delivery of a premature infant.

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

Dihydrocodeine and paracetamol are excreted in breast milk in concentrations too low to be harmful to the breast fed infant.

4.7 Effects on ability to drive and use machines

Dihydrocodeine may cause vertigo and 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

At the recommended dosage, paracetamol may cause the following side

effects:

•    Allergic reactions - rare but may include skin rash, drug fever, mucosal lesions.

•    Effects on CNS - drowsiness, impaired mental functions

•    Effects on GI system - 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. Acute pancreatitis has been reported. 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 longterm users of paracetamol, nor was the control of their disease improved after paracetamol withdrawal.

•    Effects on CVS - toxic myocarditis.

•    Effects on blood - methaemoglobinaemia, neutropenia, pancytopenia, leukopenia, thrombocytopenic purpura, haemolytic anaemia, thrombocytopenia and agranulocytosis.

•    Effects on GU system - Nephrotoxicity following therapeutic doses of paracetamol is uncommon, but papillary necrosis has been reported after prolonged administration.

•    Effects on immune system - anaphylactic shock, angioedema (frequency unknown)*

•    Effects on skin and subcutaneous tissue - Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis, fixed drug eruption (frequency unknown)*

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

Adverse effects of opioid treatment which have been reported include:

•    Allergic reactions (may be caused by histamine release) - including

rash, urticaria, difficulty breathing, increased sweating, redness or flushed face.

•    Effects on CNS - confusion, drowsiness, vertigo, dizziness, changes in mood, hallucinations, CNS excitation (restlessness/excitement), convulsions, mental depression, headache, trouble sleeping, or nightmares, raised intracranial pressure, tolerance or dependence.

•    Effects on GI system - constipation, GI irritation, biliary spasm, nausea, vomiting, loss of appetite, dry mouth, paralytic ileus or toxic megacolon.

•    Effects on CVS - bradycardia, palpitations, hypotension.

•    Effects on sensory system - blurred or double vision.

•    Effects on GU system - ureteral spasm, antidiuretic effect.

Other effects - trembling, unusual tiredness or weakness, malaise, miosis, hypothermia.

•    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.

•    Regular 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. There have been very rare occurrences of pancreatitis.

•    cannot be estimated from the available data 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.

4.9 Overdose

Paraceta

mol

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, phenobarbital, 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. 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 joint pain, haematuria and proteinuria may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Liver damage is likely in adults who have taken 10g 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.

Management

Immediate treatment is essential in the treatment of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to a 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.

Dihvdrocodeine

Symptoms

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

Management

Primary attention should be given to the establishment of a patient 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

Paracetamol has analgesic and antipyretic actions but it has no useful antiinflammatory properties.

Dihydrocodeine tartrate is an opioid analgesic. It is used for the relief of moderate to severe pain and has also been used as a cough suppressant.

5.2 Pharmacokinetic properties

Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma levels occurring about 0.5 - 2 hours 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.

It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted unchanged.

The plasma half-life is between 1 and 4 hours. 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 of Paracetamol varies from about 1 to 3 hours.

Dihydrocodeine is absorbed from the gastrointestinal tract. Oral dihydrocodeine undergoes considerable presystemic metabolism, but its subsequent metabolism is uncertain. The pharmacokinetics of dihydrocodeine may be similar to those of codeine. It is excreted almost entirely by the kidney, mainly as conjugates with glucoric acid.

Dihydrocodeine tartrate peak plasma concentrations achieved 1.5 to 2 hours after oral dosage. The elimination half-life is between 3.5 to 4.5 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, carcinogenic potential, toxicity to reproduction and development.

6.1. List of Excipients

Each tablet contains: Maize Starch

Povidone Colloidal Silica Magnesium Stearate Potassium Sorbate

6.2. Incompatibilities

This product is designed for oral administration.

Admixture with other medicines prior to ingestion is not intended or desirable.

6.3. Shelf Life

The shelf life of the product is 36 months when stored in the unopened blister strip and 60 months in plastic tubs provided the pack is re-sealed after each use.

Re-packing into any other pack may affect the shelf life and appropriate pharmaceutical judgement should be exercised.

6.4. Special Precautions for Storage

Store in a cool dry place at a temperature not exceeding 25°C. Protect from light. Keep well closed.

Nature and Contents of Container

Child Resistant Blister pack strips, 0.25mm PVC/35 gsm Glassine (Pergamin) paper/ 0.009mm Aluminium enclosed in a cardboard carton, containing 10, 12, 16, 20, 24, 30, 48, 50, 96 and 100 tablets.

Polypropylene container fitted with polypropylene cap, child resistant and/or tamper-evident appropriate, containing 25, 50, 100, 200, 500 or 1000 tablets

Polypropylene tub with plastic security cap containing 100, 200, 250, 500 or 1000 tablets

6.6. Instruction for Use/Handling

Not applicable.

7    MARKETING AUTHORISATION HOLDER

M & A Pharmachem Limited

Allenby Laboratories

Wigan Road

Westhoughton

Bolton

BL5 2AL

8    MARKETING AUTHORISATION NUMBER

PL 04077/0166

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/08/1993    /    11/04/2005

10 DATE OF REVISION OF THE TEXT

14/09/2016