- Approval Id
- 31fdec673effb1d8
- Drug Approval Emc Name
- Co-dydramol 10mg/500mg Tablets
- Drug Name
- Co-dydramol 10mg/500mg Tablets
- Company Address
- First Floor, Andrews House, College Road, Guildford, Surrey, GU1 4QB, UK
- Company Website
- https://www.zentiva.co.uk/contact/mi-form
- Company Medical Info Direct Line
- +44 (0)800 090 2408
- Company Medical Info Email
- UKMedInfo@zentiva.com
- Company Customer Care Direct Line
- +44 (0)844 8793 188
- Atc Code
- N02BE71
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Zentiva Pharma UK Limited
12 New Fetter Lane, London, EC4A 1JP, United Kingdom
- Authorisation Number
- PL 17780/0070
- Authorisation Date
- 1 October 2001/16 March 2009
- Instruction Authorisation Holder
- Zentiva Pharma UK Limited
12 New Fetter Lane, London, EC4A 1JP, United Kingdom
- Instruction Authorisation Number
- PL 17780/0070
- Instruction Authorisation Date
- 1 October 2001/16 March 2009
- Instruction Composition
- Each tablet contains 500mg paracetamol and 10mg dihydrocodeine tartrate
For the full list of excipients see section 6.1.
- Instruction Dosage Form
- Tablet.
Flat bevelled edge white tablets marked S/8 on one side
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
For the relief of mild to moderate pain.4.2 Posology and method of administration
\*\*Posology\*\*
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.
Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with dihydrocodeine in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).
Paediatric population
Children aged 12 to 15 years: One tablet every four to six hours when necessary to a maximum of four tablets in 24 hours.
Not recommended for children under 12 years of age.
\*\*Method of administration\*\*
For oral administration.4.3 Contraindications
Co-dydramol Tablets must not be given to patients with respiratory depression, chronic obstructive airways disease or liver disease.
Hypersensitivity to the active substances or any of the excipients listed in section 6.1.4.4 Special warnings and precautions for use
Dihydrocodeine may bring about histamine release, therefore it should not be given during an asthma attack and it should be administered with due care to persons liable to such attack. The dosage should be reduced in hypothyroidism and in renal insufficiency.
Alcohol should be avoided. When dihydrocodeine is prescribed for chronic use, care should be taken to avoid unnecessary increase in dosage.
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 to take other paracetamol-containing products concurrently.
Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.
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.
• 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.
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.
• 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.
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).
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.
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 dihydrocodeine.
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 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
Dihydrocodeine should be used with caution in patients taking monoamine oxidase inhibitors, CNS depressants or metoclopramide. The speed of absorption of paracetamol may be increased by metoclopramide and domperidone and absorption reduced by cholestyramine.
Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risks factors (see section 4.4).
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).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 of co-dydramol 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.
Breastfeeding
Administration to nursing women is not recommended as dihydrocodeine may be secreted in breast milk and may cause respiratory depression in the infant.4.7 Effects on ability to drive and use machines
Dihydrocodeine may cause vertigo which may affect the ability to drive or 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 safely4.8 Undesirable effects
• 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.
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).
Dihydrocodeine may cause constipation, nausea, vomiting, headache or vertigo and these are relatively common if the dose is increased above 30mg. If constipation occurs it can be treated with a gentle laxative. Tolerance and dependence may occur with dihydrocodeine especially with prolonged dosage.
There have been very rare occurrences of pancreatitis.
Blood and lymphatic system disorders
Not known: agranulocytosis, thrombocytopenia
Hypersensitivity including skin rash may occur.
Immune system disorders
Not known: anaphylactic shock, angioedema
Skin and subcutaneous disorders
Not known: Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis, fixed drug eruption
Metabolism and nutrition disorders
Not known: high anion gap metabolic acidosis.
Psychiatric disorders:
Not Known: Drug dependence (see section 4.4)
Gastrointestinal disorders:
Not known: Abdominal pain, upper
General disorders and administration site conditions:
Uncommon: drug withdrawal syndrome
Description of selected adverse reactions
High anion gap metabolic acidosis
Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors using paracetamol (see section 4.4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.
\*\*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 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
\*\*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. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, , disseminated intravascular coagulation, 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.
Management
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.
\*\*Dihydrocodeine\*\*
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
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.
Management
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.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anilides ATC code: NO2B E71
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 is a centrally acting analgesic which produces its effects by its action at opioid binding sites within the CNS.5.2 Pharmacokinetic properties
Paracetamol is well absorbed from the gastrointestinal tract, peak plasma concentrations occurring 0.5-2 hours after ingestion. It is metabolised in the liver and excreted in the urine mainly as glucuronide and sulphate conjugates - less than 5% is excreted as unmodified paracetamol. The plasma half-life is between 1 and 4 hours. Binding to plasma proteins is minimal as therapeutic concentrations but increases as plasma concentrations increase.
Oral dihydrocodeine undergoes considerable presystemic metabolism, but its subsequent metabolism is uncertain. 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.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
Pregelatinised starch
Maize starch
Povidone
Potassium sorbate
Purified talc
Stearic acid
Magnesium stearate
Microcrystalline cellulose6.2 Incompatibilities
Not applicable6.3 Shelf life
2 years in polypropylene bottles.
3 years in PVC blisters.6.4 Special precautions for storage
No special precautions for storage.6.5 Nature and contents of container
White polypropylene bottles with a cotton wool plug and a white wadless polypropylene screw cap.
Pack size: 100, 500 tablets.
PVC blister strips contained in cardboard cartons.
Pack size: 30, 60, 100 tablets.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
No special requirements
- Instruction Content
- ## Composition
Each tablet contains 500mg paracetamol and 10mg dihydrocodeine tartrate
For the full list of excipients see section 6.1.
## Pharmaceutical Form
Tablet.
Flat bevelled edge white tablets marked S/8 on one side
## Clinical Particulars
4.1 Therapeutic indications
For the relief of mild to moderate pain.4.2 Posology and method of administration
\*\*Posology\*\*
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.
Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with dihydrocodeine in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).
Paediatric population
Children aged 12 to 15 years: One tablet every four to six hours when necessary to a maximum of four tablets in 24 hours.
Not recommended for children under 12 years of age.
\*\*Method of administration\*\*
For oral administration.4.3 Contraindications
Co-dydramol Tablets must not be given to patients with respiratory depression, chronic obstructive airways disease or liver disease.
Hypersensitivity to the active substances or any of the excipients listed in section 6.1.4.4 Special warnings and precautions for use
Dihydrocodeine may bring about histamine release, therefore it should not be given during an asthma attack and it should be administered with due care to persons liable to such attack. The dosage should be reduced in hypothyroidism and in renal insufficiency.
Alcohol should be avoided. When dihydrocodeine is prescribed for chronic use, care should be taken to avoid unnecessary increase in dosage.
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 to take other paracetamol-containing products concurrently.
Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.
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.
• 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.
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.
• 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.
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).
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.
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 dihydrocodeine.
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 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
Dihydrocodeine should be used with caution in patients taking monoamine oxidase inhibitors, CNS depressants or metoclopramide. The speed of absorption of paracetamol may be increased by metoclopramide and domperidone and absorption reduced by cholestyramine.
Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risks factors (see section 4.4).
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).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 of co-dydramol 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.
Breastfeeding
Administration to nursing women is not recommended as dihydrocodeine may be secreted in breast milk and may cause respiratory depression in the infant.4.7 Effects on ability to drive and use machines
Dihydrocodeine may cause vertigo which may affect the ability to drive or 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 safely4.8 Undesirable effects
• 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.
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).
Dihydrocodeine may cause constipation, nausea, vomiting, headache or vertigo and these are relatively common if the dose is increased above 30mg. If constipation occurs it can be treated with a gentle laxative. Tolerance and dependence may occur with dihydrocodeine especially with prolonged dosage.
There have been very rare occurrences of pancreatitis.
Blood and lymphatic system disorders
Not known: agranulocytosis, thrombocytopenia
Hypersensitivity including skin rash may occur.
Immune system disorders
Not known: anaphylactic shock, angioedema
Skin and subcutaneous disorders
Not known: Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis, fixed drug eruption
Metabolism and nutrition disorders
Not known: high anion gap metabolic acidosis.
Psychiatric disorders:
Not Known: Drug dependence (see section 4.4)
Gastrointestinal disorders:
Not known: Abdominal pain, upper
General disorders and administration site conditions:
Uncommon: drug withdrawal syndrome
Description of selected adverse reactions
High anion gap metabolic acidosis
Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors using paracetamol (see section 4.4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.
\*\*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 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
\*\*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. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, , disseminated intravascular coagulation, 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.
Management
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.
\*\*Dihydrocodeine\*\*
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
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.
Management
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.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anilides ATC code: NO2B E71
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 is a centrally acting analgesic which produces its effects by its action at opioid binding sites within the CNS.5.2 Pharmacokinetic properties
Paracetamol is well absorbed from the gastrointestinal tract, peak plasma concentrations occurring 0.5-2 hours after ingestion. It is metabolised in the liver and excreted in the urine mainly as glucuronide and sulphate conjugates - less than 5% is excreted as unmodified paracetamol. The plasma half-life is between 1 and 4 hours. Binding to plasma proteins is minimal as therapeutic concentrations but increases as plasma concentrations increase.
Oral dihydrocodeine undergoes considerable presystemic metabolism, but its subsequent metabolism is uncertain. 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.
## Pharmaceutical Particulars
6.1 List of excipients
Pregelatinised starch
Maize starch
Povidone
Potassium sorbate
Purified talc
Stearic acid
Magnesium stearate
Microcrystalline cellulose6.2 Incompatibilities
Not applicable6.3 Shelf life
2 years in polypropylene bottles.
3 years in PVC blisters.6.4 Special precautions for storage
No special precautions for storage.6.5 Nature and contents of container
White polypropylene bottles with a cotton wool plug and a white wadless polypropylene screw cap.
Pack size: 100, 500 tablets.
PVC blister strips contained in cardboard cartons.
Pack size: 30, 60, 100 tablets.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
No special requirements
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