- Approval Id
- 6ead2a06091051ac
- Drug Approval Emc Name
- Paracetamol 1000 mg Tablets
- Drug Name
- Paracetamol 1000 mg Tablets
- Company Name
- Sigma Pharmaceuticals PLC (Special Concept Development / RxFarma)
- Company Address
- HD House, Imperial Way, North Watford, Hertfordshire, WD24 4LQ, UK
- Company Website
- http://www.sigmaplc.com/our-product-offerings/rxfa
- Company Telephone
- +44 (0)800 358 0163
- Company Medical Info Direct Line
- +44 (0)800 358 0163
- Company Medical Info Email
- medinfo@rxfarma.co.uk
- Company Customer Care Direct Line
- +44 (0)800 358 0163
- Atc Code
- N02BE01
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Special Concept Development (UK) Limited
Units 1-7, Colonial Way, Watford
WD24 4YR, United Kingdom
- Authorisation Number
- PL 36722/0113
- Authorisation Date
- 07/02/2019
- Instruction Authorisation Holder
- Special Concept Development (UK) Limited
Units 1-7, Colonial Way, Watford
WD24 4YR, United Kingdom
- Instruction Authorisation Number
- PL 36722/0113
- Instruction Authorisation Date
- 07/02/2019
- Instruction Composition
- Each tablet contains 1000 mg paracetamol.
For the full list of excipients, see section 6.1
- Instruction Dosage Form
- White to off white, caplet shaped tablets, plain on both sides.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Paracetamol 1000 mg Tablets is a mild analgesic and antipyretic, and is recommended for the treatment of most painful and febrile conditions, for example, headache including migraine and tension headaches, toothache, backache, rheumatic and muscle pains, dysmenorrhoea, sore throat, and for relieving the fever, aches and pains of colds and flu. Also recommended for the symptomatic relief of pain due to non-serious arthritis.4.2 Posology and method of administration
\*\*\*Posology\*\*\*
\*Adults, the elderly and children 16 years and over:\*
Take one tablet every 4-6 hours as required.
\*\*Not recommended for children under 16 years if age.\*\*
The dose should not be repeated more frequently than every 4 hours and not more than 4 doses should be taken in any 24 hours.
\*Renal impairment:\*
It is recommended when giving paracetamol to patients with renal impairment, to reduce the dose and to increase the minimum interval between each administration to at least 6 hours unless directed otherwise by a physician. See table:
| | |
| --- | --- |
| Glomerular filtration rate | Dose |
| 10-50 ml/min | 500 mg every 6 hours |
| <10 ml/min | 500 mg every 8 hours |
This product is not suitable for patients with renal insufficiency when a reduced dose is required. More appropriate forms are available for that circumstance.
\*Hepatic impairment:\*
In patients with hepatic impairment or Gilbert's Syndrome, the dose should be reduced or the dosing interval prolonged. The daily dose should not exceed 2 g/day unless directed by a physician.
\*\*\*Method of administration\*\*\*
Oral.4.3 Contraindications
Hypersensitivity to paracetamol or any of the excipients listed in section 6.1.4.4 Special warnings and precautions for use
Prolonged or frequent use is discouraged. Patients should be advised not to take other Paracetamol containing products concurrently. Taking multiple daily doses in one administration can severly damage the liver; in such cases unconsciousness does not occur. However, medical assistance should be sought immediately. Prolonged use except under medical supervision may be harmful. In adolescents treated with 60 mg/kg daily of Paracetamol, the combination with another antipyretic is not justified except in the case of ineffectiveness.
Caution is advised in the administration of Paracetamol to patients with moderate and severe renal insufficiency, mild to moderate hepatic insufficiency (including Gilbert's syndrome), severe hepatic insufficiency (Child-Pugh>9), acute hepatitis, concomitant treatment with medicinal products affecting hepatic functions, glucose-6- phosphatedehydrogenase deficiency, haemolytic anaemia, alcool abuse dehydration and chronic malnutrition (see section 4.2).
The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Caution should be excercised in cases of chronic alcholism. The daily dose should not exceed 2 grams in such cases. Alcohol should not be used during the treatment with Paracetamol.
Patients who have been diagnosed with liver or kidney impairment must seek medical advice before taking this medication. Underlying liver disease increase the risk or paracetamol related liver damage.
Do not exceed the stated dose.
Patients should be advised to consult a doctor if they suffer from non-serious arthritis and need to take painkillers every day.
Caution should be exercised in patients with glutathione depleted states, as the use of paracetamol may increase the risk of metabolic acidosis (refer also to section 4.9).
Use with caution in patients with glutathione depletion due to metabolic deficiencies.
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.
If symptoms, medical advice must be sought.
Keep out of the sight and reach of children.
Caution is advised in asthmatic patients sensitive to aspirin, because light reaction bronchospasm with paracetamol (cross-reaction) has been reported in less than 5% of patients tested.
Abrupt discontinuation of long-term use of high dosed analgesics, taken not as directed, may cause headache, tiredness, muscular pain, nervousness and vegetative syptoms. The withdrawal symptoms subside within a few days. Patients should be advised to consult their doctor if headaches become persistent.
Immediate medical advice should be sought in the event of an overdosage even if the patient feels well because of the risk of irreversible liver damage (see section 4.9).
\*\*\*Pack Label:\*\*\*
Immediate medical advice should be sought in the event of an overdose, even if you feel well.
Do not take with any other paracetamol-containing products.
\*\*\*Patient Information Leaflet:\*\*\*
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.
Intereference with laboratory tests: Paracetamol may affect uric acid tests by wolframatop phosphoric acid, and blood sugar tests by glucose-oxydase-peroxydase.4.5 Interaction with other medicinal products and other forms of interaction
Hepatotoxic substances may increase the possibility of Paracetamol accumulation and overdose. The risk of hepatotoxicity of paracetamol may be increased by drugs which induce liver microsomal enzymes such as barbiturates, tricyclic antidepressants, and alcohol.
Probenecid causes an almost 2-fold reduction in clearance of Paracetamol by inhibiting its conjugtion with glucoronid acid. A reduction of the Paracetamol dose should be considered for concomitant treatment with probenecid.
The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.
The speed of absorption of paracetamol tablets may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. Salicylamide may prolong the elimination t1/2 of Paracetamol.
Concomitant use of Paracetamol (4 g per day for at least 4 days) with oral anticoagulants may lead to slight variations of INR values. In this case, increased monitoring of INR values should be done during the duration of the combination and after its discontinuation.
Rifampicin and some antiepileptics such as carbamazepine, phenytoin, phenobarbial and primidone may interact with paracetamol tablets.
Isoniazid: Reduction of paracetamol clearance, with possible potentiation of its action and/or toxicity, by inhibiting its metabolism in the liver.
Lamotrigine: Decrease in the bioavailability of lamotrigine, with possible reduction of its effect, due to possible induction of its metabolism in the liver.
Co-administration of acetaminophen with zidovudine may result in nuetropenia or hepatotoxicity. However, these effects have not been consistently reported. The chronic/multiple-dose acetaminophen use in patients on zidovudine therapy should be avoided. However, if chronic acetaminophen and zidovudine are to be given concurrently, not only white blood count should be monitored, but also liver function tests, particularly in malnourished patients.
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)4.6 Fertility, pregnancy and lactation
\*\*Pregnancy:\*\*
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 if clinically needed, however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.
\*\*Lactation:\*\*
After oral administration, paracetamol is excreted into breast milk in small quantities in recommended dosages. No undesirable effects on nursing infants have been reported. Consequently, paracetamol tablets may be used in breast- feeding. Available published data do not contraindicate breastfeeding.
\*\*Fertility:\*\*
There are no available data on the effect of paracetamol on fertility.4.7 Effects on ability to drive and use machines
None.4.8 Undesirable effects
The frequency using the following convention: 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 available data), including isolated reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
| | | |
| --- | --- | --- |
| \*\*Frequency\*\* | \*\*System\*\* | \*\*Symptoms\*\* |
| Rare (> 1/10,000 - < 1/1000) | Blood and lymphatic system disorders | Platelet disorders, stem cell disorders, agranulocytosis, leukopenia, thrombocytopenia, haemolytic anaemia, pancytopenia |
| Immune system disorders | Allergies (excluding angioedema) |
| Psychiatric disorders | Depression, confusion, hallucinations |
| Nervous system disorders | Tremor, headache |
| Eye disorders | Abnormal vision |
| Cardiac disorders | Oedema |
| Gastrointestinal disorders | Haemorrhage, abdominal pain, diarrhoea, nausea, vomiting |
| Hepato-biliary disorders | Hepatic function abnormal, hepatic failure, hepatic necrosis, jaundice |
| Skin and subcutaneous tissue disorders | Pruritus, rash, sweating, purpura, angioedema, urticarial |
| General disorders and administration site conditions | Dizziness (excluding vertigo) malaise, pyrexia, sedation, drug interaction |
| Injury, poisoning and procedural complications | Overdose and poisoning |
| Very Rare (< 10,000) | Respiratory, thoracic and mediastinal disorders | Bronchospasm |
| Hepato-biliary disorders | Hepatotoxicity |
| General disorders and administration site conditions | Hypersensitivity reaction (requiring discontinuation of treatment) |
| Metabolism and nutrition disorders | Hypoglycaemia |
| Renal and urinary disorders | Sterile pyuria (cloudy urine) and renal side effects |
Post Marketing Data
| | | |
| --- | --- | --- |
| \*\*Body System\*\* | \*\*Undesirable effect\*\* | \*\*Frequency\*\* |
| Blood and lymphatic system disorders | Thrombocytopenia Agranulocytosis | Very Rare |
| Immune system disorders | Anaphylaxis Cutaneous hypersensitivity reactions including, among others, skin rashes and angiodema. Very rare cases of serious skin reactions have been reported. | Very Rare |
| Respiratory, thoracic and mediastinal disorders | Bronchospasm\\* | Very Rare |
| Hepatobiliary disorders | Hepatic dysfunction | Very Rare |
| Metabolism and nutrition disorders | High anion gap metabolic acidosis | Not known |
\\* There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.
\*\*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.
Interstitial nephritis has been reported incidentally after prolonged use of high doses. Some cases of epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme, oedema of the larynx, anaphylactic shock, anaemia, liver alteration and hepatitis, renal alteration (severe renal impairment, nephrite interstitial, haematuria, anuresis) gastrointestinal effects and vertigo have been reported.
\*\*\*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 MHRA Yellow Card in the Google Play or Apple App store.4.9 Overdose
There is a risk of poisoning, particularly in ederly subjects, in young children, in patients with liver disease, in cases of chronic alcoholism and in patients with chronic malnutrition. Overdose of Paracetamol is poteentially fatal in all populations.
Symptoms generally appear within the first 24 hours and comprise: nausea, vomiting, anorexia, pallor and abdominal pain. Immediate emergency measures are necessary in case of paracetamol overdose, even when no symptoms are present.
Overdose, 10 g or more of Paracetamol in adults or 150 mg/kg of body weight, causes liver damage, liver cell necrosis likely to induce complete and irreversible necrosis, resulting in hepatocellular insufficiency, metabolic acidosis and encephalopathy which may lead to coma and death. Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed together with increased prothrombin levels that may appear 12 to 48 hours after adminstration.
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:
a, Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.
Or
b, Regularly consumes ethanol in excess of recommended amounts.
Or
c, 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, 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 Nacetylcysteine 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 24h from ingestion should be discussed with the NPIS or a liver unit.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics and antipyretics, anilides; ATC-code:N02B E01
Paracetamol is an antipyretic analgesic. The mechanism of action is probably similar to that of aspirin and dependant on the inhibition of prostaglandin synthesis. This inhibition appears, however, to be on a selective basis.5.2 Pharmacokinetic properties
\*\*Absorption\*\*
The absorption of paracetamol by the oral route is rapid and completely from gastrointestinal tract. Maximum plasma concentrations are reached 30 to 60 minutes following ingestion and the plasma half-life is 1 - 4 hours after therapeutic doses.
\*\*Distribution\*\*
Paracetamol is distributed rapidly throughout all tissues. Concentration are comparable in blood, saliva and plasma. Protein binding is low. Binding of the drug to plasma proteins is variable; 20 to 30 % may be bound at the concentrations encountered during acute intoxication.
\*\*Metabolism\*\*
Paracetamol is metabolised mainly in the liver following two major metabolic pathways: glucuronic acid and sulfuric acid conjugates. The latter route is rapidly saturated at doses higher than the therapeutic dose. A minor route, catalysed by the cytochrome P450, results in the formation of an intermediate reagent (N-acetyl-p- benzoquinoneimine) which under normal conditions of use is rapidly detoxified by glutathione and eliminated in the urine, after conjugation with cysteine and mercaptopuric acid. Conversely, when massive intoxication occurs, the quantity of this toxic metabolite is increased.
\*\*Elimination\*\*
Elimination is essentially through the urine. 90% - 100% of the ingested dose is eliminated via the kidneys within 24 hours, principally as glucuronide (60 60 80%) and sulphate conjugates (20 to 30%). Less than 5% is eliminated in unchanged form.
Elimination half-life is about 2 hours. However, practically no paracetamol is excreted unchanged and the bulk is excreted after hepatic conjugation.
\*\*Special patient groups\*\*
Renal Insufficiency: In cases of severe renal insufficiency (creatinine clearance lower than 10 ml/min) the elimination of paracetamol and its metabolites is delayed.
Elderly Subjects: The capacity for conjugation is not modified.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
Povidone
Magnesium stearate6.2 Incompatibilities
Not applicable.6.3 Shelf life
2 years.6.4 Special precautions for storage
Store in the original package in order to protect from light.6.5 Nature and contents of container
PVC/PVdC/aluminium blisters: 20, 30, 40, 50 & 100 tablets
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
Each tablet contains 1000 mg paracetamol.
For the full list of excipients, see section 6.1
## Pharmaceutical Form
White to off white, caplet shaped tablets, plain on both sides.
## Clinical Particulars
4.1 Therapeutic indications
Paracetamol 1000 mg Tablets is a mild analgesic and antipyretic, and is recommended for the treatment of most painful and febrile conditions, for example, headache including migraine and tension headaches, toothache, backache, rheumatic and muscle pains, dysmenorrhoea, sore throat, and for relieving the fever, aches and pains of colds and flu. Also recommended for the symptomatic relief of pain due to non-serious arthritis.4.2 Posology and method of administration
\*\*\*Posology\*\*\*
\*Adults, the elderly and children 16 years and over:\*
Take one tablet every 4-6 hours as required.
\*\*Not recommended for children under 16 years if age.\*\*
The dose should not be repeated more frequently than every 4 hours and not more than 4 doses should be taken in any 24 hours.
\*Renal impairment:\*
It is recommended when giving paracetamol to patients with renal impairment, to reduce the dose and to increase the minimum interval between each administration to at least 6 hours unless directed otherwise by a physician. See table:
| | |
| --- | --- |
| Glomerular filtration rate | Dose |
| 10-50 ml/min | 500 mg every 6 hours |
| <10 ml/min | 500 mg every 8 hours |
This product is not suitable for patients with renal insufficiency when a reduced dose is required. More appropriate forms are available for that circumstance.
\*Hepatic impairment:\*
In patients with hepatic impairment or Gilbert's Syndrome, the dose should be reduced or the dosing interval prolonged. The daily dose should not exceed 2 g/day unless directed by a physician.
\*\*\*Method of administration\*\*\*
Oral.4.3 Contraindications
Hypersensitivity to paracetamol or any of the excipients listed in section 6.1.4.4 Special warnings and precautions for use
Prolonged or frequent use is discouraged. Patients should be advised not to take other Paracetamol containing products concurrently. Taking multiple daily doses in one administration can severly damage the liver; in such cases unconsciousness does not occur. However, medical assistance should be sought immediately. Prolonged use except under medical supervision may be harmful. In adolescents treated with 60 mg/kg daily of Paracetamol, the combination with another antipyretic is not justified except in the case of ineffectiveness.
Caution is advised in the administration of Paracetamol to patients with moderate and severe renal insufficiency, mild to moderate hepatic insufficiency (including Gilbert's syndrome), severe hepatic insufficiency (Child-Pugh>9), acute hepatitis, concomitant treatment with medicinal products affecting hepatic functions, glucose-6- phosphatedehydrogenase deficiency, haemolytic anaemia, alcool abuse dehydration and chronic malnutrition (see section 4.2).
The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Caution should be excercised in cases of chronic alcholism. The daily dose should not exceed 2 grams in such cases. Alcohol should not be used during the treatment with Paracetamol.
Patients who have been diagnosed with liver or kidney impairment must seek medical advice before taking this medication. Underlying liver disease increase the risk or paracetamol related liver damage.
Do not exceed the stated dose.
Patients should be advised to consult a doctor if they suffer from non-serious arthritis and need to take painkillers every day.
Caution should be exercised in patients with glutathione depleted states, as the use of paracetamol may increase the risk of metabolic acidosis (refer also to section 4.9).
Use with caution in patients with glutathione depletion due to metabolic deficiencies.
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.
If symptoms, medical advice must be sought.
Keep out of the sight and reach of children.
Caution is advised in asthmatic patients sensitive to aspirin, because light reaction bronchospasm with paracetamol (cross-reaction) has been reported in less than 5% of patients tested.
Abrupt discontinuation of long-term use of high dosed analgesics, taken not as directed, may cause headache, tiredness, muscular pain, nervousness and vegetative syptoms. The withdrawal symptoms subside within a few days. Patients should be advised to consult their doctor if headaches become persistent.
Immediate medical advice should be sought in the event of an overdosage even if the patient feels well because of the risk of irreversible liver damage (see section 4.9).
\*\*\*Pack Label:\*\*\*
Immediate medical advice should be sought in the event of an overdose, even if you feel well.
Do not take with any other paracetamol-containing products.
\*\*\*Patient Information Leaflet:\*\*\*
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.
Intereference with laboratory tests: Paracetamol may affect uric acid tests by wolframatop phosphoric acid, and blood sugar tests by glucose-oxydase-peroxydase.4.5 Interaction with other medicinal products and other forms of interaction
Hepatotoxic substances may increase the possibility of Paracetamol accumulation and overdose. The risk of hepatotoxicity of paracetamol may be increased by drugs which induce liver microsomal enzymes such as barbiturates, tricyclic antidepressants, and alcohol.
Probenecid causes an almost 2-fold reduction in clearance of Paracetamol by inhibiting its conjugtion with glucoronid acid. A reduction of the Paracetamol dose should be considered for concomitant treatment with probenecid.
The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.
The speed of absorption of paracetamol tablets may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. Salicylamide may prolong the elimination t1/2 of Paracetamol.
Concomitant use of Paracetamol (4 g per day for at least 4 days) with oral anticoagulants may lead to slight variations of INR values. In this case, increased monitoring of INR values should be done during the duration of the combination and after its discontinuation.
Rifampicin and some antiepileptics such as carbamazepine, phenytoin, phenobarbial and primidone may interact with paracetamol tablets.
Isoniazid: Reduction of paracetamol clearance, with possible potentiation of its action and/or toxicity, by inhibiting its metabolism in the liver.
Lamotrigine: Decrease in the bioavailability of lamotrigine, with possible reduction of its effect, due to possible induction of its metabolism in the liver.
Co-administration of acetaminophen with zidovudine may result in nuetropenia or hepatotoxicity. However, these effects have not been consistently reported. The chronic/multiple-dose acetaminophen use in patients on zidovudine therapy should be avoided. However, if chronic acetaminophen and zidovudine are to be given concurrently, not only white blood count should be monitored, but also liver function tests, particularly in malnourished patients.
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)4.6 Fertility, pregnancy and lactation
\*\*Pregnancy:\*\*
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 if clinically needed, however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.
\*\*Lactation:\*\*
After oral administration, paracetamol is excreted into breast milk in small quantities in recommended dosages. No undesirable effects on nursing infants have been reported. Consequently, paracetamol tablets may be used in breast- feeding. Available published data do not contraindicate breastfeeding.
\*\*Fertility:\*\*
There are no available data on the effect of paracetamol on fertility.4.7 Effects on ability to drive and use machines
None.4.8 Undesirable effects
The frequency using the following convention: 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 available data), including isolated reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
| | | |
| --- | --- | --- |
| \*\*Frequency\*\* | \*\*System\*\* | \*\*Symptoms\*\* |
| Rare (> 1/10,000 - < 1/1000) | Blood and lymphatic system disorders | Platelet disorders, stem cell disorders, agranulocytosis, leukopenia, thrombocytopenia, haemolytic anaemia, pancytopenia |
| Immune system disorders | Allergies (excluding angioedema) |
| Psychiatric disorders | Depression, confusion, hallucinations |
| Nervous system disorders | Tremor, headache |
| Eye disorders | Abnormal vision |
| Cardiac disorders | Oedema |
| Gastrointestinal disorders | Haemorrhage, abdominal pain, diarrhoea, nausea, vomiting |
| Hepato-biliary disorders | Hepatic function abnormal, hepatic failure, hepatic necrosis, jaundice |
| Skin and subcutaneous tissue disorders | Pruritus, rash, sweating, purpura, angioedema, urticarial |
| General disorders and administration site conditions | Dizziness (excluding vertigo) malaise, pyrexia, sedation, drug interaction |
| Injury, poisoning and procedural complications | Overdose and poisoning |
| Very Rare (< 10,000) | Respiratory, thoracic and mediastinal disorders | Bronchospasm |
| Hepato-biliary disorders | Hepatotoxicity |
| General disorders and administration site conditions | Hypersensitivity reaction (requiring discontinuation of treatment) |
| Metabolism and nutrition disorders | Hypoglycaemia |
| Renal and urinary disorders | Sterile pyuria (cloudy urine) and renal side effects |
Post Marketing Data
| | | |
| --- | --- | --- |
| \*\*Body System\*\* | \*\*Undesirable effect\*\* | \*\*Frequency\*\* |
| Blood and lymphatic system disorders | Thrombocytopenia Agranulocytosis | Very Rare |
| Immune system disorders | Anaphylaxis Cutaneous hypersensitivity reactions including, among others, skin rashes and angiodema. Very rare cases of serious skin reactions have been reported. | Very Rare |
| Respiratory, thoracic and mediastinal disorders | Bronchospasm\\* | Very Rare |
| Hepatobiliary disorders | Hepatic dysfunction | Very Rare |
| Metabolism and nutrition disorders | High anion gap metabolic acidosis | Not known |
\\* There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.
\*\*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.
Interstitial nephritis has been reported incidentally after prolonged use of high doses. Some cases of epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme, oedema of the larynx, anaphylactic shock, anaemia, liver alteration and hepatitis, renal alteration (severe renal impairment, nephrite interstitial, haematuria, anuresis) gastrointestinal effects and vertigo have been reported.
\*\*\*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 MHRA Yellow Card in the Google Play or Apple App store.4.9 Overdose
There is a risk of poisoning, particularly in ederly subjects, in young children, in patients with liver disease, in cases of chronic alcoholism and in patients with chronic malnutrition. Overdose of Paracetamol is poteentially fatal in all populations.
Symptoms generally appear within the first 24 hours and comprise: nausea, vomiting, anorexia, pallor and abdominal pain. Immediate emergency measures are necessary in case of paracetamol overdose, even when no symptoms are present.
Overdose, 10 g or more of Paracetamol in adults or 150 mg/kg of body weight, causes liver damage, liver cell necrosis likely to induce complete and irreversible necrosis, resulting in hepatocellular insufficiency, metabolic acidosis and encephalopathy which may lead to coma and death. Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed together with increased prothrombin levels that may appear 12 to 48 hours after adminstration.
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:
a, Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.
Or
b, Regularly consumes ethanol in excess of recommended amounts.
Or
c, 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, 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 Nacetylcysteine 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 24h from ingestion should be discussed with the NPIS or a liver unit.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics and antipyretics, anilides; ATC-code:N02B E01
Paracetamol is an antipyretic analgesic. The mechanism of action is probably similar to that of aspirin and dependant on the inhibition of prostaglandin synthesis. This inhibition appears, however, to be on a selective basis.5.2 Pharmacokinetic properties
\*\*Absorption\*\*
The absorption of paracetamol by the oral route is rapid and completely from gastrointestinal tract. Maximum plasma concentrations are reached 30 to 60 minutes following ingestion and the plasma half-life is 1 - 4 hours after therapeutic doses.
\*\*Distribution\*\*
Paracetamol is distributed rapidly throughout all tissues. Concentration are comparable in blood, saliva and plasma. Protein binding is low. Binding of the drug to plasma proteins is variable; 20 to 30 % may be bound at the concentrations encountered during acute intoxication.
\*\*Metabolism\*\*
Paracetamol is metabolised mainly in the liver following two major metabolic pathways: glucuronic acid and sulfuric acid conjugates. The latter route is rapidly saturated at doses higher than the therapeutic dose. A minor route, catalysed by the cytochrome P450, results in the formation of an intermediate reagent (N-acetyl-p- benzoquinoneimine) which under normal conditions of use is rapidly detoxified by glutathione and eliminated in the urine, after conjugation with cysteine and mercaptopuric acid. Conversely, when massive intoxication occurs, the quantity of this toxic metabolite is increased.
\*\*Elimination\*\*
Elimination is essentially through the urine. 90% - 100% of the ingested dose is eliminated via the kidneys within 24 hours, principally as glucuronide (60 60 80%) and sulphate conjugates (20 to 30%). Less than 5% is eliminated in unchanged form.
Elimination half-life is about 2 hours. However, practically no paracetamol is excreted unchanged and the bulk is excreted after hepatic conjugation.
\*\*Special patient groups\*\*
Renal Insufficiency: In cases of severe renal insufficiency (creatinine clearance lower than 10 ml/min) the elimination of paracetamol and its metabolites is delayed.
Elderly Subjects: The capacity for conjugation is not modified.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
Povidone
Magnesium stearate6.2 Incompatibilities
Not applicable.6.3 Shelf life
2 years.6.4 Special precautions for storage
Store in the original package in order to protect from light.6.5 Nature and contents of container
PVC/PVdC/aluminium blisters: 20, 30, 40, 50 & 100 tablets
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
