- Approval Id
- f2d28740c1e405db
- Drug Approval Emc Name
- UNIPHYLLIN 300mg prolonged release tablets
- Drug Name
- UNIPHYLLIN 300mg prolonged release tablets
- Company Name
- Ennogen IP Ltd
- Company Address
- Unit G4, Riverside Industrial Estate, Riverside Way, Dartford, DA1 5BS, UK
- Company Telephone
- +44 (0)1322 629 220
- Company Medical Info Direct Line
- +44 (0)1322 629 220
- Company Medical Info Email
- medicalinformation@ennogen.com
- Company Customer Care Direct Line
- +44 (0)1322 629 220
- Company Stock Availability
- +44 (0)1322 629 220
- Atc Code
- R03DA04
- Legal Category
- Pharmacy
- Authorisation Holder
- Ennogen IP Ltd
Unit G4, Riverside Industrial Estate,
Riverside Way,
Dartford, DA1 5BS, UK
- Authorisation Number
- PL 55612/0064
- Authorisation Date
- 22 February 1988/ 15 May 2003
- Instruction Authorisation Holder
- Ennogen IP Ltd
Unit G4, Riverside Industrial Estate,
Riverside Way,
Dartford, DA1 5BS, UK
- Instruction Authorisation Number
- PL 55612/0064
- Instruction Authorisation Date
- 22 February 1988/ 15 May 2003
- Instruction Composition
- Each prolonged-release tablet contains 300 mg theophylline as 330 mg theophylline monohydrate.
For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- Prolonged release tablets
Capsule shaped, white, tablet plain on one side and 'U300' on the other.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
For the treatment and prophylaxis of bronchospasm associated with asthma, chronic obstructive pulmonary disease and chronic bronchitis. Also indicated for the treatment of left ventricular and congestive cardiac failure.
Theophylline should not be used as first drug of choice in the treatment of asthma in children.4.2 Posology and method of administration
Posology
\*Adults and the elderly\*
The usual maintenance dose is 200 mg 12 hourly. This may be titrated to either 300 mg or 400 mg dependent on the therapeutic response.
\*Paediatric population aged 6 years and above\*
The usual paediatric maintenance dose is 9 mg/kg twice daily. Some children with chronic asthma require and tolerate much higher doses (10-16 mg/kg twice daily).
Clearance is increased in children compared to values observed in adult subjects. The rapid clearance observed in children decreases towards adult values in late teens.
Therefore, lower dosages (based on usual adult dose) may be required for adolescents.
UNIPHYLLIN tablets should not be used in children below 6 years of age. Other dosage forms are available that are more suitable for children aged less than 6 years.
Theophylline distributes poorly into body fat, therefore mg/kg doses should be calculated on the basis of lean (ideal) bodyweight.
Plasma theophylline concentrations should ideally be maintained between 5 and 12 micrograms/ml. A plasma level of 5 micrograms /ml probably represents the lower level of clinical effectiveness. Significant adverse reactions are usually seen at plasma theophylline levels greater than 20 micrograms /ml. Monitoring of plasma theophylline concentrations may be required when:
• higher dosages are prescribed;
• patients have co-morbidities resulting in impaired clearance;
• theophylline is co-administered with medication that reduces theophylline clearance.
Patients vary in their response to xanthines and it may be necessary to titrate the dose on an individual basis.
It may be appropriate to administer a larger evening or morning dose in some patients, in order to achieve optimum therapeutic effect when symptoms are most severe e.g. at the time of the 'morning dip' in lung function.
In patients whose night time or day time symptoms persist despite other therapy and who are not currently receiving theophylline, then the total daily requirement of UNIPHYLLIN tablets (as specified above) may be added to their treatment regimen as either a single evening or morning dose.
Method of administration
Oral
These tablets must be swallowed whole and not broken, crushed or chewed as doing so may lead to a rapid release of theophylline with the potential for toxicity.
Missed dose
If a patient forgets to take a dose but remembers within 4 hours of the time the dose was due to be taken, the tablets can be taken straight away. The next dose should be taken at the normal time. Beyond 4 hours the prescriber may need to consider alternative treatment until the next dose is due.4.3 Contraindications
Hypersensitivity to xanthines or to any of the excipients listed in section 6.1.
Patients with porphyria.
Concomitant administration with ephedrine in children less than 6 years of age (or less than 22 kg).
Theophylline is contraindicated in children under 6 months of age.4.4 Special warnings and precautions for use
The patient's response to therapy should be carefully monitored – worsening of asthma symptoms requires medical attention.
Due to potential decreased theophylline clearance, dose reduction and monitoring of serum theophylline concentrations may be required in elderly patients and patients with:
• cardiac disease
• hepatic disease
• exacerbations of lung disease
• hypothyroidism
• fever
• viral infections.
Due to potential increased theophylline clearance, dose increase and monitoring of serum theophylline concentrations may be required in patients with hyperthyroidism (and when starting acute hyperthyroidism treatment) and cystic fibrosis.
Theophylline may:
• act as a gastrointestinal tract irritant and increase gastric secretion, therefore caution should be exercised in patients with peptic ulcers;
• exacerbate cardiac arrhythmias and therefore caution should be exercised in patients with cardiac disorders;
• exacerbate frequency and duration of seizures and therefore caution should be exercised in patients with history of seizures and alternative treatment considered.
Use with caution in patients with severe hypertension or chronic alcoholism. Caution should be exercised in elderly males with pre-existing partial urinary tract obstruction, such as prostatic enlargement, due to risk of urinary retention.
Particular care is advised in patients suffering from severe asthma who require acute theophylline administration. It is recommended that serum theophylline concentrations are monitored in such situations.
In case of insufficient effect of the recommended dose and in case of adverse events, theophylline plasma concentration should be monitored.4.5 Interaction with other medicinal products and other forms of interaction
The following increase clearance of theophylline and it may therefore be necessary to increase dosage to ensure a therapeutic effect: aminoglutethimide, carbamazepine, isoprenaline, phenytoin, rifampicin, ritonavir, sulphinpyrazone, barbiturates and hypericum perforatum (St John's Wort).
Smoking and alcohol consumption can also increase clearance of theophylline.
The following reduce clearance and a reduced dosage may therefore be necessary to avoid side-effects: aciclovir, allopurinol, carbimazole, cimetidine, clarithromycin, diltiazem, disulfiram, erythromycin, fluconazole, interferon, isoniazid, methotrexate, mexiletine, nizatidine, pentoxifylline, propafenone, propranolol, thiabendazole, verapamil and oral contraceptives (see section 4.9).
Theophylline has been shown to interact with some quinolone antibiotics including ciprofloxacin and enoxacin which may result in elevated plasma theophylline levels.
The concomitant use of theophylline and fluvoxamine should usually be avoided. Where this is not possible, patients should have their theophylline dose reduced and plasma theophylline should be monitored closely.
Factors such as viral infections, liver disease and heart failure also reduce theophylline clearance (see section 4.9). There are conflicting reports concerning the potentiation of theophylline by influenza vaccine and physicians should be aware that interaction may occur resulting in increased serum theophylline levels. A reduction of dosage may also be necessary in elderly patients. Thyroid disease or associated treatment may alter theophylline plasma levels. Concurrent administration of theophylline may:
• inhibit the effect of adenosine receptor agonists (adenosine, regadenoson, dipyridamol) and may reduce their toxicity when used for cardiac perfusion scanning;
• oppose the sedatory effect of benzodiazepines;
• result in the occurrence of arrhythmias with halothane;
• result in thrombocytopenia with lomustine;
• increase urinary lithium clearance.
Therefore these drugs should be used with caution. Theophylline may decrease steady state phenytoin levels.
Hypokalaemia resulting from beta2 agonist therapy, steroids, diuretics and hypoxia may be potentiated by xanthines. Particular care is advised in patients suffering from severe asthma who require hospitalisation. It is recommended that serum potassium concentrations are monitored in such situations.
Care should be taken in its concomitant use with β-adrenergic agonists, glucagon and other xanthine drugs, as these will potentiate the effects of theophylline.
Co-administration with ketamine may cause reduced convulsive threshold; with doxapram may cause increased CNS stimulation.
The incidence of toxic effects may be enhanced by the concomitant use of ephedrine.4.6 Pregnancy and lactation
There are no adequate data from well controlled studies of the use of theophylline in pregnant women. Theophylline has been reported to give rise to teratogenic effects in mice, rats and rabbits (See section 5.3). The potential risk for humans is unknown. Theophylline should not be administered during pregnancy unless clearly necessary. Theophylline is secreted in breast milk, and may be associated with irritability in the infant, therefore it should only be given to breast feeding women when the anticipated benefits outweigh the risk to the child.4.7 Effects on ability to drive and use machines
No known effects.4.8 Undesirable effects
The following adverse drug reactions have been reported in the post-marketing setting for theophylline. Frequencies of “not known” have been assigned as accurate frequencies cannot be estimated from the available clinical trial data.
| | |
| --- | --- |
| \*\*Immune system disorders\*\* | Anaphylactic reaction |
| Anaphylactoid reaction |
| Hypersensitivity |
| \*\*Metabolism and nutrition disorders\*\* | Hyperuricaemia |
| \*\*Psychiatric disorders\*\* | Agitation |
| Anxiety |
| Insomnia |
| Sleep disorder |
| \*\*Nervous system disorders\*\* | Convulsions |
| Dizziness |
| Headache |
| Tremor |
| \*\*Cardiac disorders\*\* | Atrial tachycardia |
| Palpitations |
| Sinus tachycardia |
| \*\*Gastrointestinal disorders\*\* | Abdominal pain |
| Diarrhoea |
| Gastric irritation |
| Gastro-oesophageal reflux |
| Nausea |
| Vomiting |
| \*\*Skin and subcutaneous tissue disorders\*\* | Pruritus |
| Rash |
| \*\*Renal and urinary disorders\*\* | Diuresis |
| Urinary retention\\* |
\\* Please refer to section 4.4 as theophylline may induce urinary retention in elderly males with pre-existing partial urinary tract obstruction.
Reporting of 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
Theophylline has a low therapeutic index. Theophylline toxicity is most likely to occur when serum concentrations exceed 20 micrograms/ml and becomes progressively more severe at higher serum concentrations.
Over 3 g could be serious in an adult (40 mg/kg in a child). The fatal dose may be as little as 4.5 g in an adult (60 mg/kg in a child), but is generally higher.
Symptoms
Warning: Serious symptoms may develop as long as 12 hours after overdosage with prolonged release formulations.
Alimentary symptoms: Nausea, vomiting (which is often severe), epigastric pain and haematemesis. Consider pancreatitis if abdominal pain persists.
Neurological symptoms: Restlessness, hypertonia, exaggerated limb reflexes, convulsions, seizures. Coma may develop in very severe cases.
Cardiovascular symptoms: Hypotension. Sinus tachycardia is common. Ectopic beats and supraventricular and ventricular tachycardia may follow.
Metabolic symptoms: Hypokalaemia due to shift of potassium from plasma into cells is common, can develop rapidly and may be severe. Hyperglycaemia, hypomagnesaemia and metabolic acidosis may also occur. Rhabdomyolysis may also occur.
Management
Activated charcoal or gastric lavage should be considered if a significant overdose has been ingested within 1-2 hours. Repeated doses of activated charcoal given by mouth can enhance theophylline elimination. Measure the plasma potassium concentration urgently, repeat frequently and correct hypokalaemia. BEWARE! If large amounts of potassium have been given, serious hyperkalaemia may develop during recovery. If plasma potassium is low, then the plasma magnesium concentration should be measured as soon as possible.
In the treatment of ventricular arrhythmias, proconvulsant antiarrhythmic agents such as lignocaine (lidocaine) should be avoided because of the risk of causing or exacerbating seizures.
Measure the plasma theophylline concentration regularly when severe poisoning is suspected, until concentrations are falling. Vomiting should be treated with an antiemetic such as metoclopramide or ondansetron.
Tachycardia with an adequate cardiac output is best left untreated. Beta- blockers may be given in extreme cases but not if the patient is asthmatic. Control isolated convulsions with intravenous diazepam. Exclude hypokalaemia as a cause.
Particularly in the setting of theophylline overdose induced convulsions, efficacy of some anticonvulsant drugs, such as benzodiazepines, may be reduced through suspected pharmacodynamic interactions.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Theophylline is a bronchodilator. In addition it affects the function of a number of cells involved in the inflammatory processes associated with asthma and chronic obstructive airways disease. Of most importance may be enhanced suppressor, T-lymphocyte activity and reduction of eosinophil and neutrophil function. These actions may contribute to an anti-inflammatory prophylactic activity in asthma and chronic obstructive airways disease. Theophylline stimulates the myocardium and produces a diminution of venous pressure in congestive heart failure leading to marked increase in cardiac output.5.2 Pharmacokinetic properties
Absorption
Following oral administration, theophylline is efficiently absorbed and is associated with an absolute bioavailability approximating 100%. Following oral administration of UNIPHYLLIN tablets, the delivery of theophylline is controlled and, at steady state, peak concentrations are typically seen after approximately 5 hours.
An effective plasma concentration is considered to be 5-12 micrograms/ml, although plasma concentrations up to 20 micrograms/ml may be necessary to achieve efficacy in some cases. Do not exceed 20 micrograms/ml.
Distribution and protein binding
Theophylline is distributed through all body compartments; approximately 60% is bound to plasma proteins.
An effective plasma concentration is considered to be 5-12 micrograms/ml, although plasma concentrations up to 20 micrograms/ml may be necessary to achieve efficacy in some cases. Do not exceed 20 micrograms/ml.
Biotransformation
Theophylline is metabolised in the liver to 1, 3-dimethyl uric acid and 3- methylxanthine.
Elimination
Theophylline and its metabolites are excrete mainlyin the urine. Approximately 10% is excreted unchanged. The mean elimination half life associated with UNIPHYLLIN tablets is approximately 7 hours.
Factors affecting clearance
The predominant factors which alter theophylline clearance are: age, body weight, diet, smoking habits, other drugs and cardiorespiratory or hepatic disease. Clearance is increased in children compared to values observed in adult subjects. Clearance decreases towards adult values in late teens.
Linearity
Studies involving prolonged-release UNIPHYLLIN tablets have demonstrated approximately dose-proportional pharmacokinetics across the 200-600 mg dose range.5.3 Preclinical safety data
Genotoxicity and carcinogenicity
\*In vitro\* and \*in vivo\* assays have shown both positive and negative genotoxic results for theophylline. However, oral theophylline administered daily to rats and mice for 2 years did not show carcinogenicity. Therefore, it is unlikely that theophylline poses a carcinogenic risk in humans.
Reproductive and developmental toxicity
Theophylline has been shown to have effects upon the male reproductive system in rodents, but at doses considered in excess of the maximum human dose indicating little relevance to clinical use.
Several embryofetal development studies in rats, mice and rabbits have demonstrated developmental effects independent from maternal toxicity at high doses of theophylline. Therefore, theophylline should be considered to have the potential for developmental toxicity in humans.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
Hydroxyethylcellulose
Povidone (K25)
Cetostearyl Alcohol
Macrogol 6000
Talc
Magnesium Stearate6.2 Incompatibilities
Not applicable.6.3 Shelf life
Three years6.4 Special precautions for storage
Do not store above 25ºC.6.5 Nature and contents of container
PVdC coated PVC/aluminium backed blister packs containing 8 or 56 tablets. Polypropylene containers with polyethylene lids containing 250 or 1000 tablets.6.6 Special precautions for disposal and other handling
None.
- Instruction Content
- ## Composition
Each prolonged-release tablet contains 300 mg theophylline as 330 mg theophylline monohydrate.
For the full list of excipients, see section 6.1.
## Pharmaceutical Form
Prolonged release tablets
Capsule shaped, white, tablet plain on one side and 'U300' on the other.
## Clinical Particulars
4.1 Therapeutic indications
For the treatment and prophylaxis of bronchospasm associated with asthma, chronic obstructive pulmonary disease and chronic bronchitis. Also indicated for the treatment of left ventricular and congestive cardiac failure.
Theophylline should not be used as first drug of choice in the treatment of asthma in children.4.2 Posology and method of administration
Posology
\*Adults and the elderly\*
The usual maintenance dose is 200 mg 12 hourly. This may be titrated to either 300 mg or 400 mg dependent on the therapeutic response.
\*Paediatric population aged 6 years and above\*
The usual paediatric maintenance dose is 9 mg/kg twice daily. Some children with chronic asthma require and tolerate much higher doses (10-16 mg/kg twice daily).
Clearance is increased in children compared to values observed in adult subjects. The rapid clearance observed in children decreases towards adult values in late teens.
Therefore, lower dosages (based on usual adult dose) may be required for adolescents.
UNIPHYLLIN tablets should not be used in children below 6 years of age. Other dosage forms are available that are more suitable for children aged less than 6 years.
Theophylline distributes poorly into body fat, therefore mg/kg doses should be calculated on the basis of lean (ideal) bodyweight.
Plasma theophylline concentrations should ideally be maintained between 5 and 12 micrograms/ml. A plasma level of 5 micrograms /ml probably represents the lower level of clinical effectiveness. Significant adverse reactions are usually seen at plasma theophylline levels greater than 20 micrograms /ml. Monitoring of plasma theophylline concentrations may be required when:
• higher dosages are prescribed;
• patients have co-morbidities resulting in impaired clearance;
• theophylline is co-administered with medication that reduces theophylline clearance.
Patients vary in their response to xanthines and it may be necessary to titrate the dose on an individual basis.
It may be appropriate to administer a larger evening or morning dose in some patients, in order to achieve optimum therapeutic effect when symptoms are most severe e.g. at the time of the 'morning dip' in lung function.
In patients whose night time or day time symptoms persist despite other therapy and who are not currently receiving theophylline, then the total daily requirement of UNIPHYLLIN tablets (as specified above) may be added to their treatment regimen as either a single evening or morning dose.
Method of administration
Oral
These tablets must be swallowed whole and not broken, crushed or chewed as doing so may lead to a rapid release of theophylline with the potential for toxicity.
Missed dose
If a patient forgets to take a dose but remembers within 4 hours of the time the dose was due to be taken, the tablets can be taken straight away. The next dose should be taken at the normal time. Beyond 4 hours the prescriber may need to consider alternative treatment until the next dose is due.4.3 Contraindications
Hypersensitivity to xanthines or to any of the excipients listed in section 6.1.
Patients with porphyria.
Concomitant administration with ephedrine in children less than 6 years of age (or less than 22 kg).
Theophylline is contraindicated in children under 6 months of age.4.4 Special warnings and precautions for use
The patient's response to therapy should be carefully monitored – worsening of asthma symptoms requires medical attention.
Due to potential decreased theophylline clearance, dose reduction and monitoring of serum theophylline concentrations may be required in elderly patients and patients with:
• cardiac disease
• hepatic disease
• exacerbations of lung disease
• hypothyroidism
• fever
• viral infections.
Due to potential increased theophylline clearance, dose increase and monitoring of serum theophylline concentrations may be required in patients with hyperthyroidism (and when starting acute hyperthyroidism treatment) and cystic fibrosis.
Theophylline may:
• act as a gastrointestinal tract irritant and increase gastric secretion, therefore caution should be exercised in patients with peptic ulcers;
• exacerbate cardiac arrhythmias and therefore caution should be exercised in patients with cardiac disorders;
• exacerbate frequency and duration of seizures and therefore caution should be exercised in patients with history of seizures and alternative treatment considered.
Use with caution in patients with severe hypertension or chronic alcoholism. Caution should be exercised in elderly males with pre-existing partial urinary tract obstruction, such as prostatic enlargement, due to risk of urinary retention.
Particular care is advised in patients suffering from severe asthma who require acute theophylline administration. It is recommended that serum theophylline concentrations are monitored in such situations.
In case of insufficient effect of the recommended dose and in case of adverse events, theophylline plasma concentration should be monitored.4.5 Interaction with other medicinal products and other forms of interaction
The following increase clearance of theophylline and it may therefore be necessary to increase dosage to ensure a therapeutic effect: aminoglutethimide, carbamazepine, isoprenaline, phenytoin, rifampicin, ritonavir, sulphinpyrazone, barbiturates and hypericum perforatum (St John's Wort).
Smoking and alcohol consumption can also increase clearance of theophylline.
The following reduce clearance and a reduced dosage may therefore be necessary to avoid side-effects: aciclovir, allopurinol, carbimazole, cimetidine, clarithromycin, diltiazem, disulfiram, erythromycin, fluconazole, interferon, isoniazid, methotrexate, mexiletine, nizatidine, pentoxifylline, propafenone, propranolol, thiabendazole, verapamil and oral contraceptives (see section 4.9).
Theophylline has been shown to interact with some quinolone antibiotics including ciprofloxacin and enoxacin which may result in elevated plasma theophylline levels.
The concomitant use of theophylline and fluvoxamine should usually be avoided. Where this is not possible, patients should have their theophylline dose reduced and plasma theophylline should be monitored closely.
Factors such as viral infections, liver disease and heart failure also reduce theophylline clearance (see section 4.9). There are conflicting reports concerning the potentiation of theophylline by influenza vaccine and physicians should be aware that interaction may occur resulting in increased serum theophylline levels. A reduction of dosage may also be necessary in elderly patients. Thyroid disease or associated treatment may alter theophylline plasma levels. Concurrent administration of theophylline may:
• inhibit the effect of adenosine receptor agonists (adenosine, regadenoson, dipyridamol) and may reduce their toxicity when used for cardiac perfusion scanning;
• oppose the sedatory effect of benzodiazepines;
• result in the occurrence of arrhythmias with halothane;
• result in thrombocytopenia with lomustine;
• increase urinary lithium clearance.
Therefore these drugs should be used with caution. Theophylline may decrease steady state phenytoin levels.
Hypokalaemia resulting from beta2 agonist therapy, steroids, diuretics and hypoxia may be potentiated by xanthines. Particular care is advised in patients suffering from severe asthma who require hospitalisation. It is recommended that serum potassium concentrations are monitored in such situations.
Care should be taken in its concomitant use with β-adrenergic agonists, glucagon and other xanthine drugs, as these will potentiate the effects of theophylline.
Co-administration with ketamine may cause reduced convulsive threshold; with doxapram may cause increased CNS stimulation.
The incidence of toxic effects may be enhanced by the concomitant use of ephedrine.4.6 Pregnancy and lactation
There are no adequate data from well controlled studies of the use of theophylline in pregnant women. Theophylline has been reported to give rise to teratogenic effects in mice, rats and rabbits (See section 5.3). The potential risk for humans is unknown. Theophylline should not be administered during pregnancy unless clearly necessary. Theophylline is secreted in breast milk, and may be associated with irritability in the infant, therefore it should only be given to breast feeding women when the anticipated benefits outweigh the risk to the child.4.7 Effects on ability to drive and use machines
No known effects.4.8 Undesirable effects
The following adverse drug reactions have been reported in the post-marketing setting for theophylline. Frequencies of “not known” have been assigned as accurate frequencies cannot be estimated from the available clinical trial data.
| | |
| --- | --- |
| \*\*Immune system disorders\*\* | Anaphylactic reaction |
| Anaphylactoid reaction |
| Hypersensitivity |
| \*\*Metabolism and nutrition disorders\*\* | Hyperuricaemia |
| \*\*Psychiatric disorders\*\* | Agitation |
| Anxiety |
| Insomnia |
| Sleep disorder |
| \*\*Nervous system disorders\*\* | Convulsions |
| Dizziness |
| Headache |
| Tremor |
| \*\*Cardiac disorders\*\* | Atrial tachycardia |
| Palpitations |
| Sinus tachycardia |
| \*\*Gastrointestinal disorders\*\* | Abdominal pain |
| Diarrhoea |
| Gastric irritation |
| Gastro-oesophageal reflux |
| Nausea |
| Vomiting |
| \*\*Skin and subcutaneous tissue disorders\*\* | Pruritus |
| Rash |
| \*\*Renal and urinary disorders\*\* | Diuresis |
| Urinary retention\\* |
\\* Please refer to section 4.4 as theophylline may induce urinary retention in elderly males with pre-existing partial urinary tract obstruction.
Reporting of 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
Theophylline has a low therapeutic index. Theophylline toxicity is most likely to occur when serum concentrations exceed 20 micrograms/ml and becomes progressively more severe at higher serum concentrations.
Over 3 g could be serious in an adult (40 mg/kg in a child). The fatal dose may be as little as 4.5 g in an adult (60 mg/kg in a child), but is generally higher.
Symptoms
Warning: Serious symptoms may develop as long as 12 hours after overdosage with prolonged release formulations.
Alimentary symptoms: Nausea, vomiting (which is often severe), epigastric pain and haematemesis. Consider pancreatitis if abdominal pain persists.
Neurological symptoms: Restlessness, hypertonia, exaggerated limb reflexes, convulsions, seizures. Coma may develop in very severe cases.
Cardiovascular symptoms: Hypotension. Sinus tachycardia is common. Ectopic beats and supraventricular and ventricular tachycardia may follow.
Metabolic symptoms: Hypokalaemia due to shift of potassium from plasma into cells is common, can develop rapidly and may be severe. Hyperglycaemia, hypomagnesaemia and metabolic acidosis may also occur. Rhabdomyolysis may also occur.
Management
Activated charcoal or gastric lavage should be considered if a significant overdose has been ingested within 1-2 hours. Repeated doses of activated charcoal given by mouth can enhance theophylline elimination. Measure the plasma potassium concentration urgently, repeat frequently and correct hypokalaemia. BEWARE! If large amounts of potassium have been given, serious hyperkalaemia may develop during recovery. If plasma potassium is low, then the plasma magnesium concentration should be measured as soon as possible.
In the treatment of ventricular arrhythmias, proconvulsant antiarrhythmic agents such as lignocaine (lidocaine) should be avoided because of the risk of causing or exacerbating seizures.
Measure the plasma theophylline concentration regularly when severe poisoning is suspected, until concentrations are falling. Vomiting should be treated with an antiemetic such as metoclopramide or ondansetron.
Tachycardia with an adequate cardiac output is best left untreated. Beta- blockers may be given in extreme cases but not if the patient is asthmatic. Control isolated convulsions with intravenous diazepam. Exclude hypokalaemia as a cause.
Particularly in the setting of theophylline overdose induced convulsions, efficacy of some anticonvulsant drugs, such as benzodiazepines, may be reduced through suspected pharmacodynamic interactions.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Theophylline is a bronchodilator. In addition it affects the function of a number of cells involved in the inflammatory processes associated with asthma and chronic obstructive airways disease. Of most importance may be enhanced suppressor, T-lymphocyte activity and reduction of eosinophil and neutrophil function. These actions may contribute to an anti-inflammatory prophylactic activity in asthma and chronic obstructive airways disease. Theophylline stimulates the myocardium and produces a diminution of venous pressure in congestive heart failure leading to marked increase in cardiac output.5.2 Pharmacokinetic properties
Absorption
Following oral administration, theophylline is efficiently absorbed and is associated with an absolute bioavailability approximating 100%. Following oral administration of UNIPHYLLIN tablets, the delivery of theophylline is controlled and, at steady state, peak concentrations are typically seen after approximately 5 hours.
An effective plasma concentration is considered to be 5-12 micrograms/ml, although plasma concentrations up to 20 micrograms/ml may be necessary to achieve efficacy in some cases. Do not exceed 20 micrograms/ml.
Distribution and protein binding
Theophylline is distributed through all body compartments; approximately 60% is bound to plasma proteins.
An effective plasma concentration is considered to be 5-12 micrograms/ml, although plasma concentrations up to 20 micrograms/ml may be necessary to achieve efficacy in some cases. Do not exceed 20 micrograms/ml.
Biotransformation
Theophylline is metabolised in the liver to 1, 3-dimethyl uric acid and 3- methylxanthine.
Elimination
Theophylline and its metabolites are excrete mainlyin the urine. Approximately 10% is excreted unchanged. The mean elimination half life associated with UNIPHYLLIN tablets is approximately 7 hours.
Factors affecting clearance
The predominant factors which alter theophylline clearance are: age, body weight, diet, smoking habits, other drugs and cardiorespiratory or hepatic disease. Clearance is increased in children compared to values observed in adult subjects. Clearance decreases towards adult values in late teens.
Linearity
Studies involving prolonged-release UNIPHYLLIN tablets have demonstrated approximately dose-proportional pharmacokinetics across the 200-600 mg dose range.5.3 Preclinical safety data
Genotoxicity and carcinogenicity
\*In vitro\* and \*in vivo\* assays have shown both positive and negative genotoxic results for theophylline. However, oral theophylline administered daily to rats and mice for 2 years did not show carcinogenicity. Therefore, it is unlikely that theophylline poses a carcinogenic risk in humans.
Reproductive and developmental toxicity
Theophylline has been shown to have effects upon the male reproductive system in rodents, but at doses considered in excess of the maximum human dose indicating little relevance to clinical use.
Several embryofetal development studies in rats, mice and rabbits have demonstrated developmental effects independent from maternal toxicity at high doses of theophylline. Therefore, theophylline should be considered to have the potential for developmental toxicity in humans.
## Pharmaceutical Particulars
6.1 List of excipients
Hydroxyethylcellulose
Povidone (K25)
Cetostearyl Alcohol
Macrogol 6000
Talc
Magnesium Stearate6.2 Incompatibilities
Not applicable.6.3 Shelf life
Three years6.4 Special precautions for storage
Do not store above 25ºC.6.5 Nature and contents of container
PVdC coated PVC/aluminium backed blister packs containing 8 or 56 tablets. Polypropylene containers with polyethylene lids containing 250 or 1000 tablets.6.6 Special precautions for disposal and other handling
None.
