Drugs List

Therapeutic Indications

Uses

Bronchial asthma
Reversible airways obstruction

Contraindications

Children under 6 months
Acute tachyarrhythmia
Recent myocardial infarction

Precautions and Warnings

Children aged 6 months to 6 years
Elderly
Febrile disorder
Tobacco smoking
Viral infection
Alcoholism
Benign prostatic hyperplasia
Bladder outflow obstruction
Breastfeeding
Cardiac arrhythmias
Cardiac failure
Cardiac impairment
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic impairment
Hereditary fructose intolerance
History of seizures
Hypertension
Hyperthyroidism
Hypokalaemia
Hypothyroidism
Hypoxia
Lactose intolerance
Peptic ulcer
Porphyria
Pregnancy
Severe renal impairment

Not all available brands are licensed for use in children under 6 years
Some formulations contain lactose
Some formulations contain sucrose
Prescribing by brand recommended to ensure consistent bioavailability
Monitor serum K+ in patients on beta agonists/steroids/diuretics
Monitor serum potassium regularly in severe asthmatic or hypoxic patients
Plasma level monitoring may be useful: refer to local guidelines
Advise patient to seek medical advice if asthma seems to be worsening
Alcohol increases clearance - higher doses may be required
Dose adjustment required if patient starts/stops smoking during therapy
Advise patient not to take St John's wort concurrently

In the case of an acute asthmatic attack in a patient receiving a sustained action theophylline preparation, great caution should be taken when administering intravenous aminophylline. Half the recommended loading dose of aminophylline (generally 6mg/kg) should be given, i.e. 3mg/kg, cautiously.

Pregnancy and Lactation

Pregnancy

Use theophylline with caution in pregnancy.

Use only if there is no safer alternative or when the disease carries risk for mother and child.

Theophylline crosses the placenta, and newborn infants may have therapeutic serum levels. Transient tachycardia, irritability and vomiting have been reported in new-borns delivered from mothers consuming theophylline. These effects are more likely to occur when maternal serum levels at term are in the high therapeutic range or above (therapeutic range 8-20mcg/ml). Cord blood levels are approximately 100% of the maternal serum concentration.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Use theophylline with caution in breastfeeding.

Theophylline has a prolonged half-life in neonates which may cause retention. Milk concentrations are approximately equal to the maternal plasma levels. Estimate generally indicate that less than 1% of dose is absorbed by infant.

One reported case of irritability and fretful sleeping was reported in an infant exposed to breast milk only on days when the mother reported taking theophylline. The average milk concentration of theophylline in this case was 0.7mg/L.

Because very young infants may be more sensitive to levels that would be non-toxic in older infants, less rapidly absorbed theophylline preparations may be advisable for nursing mothers.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Agitation
Anaphylactic reaction
Anaphylactoid reaction
Anxiety
Arrhythmias
Atrial tachycardia
CNS stimulation
Convulsions
Diarrhoea
Diuresis
Dizziness
Electrolyte disturbances
Gastric irritation
Gastroesophageal reflux
Headache
Hyperglycaemia
Hypersensitivity reactions
Hypertonia
Hyperuricaemia
Insomnia
Irritability
Nausea
Palpitations
Pruritus
Rash
Restlessness
Sinus tachycardia
Tremor
Urinary retention
Vomiting

Presentation

Modified release tablets and capsules containing theophylline.

Drugs List

Therapeutic Indications

Uses

Bronchial asthma
Reversible airways obstruction

Dosage

The rate of absorption from modified release preparations may vary between brands. The pharmacist should contact the prescriber and agree the brand to be dispensed if no specific name is specified. It is also essential that a patient discharged from hospital is maintained on the same brand on which the patient was stabilised whilst in hospital.

It is not possible to ensure bioequivalence between different sustained release theophylline preparations. Once titrated to an effective dose, a patient should not be transferred to another xanthine preparation without re-titration and clinical assessment.

Adults

Elderly

Children

Therapeutic Drug Monitoring

Plasma theophylline concentration should ideally be maintained between 5 and 12mg/litre.

There is a narrow margin between the therapeutic dose and the toxic dose.

Significant adverse effects are usually seen at plasma theophylline concentrations above 20mg/litre.

Plasma theophylline level measured 4 to 8 hours after dosing and at least three days after any dosage adjustment provides a more accurate assessment of the patients' dosage need, especially as significant variations in the rate of drug elimination can occur between individuals. The following table provides a guide:

Plasma level (microgram/ml): Below 5 - Too low; Increase dose by 25%
Plasma level (microgram/ml): 5-12* - Correct; Maintain dose (*Plasma concentration of up to 20 mcg/ml can be necessary in some cases)
Plasma level (microgram/ml): 20-25 - Too high; Decrease dose by 10%
Plasma level (microgram/ml): 25-30 - Too high; Miss next dose and decrease subsequent doses by 25%
Plasma level (microgram/ml): Over 30 - Too high; Miss next two doses and decrease subsequent doses by 50%

It is advisable to recheck the plasma levels after dose adjustment, and every 6 to 12 months thereafter.

Contraindications

Children under 6 months
Acute tachyarrhythmia
Recent myocardial infarction

Precautions and Warnings

Children aged 6 months to 6 years
Elderly
Febrile disorder
Tobacco smoking
Viral infection
Alcoholism
Benign prostatic hyperplasia
Bladder outflow obstruction
Breastfeeding
Cardiac arrhythmias
Cardiac failure
Cardiac impairment
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic impairment
Hereditary fructose intolerance
History of seizures
Hypertension
Hyperthyroidism
Hypokalaemia
Hypothyroidism
Hypoxia
Lactose intolerance
Peptic ulcer
Porphyria
Pregnancy
Severe renal impairment

Not all available brands are licensed for use in children under 6 years
Some formulations contain lactose
Some formulations contain sucrose
Prescribing by brand recommended to ensure consistent bioavailability
Monitor serum K+ in patients on beta agonists/steroids/diuretics
Monitor serum potassium regularly in severe asthmatic or hypoxic patients
Plasma level monitoring may be useful: refer to local guidelines
Advise patient to seek medical advice if asthma seems to be worsening
Alcohol increases clearance - higher doses may be required
Dose adjustment required if patient starts/stops smoking during therapy
Advise patient not to take St John's wort concurrently

In the case of an acute asthmatic attack in a patient receiving a sustained action theophylline preparation, great caution should be taken when administering intravenous aminophylline. Half the recommended loading dose of aminophylline (generally 6mg/kg) should be given, i.e. 3mg/kg, cautiously.

Pregnancy and Lactation

Pregnancy

Use theophylline with caution in pregnancy.

Use only if there is no safer alternative or when the disease carries risk for mother and child.

Theophylline crosses the placenta, and newborn infants may have therapeutic serum levels. Transient tachycardia, irritability and vomiting have been reported in new-borns delivered from mothers consuming theophylline. These effects are more likely to occur when maternal serum levels at term are in the high therapeutic range or above (therapeutic range 8-20mcg/ml). Cord blood levels are approximately 100% of the maternal serum concentration.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Use theophylline with caution in breastfeeding.

Theophylline has a prolonged half-life in neonates which may cause retention. Milk concentrations are approximately equal to the maternal plasma levels. Estimate generally indicate that less than 1% of dose is absorbed by infant.

One reported case of irritability and fretful sleeping was reported in an infant exposed to breast milk only on days when the mother reported taking theophylline. The average milk concentration of theophylline in this case was 0.7mg/L.

Because very young infants may be more sensitive to levels that would be non-toxic in older infants, less rapidly absorbed theophylline preparations may be advisable for nursing mothers.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Agitation
Anaphylactic reaction
Anaphylactoid reaction
Anxiety
Arrhythmias
Atrial tachycardia
CNS stimulation
Convulsions
Diarrhoea
Diuresis
Dizziness
Electrolyte disturbances
Gastric irritation
Gastroesophageal reflux
Headache
Hyperglycaemia
Hypersensitivity reactions
Hypertonia
Hyperuricaemia
Insomnia
Irritability
Nausea
Palpitations
Pruritus
Rash
Restlessness
Sinus tachycardia
Tremor
Urinary retention
Vomiting

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

The MHRA have produced 'generic' overdose sections for the top ten drugs for which the NPIS received the greatest number of queries about management of overdose in 2002. This information is attached below:

Over 3g could be serious in an adult (40mg/kg in a child). The fatal dose may be as little as 4.5g in an adult (60mg/kg in a child), but is generally higher.

Signs and Symptoms

Warning: Serious features may develop as long as 12 hours after overdosage with sustained release formulations.

Alimentary features: Nausea, vomiting (which is often severe), epigastric pain and haematemesis. Consider pancreatitis if abdominal pain persists.

Neurological features: Restlessness, hypertonia, exaggerated limb reflexes and convulsions. Coma may develop in very severe cases.

Cardiovascular features: Sinus tachycardia is common. Ectopic beats and supraventricular and ventricular tachycardia may follow.

Metabolic features: 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.

Treatment

Activated charcoal or gastric lavage should be considered if a significant overdose has been ingested within 1 to 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.

Further Information

Last Full Review Date: October 2016

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.

Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.
Summary of Product Characteristics: Nuelin SA 175mg tablets. Meda Pharmaceuticals. Revised September 2018.

Summary of Product Characteristics: Nuelin SA 250mg tablets. Meda Pharmaceuticals. Revised September 2018.

Summary of Product Characteristics: Slo-Phyllin 60mg. 125mg, 250mg capsules. Merck Serono. Revised April 2018.

Summary of Product Characteristics: Uniphyllin Continus tablets. Napp Pharmaceuticals Ltd. Revised March 2017.

MHRA Generic Overdose Sections:
Available at: https://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Informationforlicenceapplicants/Guidance/OverdosesectionsofSPCs/Genericoverdosesections/index.htm
Last accessed: October 2016.