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Drug Reference

theophylline

xanthine bronchodilator· Brands: Uniphyllin Continus, Phyllocontin Continus, Theo-Dur, Slo-Bid, ElixophyllinIVPO

Mechanism of action
Theophylline is a methylxanthine that relaxes bronchial smooth muscle mainly by inhibiting phosphodiesterases, chiefly PDE3 and PDE4, which raises intracellular cyclic AMP and reduces smooth muscle tone. At concentrations used clinically it also blocks adenosine A1 and A2 receptors, which contributes to bronchodilation and to central respiratory stimulation. Additional actions include improved diaphragmatic contractility, enhanced mucociliary clearance, mild anti-inflammatory effects and, at low concentrations, restoration of histone deacetylase activity so that corticosteroid responsiveness is partly regained in patients with chronic obstructive pulmonary disease. The bronchodilator effect is concentration dependent and becomes clinically useful only within a narrow blood concentration window, which explains both the modest efficacy at low doses and the toxicity seen as concentrations rise.
Pharmacokinetics
Theophylline is well absorbed after oral administration, though the rate and extent depend on the formulation; sustained release products are designed to give relatively flat serum concentrations over 12 or 24 hours and should not be crushed or chewed. It is about 40 to 60 per cent bound to plasma proteins and distributes widely, with a volume of distribution around 0.5 L/kg. Elimination is almost entirely hepatic, through CYP1A2 and to a lesser extent CYP3A4, and clearance varies several fold between individuals. The half-life is typically 6 to 12 hours in healthy non-smoking adults, shorter in smokers and children, and prolonged in neonates, older people, heart failure, hepatic impairment, obesity and with enzyme inhibitors such as ciprofloxacin, erythromycin, clarithromycin and fluvoxamine. Enzyme inducers such as rifampicin, carbamazepine, phenytoin and smoking reduce the half-life. Metabolites are excreted renally. The usual target serum concentration is 10 to 20 mg/L (roughly 55 to 110 micromol/L).
Indications & dosing

Chronic asthma, maintenance add-on therapy when inhaled corticosteroids and bronchodilators give inadequate control

Modified-release product, titrated to response and to serum levels of 5 to 15 mg/L. Start lower in heart failure, hepatic impairment or interacting drugs.

  • adult · PO: 200–400 mg twice daily · Modified-release product, titrated to response and to serum levels of 5 to 15 mg/L. Start lower in heart failure, hepatic impairment or interacting drugs.

Acute severe asthma exacerbation, adjunct when first-line inhaled and systemic therapy is insufficientoff-label

Given as aminophylline over 20 to 40 minutes, then a continuous infusion. Omit the loading dose if the patient already takes theophylline. Monitor ECG and serum levels.

  • adult · IV: 5 mg/kg loading dose · Given as aminophylline over 20 to 40 minutes, then a continuous infusion. Omit the loading dose if the patient already takes theophylline. Monitor ECG and serum levels.

COPD, maintenance therapy to reduce breathlessness in selected patients

Modified-release product. Benefit is modest and is weighed against toxicity and interactions, especially in older patients with cardiac disease.

  • adult · PO: 200–400 mg twice daily · Modified-release product. Benefit is modest and is weighed against toxicity and interactions, especially in older patients with cardiac disease.

Apnoea of prematurity

Maintenance is usually 1.5 to 3 mg/kg per dose every 8 to 12 hours. Caffeine citrate is often preferred; levels and clinical response guide dosing.

  • neonatal · IV: 5–6 mg/kg loading dose · Maintenance is usually 1.5 to 3 mg/kg per dose every 8 to 12 hours. Caffeine citrate is often preferred; levels and clinical response guide dosing.

Chronic asthma in children, maintenance add-on therapy

Total daily dose initially 8 to 10 mg/kg, adjusted to serum levels. Children clear the drug faster than adults, so higher daily doses may be needed under specialist supervision.

  • pediatric · PO: 4–5 mg/kg twice daily · Total daily dose initially 8 to 10 mg/kg, adjusted to serum levels. Children clear the drug faster than adults, so higher daily doses may be needed under specialist supervision.
Contraindications & precautions
  • Hypersensitivity to theophylline, aminophylline or other xanthines · Avoid all xanthine preparations, including those in combination products.
  • Acute porphyria · Theophylline is regarded as unsafe in the acute porphyrias; seek an alternative bronchodilator.
  • Uncontrolled tachyarrhythmia, including supraventricular and ventricular arrhythmias · Theophylline is proarrhythmic and can worsen both rate and rhythm disturbance.
  • Recent myocardial infarction or unstable ischaemic heart disease · Increased myocardial oxygen demand and arrhythmia risk; avoid unless benefit clearly outweighs risk.
  • Active peptic ulcer disease · Xanthines increase gastric acid secretion and may provoke bleeding.
  • Epilepsy or other seizure disorder · Theophylline lowers the seizure threshold; toxicity can present with convulsions.
  • Untreated hyperthyroidism · Adds to tachycardia, tremor and metabolic stimulation.
  • Theophylline has a narrow therapeutic index. Monitor plasma concentrations, especially when starting or stopping interacting drugs, and aim for the lowest concentration that controls symptoms. Practice varies by formulary.
  • Clearance falls in heart failure, hepatic impairment, the elderly, obesity and acute viral illness, so reduce the dose and re-measure levels. Clearance rises in smokers and in children, who need higher weight-adjusted doses.
  • Intravenous aminophylline must be given by slow, rate-controlled infusion. Omit the loading dose in patients already taking theophylline, and monitor ECG, heart rate and serum potassium.
  • CYP1A2 inhibitors such as ciprofloxacin, fluvoxamine and clarithromycin raise theophylline levels, while inducers such as rifampicin, carbamazepine, phenytoin and tobacco smoking lower them. Dietary caffeine adds to toxicity.
  • Toxicity can present with vomiting, tremor, palpitations or seizures, and arrhythmias or convulsions may be the first sign of severe overdose. Measure levels urgently if these appear.
  • Theophylline is not first-line for acute asthma or exacerbations of COPD; use inhaled short-acting beta2 agonists and systemic corticosteroids, with theophylline as an add-on in stable disease.
Adverse effects
  • Nausea, vomiting and abdominal discomfort
  • Headache
  • Restlessness, insomnia and fine tremor
  • Palpitations and sinus tachycardia
  • Cardiac arrhythmias, including atrial fibrillation and ventricular arrhythmiasserious
  • Generalised seizures, which may be fatal and can occur without preceding warning signsserious
  • Hypokalaemiaserious
  • Hyperglycaemia
  • Gastro-oesophageal reflux and dyspepsia
Interactions
  • clarithromycinmajorAvoid concomitant use if possible. If co-administration is necessary, monitor theophylline serum concentrations closely and adjust the dose accordingly. Patients should be observed for signs of theophylline toxicity, such as nausea, palpitations, and tremors.
  • ciprofloxacinmajorAvoid concurrent use if possible, as alternative antibiotics with minimal CYP1A2 inhibition (e.g., levofloxacin) may be considered. If co-prescription is necessary, reduce the theophylline dose by up to 50% and closely monitor serum theophylline concentrations and clinical signs of toxicity. Repeat theophylline levels should be measured after initiating or adjusting ciprofloxacin therapy, and further dose adjustments made as required.
  • erythromycinmajorAvoid co-prescription if possible. If combination therapy is unavoidable, reduce the theophylline dose by approximately 30 to 50% and monitor serum theophylline concentrations closely, especially during the first few days of erythromycin therapy and after its discontinuation. Monitor for signs of theophylline toxicity.
  • levofloxacinmoderateAvoid concomitant use if possible. If co-prescription is necessary, monitor serum theophylline levels closely (e.g., before starting and within 1-2 days after adding levofloxacin) and reduce the theophylline dose as needed. Monitor the patient for clinical signs of theophylline toxicity. Consider an alternative antibiotic with less interaction potential, such as azithromycin; ciprofloxacin is itself a potent CYP1A2 inhibitor and is not an alternative.
  • carbamazepinemajorMonitor serum theophylline concentrations before and after starting or stopping carbamazepine. Adjust the theophylline dose as necessary to maintain therapeutic concentrations and clinical response. Continue monitoring until concentrations are stable. Advise patients to report signs of worsening respiratory symptoms or theophylline toxicity.
  • phenytoinmajorIf coadministration is necessary, monitor serum theophylline concentrations closely. It may be necessary to increase the theophylline dose by 20 to 50 percent and adjust based on levels. Reassess after any change in phenytoin therapy. Alternative bronchodilators should be considered.
Renal & hepatic adjustment
  • eGFR 30+: No specific dose reduction is needed. Elimination is mainly hepatic, so renal function has little effect on theophylline clearance. Continue usual dosing with routine clinical review.
  • eGFR 10–30: Start at the lower end of the dose range and check a serum level after starting or changing the dose. Metabolites are renally cleared and may accumulate, so watch for nausea, tremor and arrhythmia.
  • eGFR 0–10: Use with caution, start at a reduced dose and monitor serum levels closely. Dialysis removes theophylline and levels fall during a session, so give replacement after dialysis if the level is low and recheck.
  • Hepatic impairment (mild): Hepatic metabolism is the main route of elimination. Start at the lower end of the usual dose range, review symptoms after a few days and check a serum level if response is poor or toxicity is suspected.
  • Hepatic impairment (moderate): Reduce the initial dose by roughly 25 to 50 per cent and titrate slowly against serum levels and clinical response. Clearance falls as hepatic function worsens, so the half-life is prolonged.
  • Hepatic impairment (severe): Reduce the dose by at least 50 per cent, or choose an alternative agent such as an inhaled bronchodilator or corticosteroid. If used, check levels frequently. Accumulation is unpredictable in decompensated liver disease and many formularies advise avoiding it.
Monitoring, pregnancy & toxicity
  • Serum theophylline concentration · 3 to 5 days after starting or changing a dose, and once at steady state. Target usually 10 to 20 mg/L (55 to 110 micromol/L).
  • Heart rate and cardiac rhythm · At each dose review and during any acute illness or breathlessness. ECG if palpitations or syncope.
  • Serum potassium · Baseline and during acute exacerbations or when beta-2 agonists, diuretics or corticosteroids are given concurrently.
  • Symptoms of toxicity (nausea, vomiting, tremor, insomnia, headache, restlessness) · At every review and whenever the dose is increased.
  • Interacting medicines and smoking status · At each prescribing change of any interacting drug or after a change in smoking.
  • Serum level after starting or stopping an interacting drug, or after a change in smoking · Within a few days of the change, since clearance can alter quickly.
  • Pregnancy: Inhaled corticosteroids and inhaled beta-2 agonists are preferred for asthma in pregnancy, and theophylline is not first line. If a woman is already stable on theophylline, it is usually reasonable to continue it, because clearance changes during pregnancy and stopping a drug that has been controlling symptoms risks an exacerbation. Clearance may rise or fall as pregnancy progresses, so check serum levels and adjust the dose on clinical grounds rather than using a fixed regimen. Review the need for treatment after delivery.
  • Toxicity: Gastrointestinal: nausea, vomiting, epigastric pain and haematemesis. These are often the earliest signs, but may be absent in chronic over-dosage. · Stop the drug. Give activated charcoal if the patient presents early, or later for sustained-release preparations, provided the airway is protected. Check a serum level and seek specialist toxicology advice.
  • Toxicity: Cardiovascular: sinus tachycardia, supraventricular and ventricular arrhythmias, hypotension and, in severe cases, cardiac arrest. · Continuous ECG monitoring and intravenous fluids for hypotension. Correct hypoxia and electrolytes. Refractory arrhythmia or shock is an indication for haemodialysis or haemoperfusion, so involve a toxicologist early.
  • Toxicity: Metabolic: hypokalaemia, hypomagnesaemia, hyperglycaemia and metabolic acidosis. Hypokalaemia can be profound but shifts back as the drug clears. · Replace potassium cautiously, guided by repeated measurements, because over-correction causes hyperkalaemia during recovery. Treat acidosis if severe. Multiple-dose activated charcoal increases elimination of sustained-release preparations.
  • Toxicity: Neurological: tremor, agitation, insomnia, confusion, hallucinations, seizures and coma. Seizures may be the first sign in chronic over-dosage and are a marker of severe poisoning. · Terminate seizures with a benzodiazepine and support the airway. Seizures, life-threatening arrhythmia or a very high level are indications for haemodialysis or haemoperfusion. Do not rely on the level alone to grade severity in chronic overdose.
Clinical notes
Theophylline has a narrow therapeutic index, so effective prescribing depends on dose individualisation and, in many settings, measurement of serum concentrations, sampled as a trough for sustained release preparations. Common toxicity includes nausea, vomiting, headache, tremor, palpitations and insomnia; higher concentrations cause tachyarrhythmias, hypokalaemia, hyperglycaemia, metabolic acidosis and seizures, which may occur without preceding gastrointestinal warning in chronic overdose. Loading doses are given intravenously as aminophylline with electrocardiographic and clinical monitoring, and maintenance infusions are adjusted for age, weight, cardiac and hepatic status, smoking and interacting drugs. For asthma, inhaled corticosteroids with a short-acting beta-2 agonist remain first line and theophylline is now a later add-on option, whereas it retains a role in some patients with chronic obstructive pulmonary disease and in apnoea of prematurity. Availability, formulations, monitoring practice and the extent of use vary considerably between countries and local formularies, so the current product information and local guidance should always be checked.

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BNF; local formulary; current manufacturer summary of product characteristics (SmPC) or prescribing information; national asthma and COPD guidelines