Theophylline and quinolone antibiotics: a recognised interaction

The UK prescribing information for theophylline (as a prolonged-release tablet) says it is indicated for the treatment and prevention of bronchospasm associated with asthma, chronic obstructive pulmonary disease and chronic bronchitis, and also for the treatment of left ventricular and congestive cardiac failure. It also says that theophylline should not be the first drug of choice for asthma in children.

Quinolones, also called fluoroquinolones, are antibiotics. The NHS describes ciprofloxacin as a broad-spectrum antibiotic used for a number of bacterial infections such as uncomplicated urinary tract infections where other antibiotics are not suitable, chest infections, skin and bone infections and others, and says that tablets and liquid are only used when no other antibiotics are suitable because of the risk of serious and long-term side effects. Other quinolones named by the NHS include levofloxacin, moxifloxacin and ofloxacin.

Because ciprofloxacin is used for infections including chest infections, and theophylline is used for asthma and COPD, the two medicines can be prescribed to the same person in the same period, sometimes by different clinicians. That is why the interaction needs to be known to patients as well as prescribers.

The theophylline summary of product characteristics says that the following medicines may increase theophylline plasma concentrations: cimetidine, ciprofloxacin, macrolide antibiotics such as erythromycin, propranolol, isoniazid, oral contraceptives, mexiletine, ranitidine and fluvoxamine. It also says that theophylline has been shown to interact with some quinolone antibiotics, including ciprofloxacin and enoxacin, which may result in elevated plasma theophylline levels.

The ciprofloxacin summary of product characteristics states that concurrent administration of ciprofloxacin and theophylline can cause an undesirable increase in serum theophylline concentration, which can lead to theophylline-induced side effects that may rarely be life threatening or fatal, and that during the combination serum theophylline concentrations should be checked and the dose reduced as necessary. It also explains that ciprofloxacin inhibits an enzyme, CYP1A2, and thus may increase the concentration of other substances metabolised by it, and names theophylline among them.

The Kent and Medway Joint Medicines Formulary, a local NHS prescribing reference, says that quinolones, as enzyme inhibitors, can cause several significant drug interactions including with theophylline, and that concomitant use of theophylline and ciprofloxacin is not recommended. Prescribers are therefore expected to choose a different antibiotic where possible or to monitor closely.

The theophylline prescribing information says theophylline has a low therapeutic index, which means the gap between a helpful and a harmful amount is small. It states that significant adverse reactions are usually seen at plasma theophylline levels greater than 20 micrograms/ml, and that monitoring of levels may be needed.

In its overdose section it lists alimentary symptoms (nausea, often severe vomiting, epigastric pain and vomiting blood), neurological symptoms (agitation, restlessness, convulsions and, in very severe cases, coma), cardiovascular symptoms (low blood pressure, a fast heart rate, ectopic beats and tachycardias) and metabolic changes such as low potassium. It warns that with prolonged-release products serious symptoms may develop as long as 12 hours after an overdose.

A raised level from an interaction is not the same as an overdose of tablets, but similar symptoms can occur as levels rise. Common side effects reported for theophylline include headache, tremor, palpitations, nausea, insomnia and agitation, according to the same document. If any of these become new or worse after starting an antibiotic, tell the prescriber or call NHS 111 rather than waiting.

The prescribing information adds that smoking and alcohol can increase clearance of theophylline, and that factors such as viral infections, liver disease and heart failure reduce clearance. It lists a reduction in dose as potentially necessary in elderly patients and notes that fever, exacerbations of lung disease and certain heart conditions may mean monitoring is needed. St John's wort is listed among medicines that increase clearance and so can reduce effectiveness.

This matters because a chest infection itself, the reason for the antibiotic, can change theophylline levels. The combination of illness and a new medicine is a time when monitoring is more important than usual, and why the prescriber may ask for a blood test.

The NHS says serious side effects of ciprofloxacin are rare but include changes in mood or behaviour, confusion, muscle weakness or pain or swelling in joints or tendons (often in the ankle or calf and possibly months after stopping), tingling or numbness, ringing in the ears, palpitations, and diarrhoea containing blood or mucus. It says to stop ciprofloxacin and call a doctor or 111 now for these, and to call 999 for sudden severe pain in the stomach, chest or back, or for seizures.

The Kent and Medway formulary notes the MHRA safety warnings that quinolones may induce convulsions in patients with or without a history of convulsions, and that taking NSAIDs at the same time may also induce them. Because theophylline can also lower the seizure threshold according to its own prescribing information, which says it may exacerbate seizures in people with a history of epilepsy, this is another reason the combination attracts caution.

Keep your theophylline on your repeat medicines list and mention it whenever you are offered an antibiotic, including at urgent care, out-of-hours services and pharmacies. If you are given a quinolone, ask whether the prescriber has considered theophylline, and whether a blood level is needed.

Do not stop theophylline or the antibiotic yourself without advice. The NHS says it is very important to keep taking ciprofloxacin until the course is finished, so raise any concern with the prescriber first. If you feel worse after starting the antibiotic, especially with palpitations, severe sickness, tremor or confusion, call 111 or your GP surgery, and call 999 for a seizure.

In the UK, theophylline is usually prescribed and monitored by the GP or a respiratory specialist, and antibiotics can come from GPs, out-of-hours services, community pharmacies under some schemes, and private clinics. The risk arises because several people may prescribe. Pharmacists check interactions when dispensing and are a good point of contact. A private prescriber has no automatic access to your NHS record, so bring your medicines list.