Risk of using the combination

Macrolides can interact with statins and increase the blood levels of the statin. Increased blood levels of statins can increase the risk of muscle disorders, such as myopathy and rhabdomyolysis.

Macrolide antibiotics can inhibit liver isoenzyme cytochrome P450 (CYP) 3A4. They can also inhibit hepatic statin uptake transporters, organic anion‐transporting polypeptide (OATP) 1B1 or 1B3.

HMG-CoA reductase inhibitors (statins) may be substrates of CYP and OATP.

Levels of affected statins will increase during concurrent treatment with the relevant macrolides and will gradually return to normal after the macrolide is stopped. Understanding enzyme or transporter-based interactions provides further information.

If a statin is stopped during macrolide treatment, it is usually appropriate to restart the statin as soon as the antibiotic course is finished.

Statin-related rhabdomyolysis is uncommon even when an interacting drug increases statin levels. After a statin-free interval, statin levels slowly rise and eventually reach a steady-state. This lower statin level period is likely to balance out an increase in levels due to the remains of the interaction.

It is also easier for patients to remember to restart their statin as soon as the antibiotic course is finished.

Myopathy

Myopathy is a muscle disease, in which the muscle fibres are affected and do not function properly. This leads to muscle weakness.

Rhabdomyolysis

Rhabdomyolysis, a severe form of myopathy, is the breakdown of muscle fibres resulting in release of muscle fibre contents (myoglobin) into the bloodstream. Raised levels of myoglobin can be harmful to the kidney and may result in kidney damage.

Rhabdomyolysis is rare, but can be fatal.

Azithromycin and statins

Azithromycin can be given concomitantly with statins. However, counsel patients to report any unexpected side effects.

Azithromycin does not inhibit CYP3A4, OATP1B1 or OATP1B3. It is not expected to increase blood levels of statins. However, there have been rare reports of rhabdomyolysis or interactions involving use of azithromycin with some statins.

Clarithromycin and statins

Clarithromycin inhibits CYP3A4, OATP1B1 and OATP1B3. It increases blood levels of statins metabolised by these pathways.

Atorvastatin

Avoid the use of clarithromycin with atorvastatin and use a non-interacting antibiotic if possible.

If clarithromycin is essential to use, consider the indication for atorvastatin; it may be possible to temporarily stop atorvastatin for the duration of the clarithromycin course.

Use a lower dose of atorvastatin (maximum 20mg daily) if concurrent administration is unavoidable.

Fluvastatin

Fluvastatin can be continued with clarithromycin.

Pravastatin

Use cautiously with clarithromycin. Counsel patients regarding possible risk of an interaction and monitor for adverse effects.

Rosuvastatin

Rosuvastatin can be continued with clarithromycin.

Simvastatin

Clarithromycin is contraindicated with simvastatin.

If clarithromycin is essential to use, simvastatin must be stopped whilst the patient is taking the course of clarithromycin.

Erythromycin and statins

Erythromycin inhibits CYP3A4, OATP1B1 and OATP1B3 and increases blood levels of statins metabolised by these pathways.

Atorvastatin

Avoid use of erythromycin with atorvastatin and use a non-interacting antibiotic if possible.

If erythromycin is essential to use, consider the indication for atorvastatin; it may be possible to temporarily stop atorvastatin for the duration of the erythromycin course.

Use a lower dose of atorvastatin (maximum 20mg daily) if concurrent administration is unavoidable.

Long-term use

If erythromycin is to be used long-term, for example as a prokinetic, switch to a non-interacting statin if possible.

Use a lower dose of atorvastatin (maximum 20mg daily) if concurrent administration is unavoidable.

Fluvastatin

Fluvastatin can be continued with erythromycin.

Pravastatin

Use cautiously with erythromycin. Counsel patients regarding possible risk of an interaction and monitor for adverse effects.

Rosuvastatin

Rosuvastatin can be continued with erythromycin.

Simvastatin

Erythromycin is contraindicated with simvastatin.

If erythromycin is essential to use, simvastatin must be stopped whilst the patient is taking the course of erythromycin.

Monitoring advice

Counsel patients for any signs of myopathy. Symptoms include unexplained muscle pain, tenderness, weakness, or dark coloured urine. If myopathy does occur, the statin should be stopped immediately.

Statin metabolic pathways

Understanding the metabolic pathway of the different statins will help inform clinical judgement when deciding on the most appropriate choice of treatment.

Atorvastatin

Atorvastatin is metabolised by CYP3A4 and is a substrate of both OATP1B1 and OATP1B3.

Fluvastatin

Fluvastatin is metabolised mainly by CYP2C9 and to a lesser extent by CYP3A4 and other isoenzymes. Fluvastatin is a substrate of both OATP1B1 and OAPT1B3.

Pravastatin

Pravastatin undergoes limited metabolism by the CYP isoenzymes. Pravastatin is a substrate of both OATP1B1 and OAPT1B3.

Rosuvastatin

Rosuvastatin undergoes limited metabolism with approximately 10% of the dose being metabolised principally by CYP2C9. Rosuvastatin is a substrate of both OATP1B1 and OATP1B3.

Simvastatin

Simvastatin is metabolised by CYP3A and is a substrate of OATP1B1.

Further information

The Medicines and Healthcare products Regulatory Agency (MHRA) have produced prescribing advice for starting and maintenance doses of atorvastatin and simvastatin when used with potent CYP3A4 inhibitors, such as clarithromycin and erythromycin.

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