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Table 1 Lopinavir/ritonavir interactions with drugs commonly used in the intensive-care unit

From: Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial

Drug

Possible interaction

Management

Action at enrollment

Action after enrollment

Amiodarone

Increased risk of amiodarone toxicity (hypotension, bradycardia, sinus arrest).

Increased QT-interval prolongation

Concurrent use is contraindicated

At the time of enrollment, amiodarone therapy with no alternative is an exclusion criterion

Consider alternatives to amiodarone.

If no alternative to amiodarone is available, consider using a reduced dose.

Monitor for increased amiodarone serum concentrations, altered liver function test results and evidence of QT-interval prolongation

Fentanyl

Concurrent use of fentanyl and CYP3A4 inhibitors may result in an increased risk of fentanyl toxicity, resulting in fatal respiratory depression

In non-mechanically ventilated patients, concurrent use is contraindicated.

In mechanically ventilated patients, avoid fentanyl or use reduced doses

Consider alternatives to fentanyl.

Use lower doses and adjust the dose to target analgesia and sedative effects

Consider alternatives to fentanyl.

Use lower doses and adjust the dose to target analgesia and sedative effects

Fluconazole

Increased ritonavir exposure and risk of QT-interval prolongation

Avoid concomitant use if possible

If fluconazole is required, closely monitor electrocardiogram for QT-interval prolongation

Use alternatives to fluconazole

Use alternatives to fluconazole.

Fluconazole-mediated CYP3A4 inhibition may continue for 4–5 days after discontinuation because of its long half-life

Midazolam

Increased midazolam plasma concentrations, which can lead to midazolam toxicity

In non-mechanically ventilated patients, concurrent use is contraindicated.

In mechanically ventilated patients, avoid use of midazolam if possible. If needed, use reduced midazolam doses and monitor effects

Consider alternatives to midazolam.

Use lower doses and adjust the dose to target sedative effects

Consider alternatives to midazolam.

Use lower doses and adjust the dose to target sedative effects.

If the concomitant use of midazolam and lopinavir/ritonavir is required, closely monitor patients for midazolam adverse effects (excessive sedation, confusion and respiratory depression) and consider using a reduced midazolam dose

Quetiapine

Increased risk of QT-interval prolongation, torsades de pointes or other notable ventricular tachyarrhythmias

Concomitant administration is contraindicated

Use alternatives to quetiapine

Use alternatives to quetiapine.

If concomitant use is required, reduce the quetiapine dose to one sixth of the standard dose, and when the lopinavir/ritonavir is discontinued, the dose of quetiapine should subsequently be increased to the standard dose

Rifampin

Decreased lopinavir/ritonavir plasma concentrations.

Rifampin may enhance the toxic effect of lopinavir, specifically increasing the risk of hepatocellular toxicity

Concurrent use is contraindicated

If concomitant use is required, rifabutin 150 mg every other day or 150 mg three times a week is recommended for concomitant use with lopinavir/ritonavir

If concomitant use is required, rifabutin 150 mg every other day or 150 mg three times a week is recommended for concomitant use with lopinavir/ritonavir

Sildenafil

Increased sildenafil plasma levels, thereby increasing the risk for sildenafil adverse effects (hypotension, visual changes and priapism)

Concurrent use of lopinavir/ritonavir and sildenafil is contraindicated

Stop sildenafil if possible. If not possible, sildenafil use is an exclusion criterion for this study

Do not use sildenafil

Simvastatin

Increased risk of myopathy or rhabdomyolysis

Concomitant use of lopinavir/ritonavir with simvastatin is contraindicated

Stop simvastatin if possible. If needed, consider fluvastatin, pitavastatin or pravastatin as alternatives, because these drugs have the least potential for interaction

Do not use simvastatin. If needed, consider fluvastatin, pitavastatin or pravastatin as alternatives, because these drugs have the least potential for interaction

Atorvastatin

Atorvastatin AUC increased by 488%. Increased risk of myopathy or rhabdomyolysis

Monitor for signs of atorvastatin toxicity (rhabdomyolysis and myopathy)

Consider discontinuation of atorvastatin. If discontinuation is not possible, use with caution at the lower end of the dosing range (10–40 mg per day)

Consider alternative agents (pravastatin, fluvastatin or rosuvastatin), because these drugs have the least potential for interaction

Voriconazole

Decreased plasma concentrations of voriconazole and decreased voriconazole efficacy

Concomitant administration is contraindicated

Use alternatives to voriconazole. If no alternative exists, voriconazole use is an exclusion criterion for this study

Use alternatives to voriconazole or use with therapeutic drug monitoring. Voriconazole dose may need to be increased. If no alternative is available, discontinue lopinavir/ritonavir and continue the use of IFN-β1b.

Consider another antifungal for aspergillosis

Phenytoin

Both phenytoin and ritonavir plasma concentrations may be decreased

Use with caution

Use with caution

Monitor phenytoin levels during co-administration. Adjustment of the phenytoin or fosphenytoin dose may be warranted

  1. The information in this table was obtained from Lexicomp (http://www.wolterskluwercdi.com/lexicomp-online/) and Micromedex (https://www.micromedexsolutions.com/home/dispatch). Abbreviations: AUC area under the (receiver operating characteristic) curve, CYP3A4 cytochrome P450-3A4