4. Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered most significant for HMG-CoA reductase inhibitors are summarized in Table 4. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level |
|---|---|---|---|---|
| HMGs | cyclosporine | co-administration may lead to increased HMG concentrations and potential for enhanced pharmacologic/ adverse effects (e.g., MYO, RHAB) due to inhibition of HMG metabolism (CYP3A4; OATP1B1) by cyclosporine (CYP3A4, OATP1B1 inhibitor) | avoid adjunctive therapy, if possible; if combined therapy necessary, monitor for signs/symptoms of MYO, RHAB; use lowest recommended HMG doses; fluvastatin may be alternative as metabolized by CYP2C9 and not affected by OATP1B1 | contraindicated: pitavastatin, red yeast rice, simvastatin major: atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin |
| HMGs | fibric acid derivatives (e.g., fenofibrate, gemfibrozil) | adjunctive administration may elevate HMG serum levels, with increased risk of severe MYO, RHAB, due to inhibition of HMG metabolism (CYP2C8; OATP1B1) by gemfibrozil (CYP2C8, OATP1B1 inhibitor), or additive myopathy risk (fibrates) | avoid combination, if possible; if concurrent therapy necessary, use cautiously, closely monitor creatine kinase and observe for MYO, RHAB; use lowest recommended HMG doses | major: fluvastatin, red yeast rice moderate: atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, |
| HMGs | protease inhibitors | adjunctive administration may increase HMG serum levels and elevate potential for enhanced pharmacologic/adverse effects (e.g., MYO, RHAB) due to CYP3A4 inhibition and other unknown mechanisms | avoid combination therapy, if possible; if combined therapy necessary, monitor for increased adverse effects (e.g., MYO, RHAB) and use lowest recommended HMG dose; may consider pravastatin, an HMG not metabolized by CYP3A4 | contraindicated: lovastatin, simvastatin major: atorvastatin, rosuvastatin moderate: fluvastatin, pravastatin |
| Select HMGs | amiodarone | combined administration may increase risk of HMG adverse effects [e.g., myopathy (MYO), rhabdomyolysis (RHAB)] most likely due to inhibition of HMG metabolism (CYP3A4, CYP2C9) by amiodarone (CYP3A4, CYP2C9 inhibitor) | monitor for MYO, RHAB; use lowest recommended HMG doses; consider using HMG not metabolized by CYP3A4 or CYP2C9, such as pravastatin, if drug combination necessary | major: lovastatin, simvastatin moderate: atorvastatin, fluvastatin, pitavastatin |
| Select HMGs | azole antifungals | combined administration may lead to increased HMG concentrations and potential for enhanced pharmacologic/adverse effects (e.g., MYO, RHAB) due to inhibition of HMG metabolism (CYP3A4) by azole antifungals (CYP3A4 inhibitor); fluvastatin with increased risk of adverse effects when prescribed with fluconazole, voriconazole (CYP2C9 inhibitors) | posaconazole-HMG combination is contraindicated due to increased risk of MYO/RHAB; avoid adjunctive therapy, if possible with other combinations; if combined therapy necessary, monitor for signs/symptoms of MYO, RHAB; may consider using HMG not metabolized by CYP3A4, CYP2C9 such as pravastatin | contraindicated: atorvastatin (posaconazole), red yeast rice, lovastatin (posaconazole, voriconazole), simvastatin (posaconazole, voriconazole) major: atorvastatin (voriconazole, fluvastatin moderate: atorvastatin, lovastatin, simvastatin |
| Select HMGs | macrolide antibiotics | macrolides (CYP3A4, OATP1B1 inhibitors) prescribed with HMGs metabolized by CYP3A4 or OATP1B1 may increase HMG serum levels and elevate potential for enhanced pharmacologic/adverse effects (e.g., MYO, RHAB) | avoid macrolides with HMGs metabolized by CYP3A4, OATP1B1, if possible; pravastatin, rosuvastatin not metabolized by CYP3A4 and may be alternative HMGs; if combination necessary, monitor for MYO, RHAB | contraindicated: lovastatin (clarithromycin, erythromycin), pravastatin (clarithromycin), red yeast rice (clarithromycin, erythromycin), simvastatin (clarithromycin, erythromycin) major: atorvastatin (clarithromycin),fluvastatin (erythromycin), pitavastatin (erythromycin) moderate: atorvastatin (erythromycin), fluvastatin (clarithromycin), pravastatin (azithromycin, erythromycin), rosuvastatin (clarithromycin) |
| Select HMGs | CYP3A4 inhibitors (e.g., diltiazem, imatinib, nefazodone, verapamil, non-nucleoside reverse transcriptase inhibitors (NNRTI)) | CYP3A4 inhibitors administered with HMGs metabolized by CYP3A4 may increase HMG serum levels and elevate potential for enhanced pharmacologic/ adverse effects (e.g., MYO, RHAB) | avoid CYP3A4 inhibitors with HMGs metabolized by CYP3A4, if possible; pravastatin, pitavastatin rosuvastatin not metabolized by CYP3A4 and may be alternative HMGs; if combination necessary, use lowest recommended dose and monitor for MYO, RHAB | contraindicated: lovastatin: adagrasib, ceritinib, idelalisib, lonafarnib, mifepristone, nefazodone, ribociclib, tucatinib simvastatin: adagrasib, ceritinib, danazol, gemfibrozil, idelalisib, lonafarnib, mifepristone, nefazodone, ricociclib, tucatinib |
Legend:
- *CP = Clinical Pharmacology
- HMG = HMG CoA reductase inhibitor
- MYO = myopathy
- NNRT = non-nucleoside reverse transcriptase
- RHAB = rhabdomyolysis