4. Drug-Drug Interactions
Patient profiles will be monitored to identify regimens that may have clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for substance P/NK1 receptor antagonists are summarized in Table 4. Only those interactions classified as clinical significance level 1, contraindicated, or life threatening which have not been classified will be reviewed.
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level* |
|---|---|---|---|---|
| aprepitant | cisapride | concomitant use may increase risk of QT prolongation and torsades de points (TdP). Cisapride is a CYP3A4 substrate, and aprepitant may increase plasma concentrations of cisapride | use extreme caution if cisapride is used with IV fosaprepitant and monitor for cisapride-related adverse effects | contraindicated |
| aprepitant | CYP3A4 inducers (e.g., carbamazepine, rifampin) | adjunctive use may induce aprepitant metabolism and potential for reduced aprepitant serum levels and decreased aprepitant efficacy; CYP3A4 inducer activity may also be reduced, as aprepitant is also a CYP3A4 inducer | monitor patients for aprepitant efficacy; if needed, modify aprepitant dose or choose alternative anti-emetic without CYP3A4 inducer interaction; monitor CYP3A4 inducer activity and adjust dose as necessary | major |
| aprepitant | CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, nefazodone, clarithromycin, ritonavir) | combined use may result in reduced aprepitant metabolism, increased serum aprepitant levels, and the potential for adverse effects; however, aprepitant appears to be tolerated over a wide dosage range and is prescribed for short time periods | clinical significance of interaction not well defined; observe patients for increased aprepitant adverse effects and adjust dose if necessary | major |
| aprepitant | CYP3A4 substrates (e.g., aripiprazole, colchicine, diltiazem, phenytoin, ranolazine, ziprasidone) | combined use may result in elevated substrate plasma levels and potential for toxicity or loss of efficacy, as aprepitant is known CYP3A4 inhibitor and inducer and may interfere with metabolism of medications metabolized by CYP3A4 | use aprepitant cautiously with compounds metabolized by CYP3A4; monitor patients carefully for signs/ symptoms of substrate toxicity or loss of efficacy and adjust substrate dose as necessary | major |
| aprepitant | eliglustat | eliglustat is a CYP3A and CYP2D6 substrate. Coadministration may increase eliglustat exposure and risk of serious adverse effects | use is not recommended in patients with poor CYP2D6 or CYP3A4 metabolism. Dosing and frequency may need adjustments in intermediate and extensive metabolizers | contraindicated |
| aprepitant | flibanserin (Addyi) | combined use may lead to significant hypotension and syncope due to increased flibanserin serum levels as aprepitant is moderate CYP3A4 inhibitor and flibanserin is CYP3A4 substrate | avoid concurrent use for 2 weeks after the last dose of aprepitant, if initiating multi-day aprepitant following flibanserin use, start treatment at least 2 days after last dose of flibanserin | contraindicated |
| aprepitant | lomitapide | lomitapide concentrations may increase when co-administered with moderate CYP3A4 inhibitors | concomitant use of multi-day regimens of aprepitant with lomitapide is contraindicated. If treatment is unavoidable then lomitapide should be stopped during treatment | contraindicated |
| aprepitant | lonafarnib | lonafarnib is a CYP3A4 substrate and strong CYP3A4 inhibitor | concurrent use may increase exposure to both drugs and increase the risk of adverse effects | contraindicated |
| aprepitant | oral contraceptives (OC) | adjunctive use may result in reduced OC efficacy as AUC for both estrogen and progestin components may be reduced | alternative or back-up methods of contraception recommended during time that aprepitant is prescribed and for one month following last aprepitant dose | major |
| aprepitant | pimozide (Orap) | co-use may result in elevated plasma pimozide levels and increased risk for cardiac arrhythmias, QT interval prolongation, as aprepitant inhibits CYP3A4 (enzyme for pimozide metabolism) | adjunctive use contraindicated | contraindicated |
| aprepitant | phenytoin | combined use may result in reduced phenytoin levels and potential loss of seizure control as aprepitant induces CYP2C9, the enzyme that metabolizes phenytoin | administer cautiously together; observe for loss of seizure control | moderate |
| aprepitant | warfarin | co-administration may result in significant decreases in warfarin serum levels, INR and warfarin efficacy, as aprepitant induces CYP2C9, the enzyme involved in warfarin metabolism | monitor clotting status closely within 2-week period (especially 7 to 10 days) after each 3-day chemotherapy regimen or following single-dose therapy for PONV | moderate |
| netupitant/palonosetron (palonosetron component) | apomorphine (Apokyn) | adjunctive administration may result in hypotension and loss of consciousness due to additive hypotensive effects | avoid combined use | contraindicated |
| netupitant/palonosetron (netupitant component), rolapitant | strong CYP3A4 inducers (e.g., rifampin) | concurrent use may reduce netupitant, rolapitant efficacy with reduced serum levels due to CYP3A4-induced netupitant, rolapitant metabolism | avoid co-administration | major |
| netupitant/palonosetron (netupitant component) | CYP3A4 inhibitors | combined administration with strong CYP3A4 inhibitors may increase serum netupitant levels as netupitant is metabolized by CYP3A4; netupitant is CYP3A4 inhibitor and may increase concentrations of other medications | no netupitant dosage adjustment necessary due to single dose therapy; monitor for enhanced pharmacologic/ adverse effects and adjust dosages of other medications as necessary | moderate |
| netupitant/palonosetron (netupitant component) | CYP3A4 substrates | adjunctive use may result in enhanced substrate pharmacologic/ adverse effects as netupitant is CYP3A4 inhibitor and may increase concentrations of other medications | use cautiously together; monitor for enhanced pharmacologic/ adverse effects and adjust substrate dosages as necessary | moderate to major |
| netupitant/ palonosetron (netupitant component) | flibanserin (Addyi) | combined use may lead to significant hypotension and syncope due to increased flibanserin serum levels as netupitant is moderate CYP3A4 inhibitor and flibanserin is CYP3A4 substrate | avoid concurrent use for 1 week, if possible; if combined use necessary, consider CYP3A4 substrate dose reduction | contraindicated |
| netupitant/palonosetron (netupitant component) | lonafarnib | lonafarnib is a CYP3A4 substrate and strong CYP3A4 inhibitor | concurrent use may increase exposure to both drugs and increase the risk of adverse effects | contraindicated |
| netupitant/palonosetron (palonosetron component) | serotonergic agents | potential for serotonin syndrome with combined therapy due to additive serotonergic effects with palonosetron | monitor for signs/ symptoms of serotonin syndrome (e.g., hyperthermia, hypertension, rigidity) and discontinue combined therapy, if symptoms present | moderate - major |
| rolapitant | breast cancer resistant protein (BCRP) substrates with narrow therapeutic index (e.g., methotrexate, topotecan) | combined use may increase BCRP substrate levels and potential for adverse effects as rolapitant is BCRP inhibitor | avoid use, if possible; if adjunctive use necessary, monitor for BCRP substrate adverse events | Moderate to major |
| rolapitant | p-glycoprotein substrates with narrow therapeutic index (e.g., digoxin) | combined use may increase p-glycoprotein substrate levels and potential for adverse effects as rolapitant is p-glycoprotein inhibitor | avoid use, if possible; if adjunctive use necessary, monitor for p-glycoprotein substrate adverse events | Minor to major |
| rolapitant | pimozide | concurrent administration may increase risk of pimozide-associated QT interval prolongation/ torsades de pointes as pimozide metabolized by CYP2D6 and rolapitant is CYP2D6 inhibitor | avoid combined use, if possible; if concomitant use necessary, monitor for pimozide adverse effects | contraindicated |
| rolapitant | other CYP2D6 substrates | combined use may increase CYP2D6 substrate levels and potential for adverse effects as rolapitant is CYP2D6 inhibitor | use cautiously together; monitor for enhanced pharmacologic/ adverse effects and adjust substrate dosages as necessary | major |
| rolapitant | St. John’s wort, Hypericum perforatum | St. John’s wort is a strong CYP3A4 inducer | avoid concurrent use | contraindicated |
| rolapitant | thioridazine | combined administration may increase risk of QT interval prolongation/ torsades de pointes with thioridazine as rolapitant CYP3A4 inhibitor and thioridazine CYP3A4 substrate | avoid concurrent use | contraindicated |
Legend:
- *CP = Clinical Pharmacology