Effects of Other Drugs on Ranolazine
In vivo studies in healthy volunteers confirm that ranolazine is primarily metabolized by CYP3A. Plasma levels of ranolazine with Ranexa 1000 mg b.i.d. are increased 3.2-fold by the potent CYP3A inhibitor ketoconazole co-administered at a dose of 200 mg b.i.d. Plasma levels of ranolazine with Ranexa 1000 mg b.i.d. are increased about 1.8- to 2.3-fold by the moderately potent CYP3A inhibitor diltiazem given in daily doses from 180 to 360 mg, respectively. Plasma levels of ranolazine with Ranexa 750 mg b.i.d. are increased about 2-fold by the CYP3A and P-gp inhibitor verapamil given at a dose of 120 mg t.i.d.
Ketoconazole, diltiazem, verapamil (also a P-gp inhibitor) and other potent or moderately potent CYP3A inhibitors should not be co-administered with Ranexa (see WARNINGS) .
Less potent CYP3A inhibitors such as simvastatin (20 mg q.d.) and cimetidine (400 mg t.i.d.) do not increase the exposure to ranolazine in healthy volunteers receiving Ranexa.
No specific studies of ranolazine with CYP3A inducers have been conducted.
In vitro studies indicate that ranolazine is a P-gp substrate. Caution should be exercised when co-administering ranolazine and P-gp inhibitors such as ritonavir and cyclosporine (see PRECAUTIONS). The potent CYP2D6 inhibitor paroxetine, at a dose level of 20 mg q.d., increased ranolazine concentrations 1.2-fold in healthy volunteers receiving Ranexa 1000 mg b.i.d. No dose adjustment of Ranexa is necessary when it is co-administered with drugs inhibiting CYP2D6.
Plasma concentrations of ranolazine are not significantly altered by concomitant digoxin at 0.125 mg q.d.
Effects of Ranolazine on Other Drugs
In vitro studies indicate that ranolazine and its O-demethylated metabolite are inhibitors of CYP3A and CYP2D6. Ranolazine and its most abundant metabolites are not known to inhibit the metabolism of substrates for CYP1A2, 2C9, 2C19 or 2E1 in human liver microsomes, suggesting that ranolazine is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.
The plasma levels of simvastatin, a CYP3A substrate, and its active metabolite are each increased about 2-fold in healthy subjects receiving simvastatin 80 mg q.d. and Ranexa 1000 mg b.i.d. (see DOSAGE AND ADMINISTRATION).
The pharmacokinetics of diltiazem are not affected by ranolazine in healthy volunteers receiving diltiazem 60 mg t.i.d. and Ranexa 1000 mg b.i.d.
The inhibitory effects of ranolazine on CYP2D6 have been evaluated in extensive metabolizers of dextromethorphan. The study showed that ranolazine and/or metabolites partially inhibit CYP2D6. Concomitant use of Ranexa with other drugs metabolized by CYP2D6, such as tricyclic antidepressants and antipsychotics, has not been formally studied, but lower doses of the other drug than usually prescribed may be required in the presence of ranolazine (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
In vitro studies suggest that ranolazine is a P-gp inhibitor. In vivo ranolazine increases digoxin concentrations 1.5-fold in healthy volunteers receiving Ranexa 1000 mg b.i.d. and digoxin 0.125 mg q.d. The dose of digoxin may have to be adjusted when ranolazine is co-administered with digoxin (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).