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  • CLASSES

    Anti-anginal Agents, other

    DEA CLASS

    Rx

    DESCRIPTION

    Novel, oral antianginal for chronic angina; partial fatty-acid oxidation (PFox) inhibitor with additional ability to inhibit late sodium current resulting in a reduction of the intracellular sodium and calcium overload in ischemic myocytes.

    COMMON BRAND NAMES

    Ranexa

    HOW SUPPLIED

    Ranexa Oral Tab ER: 500mg, 1000mg

    DOSAGE & INDICATIONS

    For the treatment of chronic angina.
    NOTE: The concomitant use of ranolazine and CYP3A inducers or strong CYP3A inhibitors is contraindicated.
    NOTE: The effects of ranolazine on angina frequency and exercise tolerance are considerably smaller in women than in men.
    Oral dosage
    Adults

    500 mg PO twice daily. Based on clinical symptoms, the dose may be increased up to the maximum dose of 1,000 mg PO twice daily if needed. The ERICA trial utilized this dosing schedule, escalating to the higher dose after 1 week. Closely monitor clinical response. The concomitant use of ranolazine with other commonly administered cardiovascular medications that are not contraindicated (amlodipine, beta-blockers, nitrates, anti-hypertensive agents) is well-tolerated. The first placebo controlled trial (MARISA), which showed beneficial antianginal effects of ranolazine monotherapy, utilized a broader dosage range (500 to 1,500 mg PO twice daily).. However, doses higher than 1,000 mg PO twice daily are not currently recommended due to the risk of QT prolongation and potential for proarrhythmic effects. The subsequent ERICA trial showed statistically significant reductions in angina frequency and nitroglycerin use in patients treated with ranolazine 500 to 1,000 mg twice daily as add-on therapy for chronic angina patients refractory to amlodipine 10 mg once daily. The efficacy of ranolazine is primarily based on the CARISA trial which showed a significant improvement in exercise duration and angina symptoms with added ranolazine (vs. placebo) in patients already taking antianginal therapy. The CARISA trial randomized patients to receive placebo or fixed doses of 750 or 1,000 mg PO twice daily as add-on therapy to traditional antianginal agents. The patients were allowed to receive 1 prior antianginal therapy (i.e., atenolol, diltiazem, or amlodipine) concurrently to assess safety and efficacy.

    Adult patients taking diltiazem, verapamil, aprepitant, erythromycin, or fluconazole

    Limit the dose to 500 mg PO twice daily. The dose modification may apply to other drugs that moderately inhibit CYP3A4.

    Geriatric

    See adult dosage. Initiate therapy at the lower end of the adult dosage range.

    For the treatment of acute coronary syndromes in patients with acute myocardial infarction, NSTEMI†.
    Intravenous† and Oral dosage

    NOTE: The IV formulation is not available in the US.

    Adults

    Dosage not established. Within 48 hours of ischemic symptoms, patients were randomized to ranolazine 200 mg IV bolus over 1 hour then 80 mg/hour IV infusion for 12 to 96 hours followed by 1,000 mg PO twice daily or placebo. There was no significant difference in the primary efficacy endpoint of composite cardiovascular death, myocardial infarction, or recurrent ischemia.

    For the treatment of acute coronary syndromes in patients with unstable angina†.
    Intravenous† and Oral dosage

    NOTE: The IV formulation is not available in the US.

    Adults

    Dosage not established. Within 48 hours of ischemic symptoms, patients were randomized to ranolazine 200 mg IV bolus over 1 hour then 80 mg/hour IV infusion for 12 to 96 hours followed by 1,000 mg PO twice daily or placebo. There was no significant difference in the primary efficacy endpoint of composite cardiovascular death, myocardial infarction, or recurrent ischemia.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2000 mg/day PO.

    Elderly

    2000 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Ranolazine is contraindicated in patients with hepatic cirrhosis.

    Renal Impairment

    No specific dosage adjustments are recommended by the manufacturer. Periodic monitoring of renal function is recommended in patients with moderate to severe renal impairment (CrCl < 60 ml/min). Ranolazine should be discontinued if acute renal failure develops.
     
    Intermittent hemodialysis
    Since ranolazine is about 62% bound to plasma proteins, complete clearance by hemodialysis is not likely.

    ADMINISTRATION

    NOTE: Do NOT use ranolazine to relieve an acute angina episode. Ranolazine is a maintenance medication for angina and it must be administered on a regularly scheduled basis to reduce the symptoms of chronic stable angina.
     

    Oral Administration

    Administer with or without meals.
    Limit grapefruit juice during ranolazine administration (see Interactions).

    Oral Solid Formulations

    Extended-release tablets should be swallowed whole; do not crush, break, cut, or chew.

    STORAGE

    Ranexa:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Ranolazine is extensively metabolized to numerous metabolites, and has potential for multiple and complex cytochrome (CYP) P450 drug interactions (see Drug Interactions). Ranolazine is also associated with potential for drug interactions based on its propensity to prolong the QT interval. Ranolazine should be used with caution in patients receiving QT prolonging drugs. It is also contraindicated for use with inducers of CYP3A and strong CYP3A inhibitors (see Drug Interactions). Furthermore, the dose of ranolazine should be limited to 500 mg PO twice daily in patients taking moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, fluconazole and grapefruit juice (see Drug Interactions and Dosage).
     
    Efficacy and safety have not been evaluated for racial subgroups; there have been insufficient numbers of non-Caucasian patients enrolled during clinical trials of ranolazine.
     
    Ranolazine is not known to interfere with any laboratory test.

    Hepatic disease

    Because the QTc prolonging effect is increased by approximately 3-fold in cirrhotic patients with mild to moderate hepatic disease, ranolazine is contraindicated in patients with hepatic cirrhosis. In cirrhotic patients with mild hepatic impairment (Child-Pugh score A) or moderate hepatic impairment (Child Pugh score B), the ranolazine Cmax was increased by 30% and 80%, respectively, compared to patients without hepatic impairment; however, the manufacturer states that this increase alone is not enough to account for the 3-fold increase in prolonged QT interval seen in this patient population.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Ranolazine causes dose- and plasma concentration-related increases in the QTc interval. Use ranolazine with caution in patients with pre-existing QT prolongation, history of torsade de pointes, a family history of long QT syndrome, or congenital long QT syndrome. Further, use ranolazine with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Women, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation. The risk of QT prolongation is approximately 3-fold higher in patients with hepatic cirrhosis. The mean increase in QTc is about 6 msec, measured at the Tmax of the maximum dosage (1000 mg twice daily); however, in 5% of the population studied, increases in the QTc of >= 15 msec have been reported. Age, weight, gender, race, heart rate, CHF (NYHA Class I to IV), impairment of renal function, and diabetes have no significant effect on the relationship between ranolazine plasma concentration and increase in QTc interval. The relationship between ranolazine concentrations and QTc remains linear over a concentration range up to 4-fold greater than the concentrations produced by the maximum dosage (1000 mg twice daily), and is not affected by changes in heart rate. In data received from 7-day Holter monitor recordings in ACS patients, there was a significantly lower incidence of arrhythmias in patients treated with ranolazine vs. placebo. This difference in proarrhythmic events, however, did not result in reductions in mortality, hospitalization due to arrhythmia, or arrhythmia symptoms. Limited data are available on ranolazine and the potential for QT interval prolongation when used at high doses (> 1000 mg twice daily), long exposure, with QT interval-prolonging drugs, with potassium channel variants causing prolonged QT interval, in patients with a family history of long QT syndrome, or in patients with known acquired QT prolongation.

    Females

    In addition to the higher risk of drug-induced torsade de pointes demonstrated for females , the beneficial effects of ranolazine on angina frequency and exercise tolerance are considerably smaller in females than in males. In the CARISA trial, the improvement in Exercise Tolerance Test (ETT) in females was about 33% of that in males at the 1000 mg twice daily dosage. In the ERICA trial, the mean reduction in weekly anginal attacks was 0.3 for females and 1.3 for males. Since women generally also have a higher risk of developing drug-induced torsade de pointes , it is prudent to closely weigh the risks and benefits of ranolazine therapy before prescribing for females with chronic angina.

    Renal failure, renal impairment

    Monitor renal function after initiation and periodically for increases in serum creatinine accompanied by an increase in BUN in patients with moderate to severe renal impairment (CrCl < 60 ml/min). Discontinue ranolazine and initiate appropriate treatment if acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in BUN). Acute renal failure has been observed in patients with severe renal impairment (i.e., CrCl < 30 ml/min). A pharmacokinetic study of ranolazine in patients with severe renal impairment was stopped when 2 of 4 subjects developed acute renal failure after receiving ranolazine 500 mg twice daily for 5 days followed by 1000 mg twice daily. Increases in creatinine, BUN, and potassium were observed in 3 subjects during the 500 mg lead-in phase. Two subjects improved upon discontinuation of the drug while one subject required hemodialysis. In a separate study, compared to patients without renal impairment, Cmax was increased 40—50% in patients with mild, moderate or severe renal impairment, suggesting a similar increase in exposure in patients with renal failure independent of the degree of impairment. The pharmacokinetics of ranolazine have not been assessed in patients on dialysis.

    Driving or operating machinery, syncope

    Dizziness is common during ranolazine therapy; syncope may also occur infrequently (see Adverse Reactions). Patients should use caution when driving or operating machinery until they are aware of the effects of the medication.

    Geriatric

    No overall differences in efficacy were observed between geriatric and younger patients. There were no differences in safety for patients >= 65 years compared to younger patients, but patients >= 75 years of age on ranolazine, compared to placebo, appeared to have a higher incidence of adverse events, serious adverse events, and drug discontinuations due to adverse events. In controlled ranolazine studies, the placebo-subtracted incidence of any adverse event in patients >= 75 years old treated with ranolazine was 23%, and 11% discontinued ranolazine due to unacceptable adverse events. In CARISA and ERICA, the most commonly reported placebo-subtracted adverse events in patients >= 75 years old on ranolazine included constipation (19%), nausea (6%), and dizziness (6%). In general, dose selection for an elderly patient should be cautious, starting at the low end of the adult dosing range.

    Pregnancy

    There are no data on the use of ranolazine during pregnancy to inform any drug-associated risks. Animal studies have shown fetal toxicity (decreased fetal weight and reduced ossification) and maternal weight loss at doses 4 times the maximum recommended human dose (MRHD). No adverse effects were observed when animals were administered doses equal to the MRHD.

    Breast-feeding

    There are no data on the presence of ranolazine in human milk, the effects on the breast-fed infant, or the effects on milk production. Ranolazine is present in rat milk. Adult female rats were administered ranolazine from gestation through postnatal day 20. At maternally toxic doses, male and female pups exhibited increased mortality and decreased body weight, and female pups showed increased motor activity. The pups were potentially exposed to low amounts of ranolazine via maternal milk. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for ranolazine and any potential adverse effects on the breast-fed infant from ranolazine or from the underlying maternal condition.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 0.5-4.0
    azotemia / Delayed / 0-0.5
    renal failure (unspecified) / Delayed / 0-0.5
    pancytopenia / Delayed / 0-0.5
    pulmonary fibrosis / Delayed / 0-0.5
    angioedema / Rapid / 0-0.5

    Moderate

    constipation / Delayed / 4.5-4.5
    confusion / Early / 0.5-4.0
    hypotension / Rapid / 0.5-4.0
    palpitations / Early / 0.5-4.0
    orthostatic hypotension / Delayed / 0.5-4.0
    peripheral edema / Delayed / 0.5-4.0
    blurred vision / Early / 0.5-4.0
    hematuria / Delayed / 0.5-4.0
    dyspnea / Early / 0.5-4.0
    leukopenia / Delayed / 0-0.5
    eosinophilia / Delayed / 0-0.5
    thrombocytopenia / Delayed / 0-0.5
    hallucinations / Early / Incidence not known
    QT prolongation / Rapid / Incidence not known
    hypoglycemia / Early / Incidence not known
    urinary retention / Early / Incidence not known
    dysuria / Early / Incidence not known

    Mild

    dizziness / Early / 6.2-6.2
    headache / Early / 5.5-5.5
    nausea / Early / 4.4-4.4
    syncope / Early / 0.5-4.0
    asthenia / Delayed / 0.5-4.0
    vertigo / Early / 0.5-4.0
    tinnitus / Delayed / 0.5-4.0
    dyspepsia / Early / 0.5-4.0
    abdominal pain / Early / 0.5-4.0
    xerostomia / Early / 0.5-4.0
    anorexia / Delayed / 0.5-4.0
    vomiting / Early / 0.5-4.0
    hyperhidrosis / Delayed / 0.5-4.0
    hypoesthesia / Delayed / 0-0.5
    tremor / Early / 0-0.5
    paresthesias / Delayed / 0-0.5
    rash (unspecified) / Early / Incidence not known
    pruritus / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval such as abarelix.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with ranolazine which inhibits CYP2D6. Monitor therapeutic response during coadministration.
    Acetaminophen; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with ranolazine which inhibits CYP2D6. Monitor therapeutic response during coadministration.
    Acetaminophen; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) Oxycodone is metabolized in part by cytochrome P450 2D6 to oxymorphone, which represents < 15% of the total administered dose. Ranolazine and/or metabolites partially inhibit CYP2D6 isoenzymes based on data available. Although the concomitant use of ranolazine with oxycodone has not been studied, ranolazine may theoretically increase plasma concentrations of oxycodone, Studies of interactions with other CYP2D6 inhibitors and oxycodone have not demonstrated clinical significance.
    Acetaminophen; Propoxyphene: (Moderate) Ranolazine may theoretically increase plasma concentrations of drugs that are CYP2D6 substrates, like propoxyphene. Lower doses of propoxyphene than are usually prescribed may be needed during therapy with ranolazine. Monitor therapeutic response during coadministration.
    Acetaminophen; Tramadol: (Moderate) As ranolazine is a weak to moderate CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Afatinib: (Major) If the concomitant use of ranolazine and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of ranolazine. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and ranolazine is a P-gp inhibitor in vitro; coadministration may increase plasma concentrations of afatinib. Concomitant use of ranolazine (1000 mg twice daily) and another P-gp substrate, digoxin (0.125 mg daily), increased digoxin concentrations by 50% in healthy volunteers. Administration of the P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Albuterol: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Albuterol; Ipratropium: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Alfentanil: (Moderate) Alfentanil is metabolized by the cytochrome P450 isoenyzme. In vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of administering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, such as alfentanil, potentially leading to adverse reactions such as increased CNS or respiratory depression.
    Alfuzosin: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include alfuzosin. In addition, alfuzosin is primarily metabolized by CYP3A4 hepatic enzymes; inhibitors of CYP3A4, such as ranolazine, may inhibit alfuzosin metabolism and increase systemic exposure to alfuzosin.
    Alogliptin; Metformin: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Alprazolam: (Moderate) In patients taking drugs that inhibit CYP3A isoenzymes, use alprazolam with caution and consider alprazolam dose reduction (up to 50% dose reduction may be needed). Ranolazine may theoretically inhibit CYP3A4 metabolism of alprazolam.
    Amantadine: (Moderate) Coadminister ranolazine and amantadine with caution. Amantadine is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the amantadine dose may be necessary.
    Amiloride: (Moderate) Coadminister ranolazine and amiloride with caution. Amiloride is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the amiloride dose may be necessary.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Coadminister ranolazine and amiloride with caution. Amiloride is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the amiloride dose may be necessary.
    Amiodarone: (Major) Ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, amiodarone is known to inhibit CYP3A4 and CYP2D6. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval, such as amiodarone. Although the frequency of torsades de pointes (TdP) is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.Amiodarone also can increase the absorption of ranolazine via inhibition of P-glycoprotein transport.
    Amitriptyline; Chlordiazepoxide: (Moderate) CYP3A4 inhibitors like ranolazine may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Amlodipine; Atorvastatin: (Moderate) Ranolazine inhibits CYP3A isoenzymes and P-glycoprotein transport. Although not studied, ranolazine may theoretically increase plasma concentrations of CYP3A4 and/or P-glycoprotein substrates such as atorvastatin. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
    Amoxicillin; Clarithromycin; Lansoprazole: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including clarithromycin. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Furthermore, clarithromycin may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
    Amoxicillin; Clarithromycin; Omeprazole: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including clarithromycin. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Furthermore, clarithromycin may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
    Amprenavir: (Severe) Ranolazine is primarily metabolized by CYP3A, but it is also a substrate of P-glycoprotein. Ranolazine is contraindicated for use with moderate or potent inhibitors of CYP3A isoenzymes, including amprenavir. Ranolazine is associated with dose and plasma concentration-related increases in the QTc interval. Coadministration with amprenavir may increase the plasma concentrations of ranolazine, thus increasing the risk of drug toxicity and proarrhythmic effects.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include ranolazine.
    Apomorphine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include apomorphine. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. In one study, a single mean dose of 5.2 mg (range 2-10 mg) prolonged the QT interval by about 3 msec. However, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    Aprepitant, Fosaprepitant: (Major) The dose of ranolazine should be limited to 500 mg PO twice daily when coadministered with moderate CYP3A4 inhibitors, such as a multi-day regimen of aprepitant. Monitor for an increase in ranolazine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Ranolazine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of ranolazine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Ranolazine is also a weak in vitro CYP3A4 inhibitor in vitro and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
    Arformoterol: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Aripiprazole: (Major) Because both ranolazine and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as ranolazine. Adults receiving Abilify Maintena with ranolazine for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 and CYP2D6 inhibitor. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions.
    Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported.
    Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and ranolazine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased ranolazine concentrations. Additionally, artemether; lumefantrine is a substrate and ranolazine is an inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased artemether; lumefantrine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval such as ranolazine should be avoided. Consider ECG monitoring if ranolazine must be used with or after artemether; lumefantrine treatment.
    Asenapine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, such as asenapine, coadministration may result in additive QT prolongation.In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, potentially leading to adverse reactions, such as QT prolongation. Asenapine is a CYP3A4 substrates that also have a possible risk for QT prolongation and TdP and should be used cautiously with ranolazine.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with ranolazine which inhibits CYP2D6. Monitor therapeutic response during coadministration.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with ranolazine which inhibits CYP2D6. Monitor therapeutic response during coadministration.
    Aspirin, ASA; Oxycodone: (Moderate) Oxycodone is metabolized in part by cytochrome P450 2D6 to oxymorphone, which represents < 15% of the total administered dose. Ranolazine and/or metabolites partially inhibit CYP2D6 isoenzymes based on data available. Although the concomitant use of ranolazine with oxycodone has not been studied, ranolazine may theoretically increase plasma concentrations of oxycodone, Studies of interactions with other CYP2D6 inhibitors and oxycodone have not demonstrated clinical significance.
    Atazanavir: (Major) Coadministration of ranolazine and atazanavir; cobicistat is contraindicated. A dose reduction may be required if ranolazine is coadminsitered with atazanavir alone. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Ranolazine is metabolized mainly by CYP3A. Although not specifically mentioned by the manufacturer, atazanavir is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently.
    Atazanavir; Cobicistat: (Severe) Concomitant use of ranolazine with cobicistat is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; cobicistat is an inhibitor of both enzymes, and P-gp. Coadministration is expected to increase ranolazine plasma concentrations. Serum concentrations of cobicistat could also be increased as ranolazine is a CYP3A4 and CYP2D6 inhibitor, and cobicistat is a CYP3A4 and CYP2D6 substrate. (Major) Coadministration of ranolazine and atazanavir; cobicistat is contraindicated. A dose reduction may be required if ranolazine is coadminsitered with atazanavir alone. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Ranolazine is metabolized mainly by CYP3A. Although not specifically mentioned by the manufacturer, atazanavir is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Both atomoxetine and ranolazine are considered drugs with a possible risk of torsade de pointes (TdP); therefore, the combination should be used cautiously and with close monitoring. In addition, because atomoxetine is primarily metabolized by CYP2D6, concurrent use of CYP2D6 inhibitors such as ranolazine may theoretically increase the risk of atomoxetine-induced adverse effects. Monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation).
    Atorvastatin: (Moderate) Ranolazine inhibits CYP3A isoenzymes and P-glycoprotein transport. Although not studied, ranolazine may theoretically increase plasma concentrations of CYP3A4 and/or P-glycoprotein substrates such as atorvastatin. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
    Atorvastatin; Ezetimibe: (Moderate) Ranolazine inhibits CYP3A isoenzymes and P-glycoprotein transport. Although not studied, ranolazine may theoretically increase plasma concentrations of CYP3A4 and/or P-glycoprotein substrates such as atorvastatin. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with ranolazine is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate and ranolazine is a weak CYP3A4 inhibitor in vitro, although data are conflicting. Plasma levels of one CYP3A4 substrate, simvastatin, and its active metabolite were increased 100% by coadministration with ranolazine; mean exposure to atorvastatin was increased by 40%. However, the pharmacokinetics of diltiazem were not affected by ranolazine. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Azithromycin: (Major) There have been case reports of QT prolongation and torsade de pointes (TdP) with the use of azithromycin in post-marketing reports. Ranolazine is also associated with a possible risk for QT prolongation and torsade de pointes (TdP); therefore, concomitant use may have additive risk. Azithromycin is also a substrate for and an inhibitor of P-glycoprotein transport, an energy-dependent drug efflux pump. The inhibition of P-glycoprotein, by drugs such as ranolazine may result in an increase in the concentration of azithromycin. Similarly, ranolazine also is a substrate for and an inhibitor of P-glycoprotein transport. Coadministration with azithromycin may result in an increase in the plasma concentration of ranolazine. If ranolazine and azithromycin are coadministered, patients should be monitored closely for adverse effects of each agent.
    Barbiturates: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including barbiturates. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
    Bedaquiline: (Major) Caution is advised when administering bedaquiline concurrently with ranolazine. Ranolazine may inhibit the CYP3A4 metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving ranolazine. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving ranolazine. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; ranolazine inhibits P-gp.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include ranolazine.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include ranolazine.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering ranolazine with boceprevir due to an increased potential for ranolazine-related adverse events. If ranolazine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of ranolazine and boceprevir. Both ranolazine and boceprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4 and the drug efflux transporter, P-glycoprotein (PGP). When used in combination, the plasma concentrations of both medications may be elevated.
    Bosentan: (Moderate) Coadministration of ranolazine with CYP3A enzyme inducers such as bosentan may result in a decreased metabolism of ranolazine. Monitor antianginal response to ranolazine closely during initiation of bosentan.
    Brentuximab vedotin: (Minor) Concomitant administration of brentuximab vedotin and ranolazine, a P-glycoprotein inhibitor, may increase exposure of monomethyl auristatin E (MMAE), a P-glycoprotein substrate. MMAE is one of the 3 components released from brentuximab vedotin. If co-administration is necessary, monitor patients for adverse reactions.
    Bretylium: (Severe) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval such as Bretylium, a Class III antiarrhythmic.
    Brexpiprazole: (Moderate) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Ranolazine and/or its metabolites are moderate inhibitors of CYP2D6. If ranolazine is used in combination with brexpiprazole and a moderate to strong CYP3A4 inhibitor, the brexpiprazole dose should be reduced and the patient should be carefully monitored for brexpiprazole-related adverse reactions. It should be noted that no dosage adjustment is needed in patients taking a CYP2D6 inhibitor who are receiving brexpiprazole as adjunct treatment for major depressive disorder because CYP2D6 considerations are already factored into general dosing recommendations.
    Brigatinib: (Severe) Coadministration of ranolazine with brigatinib is contraindicated due to decreased plasma concentrations of ranolazine leading to decreased efficacy. Ranolazine is a CYP3A substrate and brigatinib induces CYP3A in vitro. Coadministration with a strong CYP3A4 inducer decreased ranolazine plasma concentrations by approximately 95%.
    Brimonidine; Timolol: (Moderate) Timolol is metabolized by CYP2D6 isoenzymes. Ranolazine, a CYP2D6 inhibitor, could theoretically impair timolol metabolism. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
    Brompheniramine; Guaifenesin; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Budesonide; Formoterol: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Bupivacaine; Lidocaine: (Major) Ranolazine is an inhibitor of the cytochrome P450 (CYP) isoenzyme 3A, and lidocaine is a substrate for this pathway. Thus, ranolazine may theoretically reduce lidocaine clearance. If concurrent therapy with ranolazine is necessary, administer lidocaine parenteral infusions with caution and monitor lidocaine serum concentrations.
    Buprenorphine: (Moderate) Buprenorphine should be used cautiously and with close monitoring with ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Buprenorphine; Naloxone: (Moderate) Buprenorphine should be used cautiously and with close monitoring with ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Bupropion: (Moderate) Bupropion inhibits CYP2D6. Coadministration of bupropion with medications that are metabolized by CYP2D6, like ranolazine, may result in increased ranolazine plasma concentrations if bupropion is added.
    Bupropion; Naltrexone: (Moderate) Bupropion inhibits CYP2D6. Coadministration of bupropion with medications that are metabolized by CYP2D6, like ranolazine, may result in increased ranolazine plasma concentrations if bupropion is added.
    Buspirone: (Moderate) Although data are not available, CYP3A4 inhibitors, such as ranolazine, may decrease systemic clearance of buspirone leading to increased or prolonged effects. If buspirone is to be administered concurrently with significant CYP3A4 inhibitors, a low dose of buspirone (i.e., 2.5 mg PO twice daily) is recommended initially. Subsequent dosage adjustments should be based on clinical response.
    Cabazitaxel: (Minor) Cabazitaxel is a CYP3A4 and P-glycoprotein (Pgp) substrate; ranolazine is a weak in vitro inhibitor of CYP3A4 as well as a P-gp inhibitor. A drug interaction study with repeated administration of aprepitant, another moderate CYP3A4 inhibitor, did not modify the exposure to cabazitaxel; however, formal drug interaction studies have not been conducted with P-gp inhibitors. Use caution when cabazitaxel is administered concomitantly with P-gp inhibitors.
    Cabozantinib: (Moderate) Monitor for an increase in ranolazine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ranolazine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ranolazine is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ranolazine is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Canagliflozin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Ranolazine is a PGP inhibitor in vitro and a PGP substrate. Theoretically, concentrations of either drug may be increased. Patients should be monitored for changes in glycemic control and possible adverse reactions.
    Canagliflozin; Metformin: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Ranolazine is a PGP inhibitor in vitro and a PGP substrate. Theoretically, concentrations of either drug may be increased. Patients should be monitored for changes in glycemic control and possible adverse reactions.
    Carbamazepine: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including carbamazepine. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy. In addition, carbamazepine may increase the absorption of ranolazine via induction of P-glycoprotein transport.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Carvedilol: (Moderate) Inhibitors of CYP2D6, like ranolazine, may inhibit the hepatic oxidative metabolism of carvedilol.
    Ceritinib: (Major) Avoid coadministration of ceritinib and ranolazine due to the potential for increased exposure to ranolazine; additive QT prolongation may also occur. Ceritinib inhibits CYP3A4 and ranolazine is predominantly metabolized by CYP3A4. Because the strength of inhibition of CYP3A4 by ceritinib is unknown, a specific recommendation for the safe use of ceritinib and ranolazine cannot be provided. The manufacturer of ranolazine provides the following recommendations for coadministration of strong and moderate CYP3A4 inhibitors: coadministration of strong CYP3A4 inhibitors is contraindicated; in patients receiving a moderate CYP3A4 inhibitor, do not exceed 500 mg twice daily of ranolazine. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs.
    Chlordiazepoxide: (Moderate) CYP3A4 inhibitors like ranolazine may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Chlordiazepoxide; Clidinium: (Moderate) CYP3A4 inhibitors like ranolazine may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Chloroquine: (Major) Coadminister chloroquine with other drugs known to prolong the QT interval, such as ranolazine, with caution. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Chlorpheniramine; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with ranolazine which inhibits CYP2D6. Monitor therapeutic response during coadministration.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpromazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval, such as chlorpromazine. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Chlorpromazine is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects.
    Cilostazol: (Moderate) Ranolazine inhibits CYP3A isoenzymes and may theoretically increase plasma concentrations of CYP3A4 substrates, like cilostazol, potentially leading to adverse reactions.
    Cimetidine: (Moderate) Coadminister ranolazine and cimetidine with caution. Cimetidine is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Cimetidine also is a CYP2D6 and CYP3A4 inhibitor, and ranolazine is a substrate for these enzymes; however, coadministration of cimetidine does not increase the plasma concentrations of ranolazine in healthy volunteers.
    Cinacalcet: (Moderate) Ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Cinacalcet is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects.
    Ciprofloxacin: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include ciprofloxacin.
    Cisapride: (Severe) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Because of the potential for TdP, use of ranolazine with cisapride is contraindicated. In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, such as cisapride, potentially leading to adverse reactions.
    Citalopram: (Major) Citalopram causes dose-dependent QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with citalopram include ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Citalopram is a known CYP2D6 inhibitor; coadministration may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. According to the manufacturer, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended.
    Clarithromycin: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including clarithromycin. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Furthermore, clarithromycin may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
    Clobazam: (Moderate) A dosage reduction of CYP2D6 substrates, such as ranolazine, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If these agents are used in combination, it is advisable to monitor the patient for ranolazine-related adverse reactions.
    Clonazepam: (Moderate) CYP3A4 inhibitors, like ranolazine, may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity.
    Clorazepate: (Moderate) CYP3A4 inhibitors, like ranolazine, may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity.
    Clozapine: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation such as ranolazine. Additionally, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates, such as clozapine. Elevated plasma concentrations of clozapine may increase the risk for QT prolongation, torsade de pointes (TdP), sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat: (Severe) Concomitant use of ranolazine with cobicistat is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; cobicistat is an inhibitor of both enzymes, and P-gp. Coadministration is expected to increase ranolazine plasma concentrations. Serum concentrations of cobicistat could also be increased as ranolazine is a CYP3A4 and CYP2D6 inhibitor, and cobicistat is a CYP3A4 and CYP2D6 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Severe) Concomitant use of ranolazine with cobicistat is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; cobicistat is an inhibitor of both enzymes, and P-gp. Coadministration is expected to increase ranolazine plasma concentrations. Serum concentrations of cobicistat could also be increased as ranolazine is a CYP3A4 and CYP2D6 inhibitor, and cobicistat is a CYP3A4 and CYP2D6 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Severe) Concomitant use of ranolazine with cobicistat is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; cobicistat is an inhibitor of both enzymes, and P-gp. Coadministration is expected to increase ranolazine plasma concentrations. Serum concentrations of cobicistat could also be increased as ranolazine is a CYP3A4 and CYP2D6 inhibitor, and cobicistat is a CYP3A4 and CYP2D6 substrate. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and ranolazine is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro as well as a P-glycoprotein (P-gp) substrate; in vitro, ranolazine is a weak inhibitor of CYP3A and a moderate P-gp inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
    Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with ranolazine which inhibits CYP2D6. Monitor therapeutic response during coadministration.
    Codeine; Guaifenesin: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with ranolazine which inhibits CYP2D6. Monitor therapeutic response during coadministration.
    Codeine; Phenylephrine; Promethazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of ranolazine with other drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ranolazine include promethazine. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Promethazine is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with ranolazine which inhibits CYP2D6. Monitor therapeutic response during coadministration.
    Codeine; Promethazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of ranolazine with other drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ranolazine include promethazine. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Promethazine is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with ranolazine which inhibits CYP2D6. Monitor therapeutic response during coadministration.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and ranolazine in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Ranolazine can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken ranolazine in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Conivaptan: (Severe) Concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and ranolazine, a CYP3A4/P-gp substrate and weak CYP3A4 inhibitor is contraindicated. Coadministration may result in elevated concentrations of both conivaptan and ranolazine. According to the manufacturer of ranolazine, concurent use with drugs known to be strong CYP3A inhibitors, such as conivaptan, is contraindicated. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with crizotinib is necessary; additionally, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs are associated with concentration-dependent QT prolongation; coadministration may result in additive QT prolongation. Additionally, ranolazine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased plasma levels of ranolazine by 100%.
    Cyclobenzaprine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, potentially leading to adverse reactions, such as QT prolongation. Drugs that are CYP3A4 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include cyclobenzaprine.
    Cyclosporine: (Severe) Cyclosporine inhibits the cytochrome P450 3A4 (CYP3A4) isoenzyme. Moderate or potent CYP3A4 inhibitors are contraindicated for use with ranolazine, a CYP3A4 substrate. Inhibition of ranolazine metabolism by cyclosporine could lead to increased ranolazine plasma concentrations. In addition, ranolazine is a substrate of P-glycoprotein (P-gp); inhibitors of P-gp may increase the absorption of ranolazine and should be coadministered with caution. When possible, it is prudent to avoid coadministration of ranolazine with cyclosporine due to the potential for increased plasma concentrations of ranolazine, which may result in QT prolongation and increase the risk for proarrhythmias. If necessary to coadminister these drugs, it is prudent to monitor the individual patient response to ranolazine therapy closely, including an evaluation of the ECG effects and antianginal benefits during coadministration.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ranolazine, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like ranolazine in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with ranolazine, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Daclatasvir: (Moderate) Systemic exposure of ranolazine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of ranolazine; monitor patients for potential adverse effects.
    Danazol: (Major) Danazol is a CYP3A4 inhibitor, and may reduce the hepatic metabolism of CYP3A4 substrates. Moderate or potent CYP3A4 inhibitors are contraindicated for use with ranolazine, a CYP3A4 substrate. Inhibition of ranolazine metabolism could lead to increased ranolazine plasma concentrations and associated QTc prolongation. Avoid coadministration of ranolazine with danazol due to the potential for reduced metabolism of ranolazine and the risk of QT prolongation.
    Dapagliflozin; Metformin: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Darunavir: (Severe) Coadministration of darunavir with ranolazine is contraindicated due to the potential for elevated ranolazine concentrations and the potential for serious and/or life threatening reactions, such as cardiac arrhythmias. Ranolazine is a CYP3A4 substrate, in addition to being a substrate for P-glycoprotein (P-gp); darunavir is an inhibitor of CYP3A4 and P-gp. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
    Darunavir; Cobicistat: (Severe) Coadministration of darunavir with ranolazine is contraindicated due to the potential for elevated ranolazine concentrations and the potential for serious and/or life threatening reactions, such as cardiac arrhythmias. Ranolazine is a CYP3A4 substrate, in addition to being a substrate for P-glycoprotein (P-gp); darunavir is an inhibitor of CYP3A4 and P-gp. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. (Severe) Concomitant use of ranolazine with cobicistat is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; cobicistat is an inhibitor of both enzymes, and P-gp. Coadministration is expected to increase ranolazine plasma concentrations. Serum concentrations of cobicistat could also be increased as ranolazine is a CYP3A4 and CYP2D6 inhibitor, and cobicistat is a CYP3A4 and CYP2D6 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Coadministration of ranolazine with strong CYP3A inhibitors, such as ritonavir-containing regimens, is contraindicated. Concurrent administration of ranolazine with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is expected to result in elevated plasma concentrations of ranolazine, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Both ritonavir and ranolazine are substrates and inhibitors of CYP3A4, CYP2D6, and P-glycoprotein (P-gp); both drugs are also associated with concentration-dependent QT prolongation. Paritaprevir also inhibits P-gp. Increased plasma concentrations of ranolazine and ritonavir increase the risk of drug toxicity and proarrhythmic effects. Plasma concentrations of the other antiviral agents may also be affected. Paritaprevir and dasabuvir (minor) are metabolized by CYP3A4, and dasabuvir, ombitasvir, and paritaprevir, are all substrates of P-gp. (Severe) Ranolazine is primarily metabolized by CYP3A, but it is also a substrate of P-glycoprotein. Ranolazine is contraindicated for use with moderate or potent inhibitors of CYP3A isoenzymes, including the anti-retroviral protease inhibitors. Ranolazine is associated with dose and plasma concentration-related increases in the QTc interval. Coadministration with anti-retroviral protease inhibitors may increase the plasma concentrations of ranolazine, thus increasing the risk of drug toxicity and proarrhythmic effects. In addition, ritonavir and several other anti-retroviral protease inhibitors can increase the absorption of ranolazine via inhibition of P-glycoprotein transport. Furthermore, ritonavir also is associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    Dasatinib: (Major) In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Cautious dasatinib administration is recommended to patients who have or may develop QT prolongation such as patients taking drugs that lead to QT prolongation. Ranolazine is is associated with a possible risk for QT prolongation and TdP. Also, ranolazine is a weak CYP3A4 inhibitor and dasatinib is metabolized by cytochrome P450 (CYP) isoenzyme 3A4. Concomitant use of dasatinib and drugs that inhibit CYP3A4 may increase exposure to dasatinib and should be avoided. Increased ranolazine concentrations may also occur. Dasatinib is a time-dependent, weak inhibitor of CYP3A4, and ranolazine is a CYP3A4 substrate.
    Daunorubicin: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval, such as daunorubicin and doxorubicin. Acute cardiotoxicity can occur during administration of daunorubicin or doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. In addition, doxorubicin is a CYP3A4 substrate and ritonavir inhibits CYP3A4. Coadministration may result in elevated plasma concentrations of doxorubicin and an added risk of adverse reactions such as QT prolongation.
    Degarelix: (Major) Since degarelix can cause QT prolongation, degarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation, such as ranolazine. Weigh the potential benefits and risks of degarelix use in patients taking other drugs that may prolong the QT interval.
    Delavirdine: (Severe) Ranolazine is metabolized mainly by CYP3A, and is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors, such as delavirdine. In addition, ranolazine is metabolized to a lesser extent by CYP2D6; delavirdine is a known CYP2D6 inhibitor. Concurrent administration may result in an increase in ranolazine concentrations.
    Desflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ranolazine. Halogenated anesthetics can prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Deutetrabenazine: (Major) For patients taking more than 24 mg/day of deutetrabenazine with ranolazine, assess the QTc interval before and after increasing the dosage of either medication. Both medications prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Dextromethorphan; Promethazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of ranolazine with other drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ranolazine include promethazine. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Promethazine is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects
    Dextromethorphan; Quinidine: (Severe) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine include ranolazine.
    Diazepam: (Moderate) CYP3A4 inhibitors, like ranolazine, may reduce the metabolism of diazepam and increase the potential for benzodiazepine toxicity.
    Digoxin: (Major) In vitro studies suggest that ranolazine is a P-glycoprotein inhibitor. Ranolazine increases digoxin concentrations by 1.5-fold in healthy volunteers receiving ranolazine (1000 mg PO twice daily) and digoxin (0.125 mg PO once daily). Measure serum digoxin concentrations before initiating ranolazine. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. In contrast, digoxin does not increase the plasma concentrations of ranolazine. No dose adjustment of ranolazine is required for patients treated with digoxin.
    Diltiazem: (Major) The dose of ranolazine, a CYP3A4 and P-glycoprotein substrate, should be limited to 500 mg PO twice daily when coadministered with diltiazem, a moderate CYP3A inhibitor. Diltiazem (180 to 360 mg daily) causes dose-dependent increases in the average steady-state concentrations of ranolazine by about 2-fold.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Disopyramide: (Major) Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP). Disopyramide is a substrate for CYP3A4. Life-threatening interactions have been reported with the coadministration of disopyramide with clarithromycin and erythromycin, both have a possible risk for QT prolongation and TdP and inhibit CYP3A4. The coadministration of disopyramide and CYP3A4 inhibitors may result in a potentially fatal interaction. Drugs with a possible risk for QT prolongation and TdP that are also inhibitors of CYP3A4 that should be used cautiously with disopyramide include ranolazine.
    Dofetilide: (Severe) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Because of the potential for TdP, use of dofetilide with ranolazine is contraindicated.
    Dolasetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dolasetron and ranolazine should be used together cautiously. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Ranolazine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, ranolazine inhibits CYP2D6 and CYP3A4, the two isoenzymes involved in the metabolism of donepezil. The clinical effects of this interaction on the response to donepezil has not been determined. According to the manufacturer for ranolazine, lower doses of CYP2D6 substrates may be required during coadministration with ranolazine. Consider using a lower dose of donepezil during coadministration with ranolazine, and monitor for adverse reactions and clinical response.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Ranolazine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, ranolazine inhibits CYP2D6 and CYP3A4, the two isoenzymes involved in the metabolism of donepezil. The clinical effects of this interaction on the response to donepezil has not been determined. According to the manufacturer for ranolazine, lower doses of CYP2D6 substrates may be required during coadministration with ranolazine. Consider using a lower dose of donepezil during coadministration with ranolazine, and monitor for adverse reactions and clinical response. (Moderate) Coadminister ranolazine and memantine with caution. Memantine is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the memantine dose may be necessary.
    Dopamine: (Moderate) Coadminister ranolazine and dopamine with caution. Dopamine is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the dopamine dose may be necessary.
    Dorzolamide; Timolol: (Moderate) Timolol is metabolized by CYP2D6 isoenzymes. Ranolazine, a CYP2D6 inhibitor, could theoretically impair timolol metabolism. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
    Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, including ranolazine, may inhibit the conversion of doxercalciferol to its active metabolite and result in decreased efficacy of doxercalciferol.
    Doxorubicin: (Major) In vitro, ranolazine is a moderate CYP2D6 and P-glycoprotein (P-gp) inhibitor, and a mild CYP3A4 inhiibitor; doxorubicin is a major substrate of CYP2D6, CYP3A4, and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, CYP3A4, and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Additionally, acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Avoid coadministration of ranolazine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dronabinol, THC: (Moderate) Use caution if coadministration of dronabinol with ranolazine is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; ranolazine is a weak inhibitor of CYP3A4 in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Severe) Concomitant use of dronedarone and ranolazine is contraindicated due to the risk of QT prolongation. Both dronedarone and ranolazine prolong the QT-interval in a dose-related manner. In addition, coadministration of dronedarone and ranolazine may result in elevated plasma concentrations of both drugs, further increasing the risk of QT prolongation and torsade de pointes (TdP). Dronedarone and ranolazine are both substrates and inhibitors of CYP3A. In addition, ranolazine is a substrate of P-glycoprotein (P-gp), and dronedarone is a P-gp inhibitor.
    Droperidol: (Major) Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. If coadministration is necessary, ranolazine should be used cautiously with drugs that prolong the QT interval, such as droperidol. In addition, droperidol is a substrate for CYP3A4 and P-glycoprotein (P-gp). Ranolazine is an inhibitor of CYP3A4 and P-gp. Concurrent administration of ranolazine and droperdol may result in increased droperidol concentrations.
    Drospirenone; Ethinyl Estradiol: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Duloxetine: (Moderate) Ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Metoclopramide is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects.
    Dutasteride; Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of ranolazine. Tamsulosin is extensively metabolized by CYP2D6 and CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Therefore, concomitant use with drugs that inhibit both CYP2D6 and CYP3A4, such as ranolazine, should be avoided.
    Edoxaban: (Moderate) Coadministration of edoxaban and ranolazine may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and in vitro data indicate ranolazine is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ranolazine; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz: (Severe) Ranolazine is metabolized mainly by CYP3A and is contraindicated in patients receiving drugs known to be CYP3A inducers. Efavirenz induces CYP3A4. Although not specifically mentioned by the manufacturer, coadministration of ranolazine with a CYP3A enzyme inducer such as efavirenz may result in decreased ranolazine plasma concentrations and decreased efficacy. Additionally, both efavirenz and ranolazine have been associated with QT prolongation.
    Efavirenz; Emtricitabine; Tenofovir: (Severe) Ranolazine is metabolized mainly by CYP3A and is contraindicated in patients receiving drugs known to be CYP3A inducers. Efavirenz induces CYP3A4. Although not specifically mentioned by the manufacturer, coadministration of ranolazine with a CYP3A enzyme inducer such as efavirenz may result in decreased ranolazine plasma concentrations and decreased efficacy. Additionally, both efavirenz and ranolazine have been associated with QT prolongation. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with ranolazine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ranolazine is a substrate and mild inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Eliglustat: (Major) Coadminister ranolazine and eliglustat with caution. Based on in vitro pharmacokinetic data, coadministration is not recommended in CYP2D6 poor metabolizers (PMs) and a dosage reduction of eliglustat to 84 mg PO once daily is required in extensive or intermediate CYP2D6 metabolizers (EMs or IMs). In addition, coadministration of eliglustat with both ranolazine and a strong or moderate CYP3A inhibitor is contraindicated in all patients. Both eliglustat and ranolazine can independently prolong the QT interval, and coadministration increases this risk. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. In vitro data indicate ranolazine is a CYP2D6 and P-glycoprotein (P-gp) substrate, as well as a weak inhibitor of CYP3A and moderate inhibitor of CYP2D6. Eliglustat is a CYP2D6 and CYP3A substrate and CYP2D6 and P-gp inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration of ranolazine and eliglustat may result in additive effects on the QT interval and, potentially, increased plasma concentrations of one or both drugs, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). For coadministration with P-gp substrates and CYP2D6 substrates, eliglustat's product labeling recommends monitoring therapeutic drug concentrations of the P-gp substrate, if possible, or consideration of a dosage reduction and titrating to clinical effect.
    Empagliflozin; Metformin: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, potentially leading to adverse reactions, such as QT prolongation. Rilpivirine is a CYP3A4 substrate and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Caution is advised with coadministration.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, potentially leading to adverse reactions, such as QT prolongation. Rilpivirine is a CYP3A4 substrate and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Caution is advised with coadministration. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Encainide: (Major) Concomitant use of ranolazine with CYP2D6 substrates like encainide may theoretically increase plasma concentrations of encainide. Lower doses of encainide may be needed during therapy with ranolazine. Monitor therapeutic response during coadministration.
    Enflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ranolazine. Halogenated anesthetics can prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Enzalutamide: (Severe) The concomitant use of enzalutamide with ranolazine is contraindicated due to decreased plasma concentrations of ranolazine resulting in decreased efficacy. Enzalutamide is a strong CYP3A4 inducer and ranolazine is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inducer decreased the plasma concentrations of ranolazine by approximately 95%
    Epirubicin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering ranolazine with epirubicin. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Acute cardiotoxicity can also occur during administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Ergot alkaloids: (Major) In vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, such as ergot alkaloids, potentially leading to adverse reactions.
    Eribulin: (Major) Eribulin has been associated with QT prolongation. If eribulin and another drug that prolongs the QT interval, such as ranolazine, must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erlotinib: (Moderate) Use caution if coadministration of erlotinib with ranolazine is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both ranolazine and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Ranolazine is a weak CYP3A4 inhibitor in vitro. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Ranolazine increased plasma levels of another CYP3A4 substrate, simvastatin, by 100% in healthy volunteers; however, the pharmacokinetics of the CYP3A4 substrate diltiazem were not affected by ranolazine. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with ranolazine may also increase erlotinib exposure.
    Erythromycin: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval, such as erythromycin. Furthermore, the dose of ranolazine, a CYP3A4 and P-glycoprotein substrate, should be limited to 500 mg PO twice daily when coadministered with erythromycin, a moderate CYP3A inhibitor. Furthermore, erythromycin may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
    Erythromycin; Sulfisoxazole: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval, such as erythromycin. Furthermore, the dose of ranolazine, a CYP3A4 and P-glycoprotein substrate, should be limited to 500 mg PO twice daily when coadministered with erythromycin, a moderate CYP3A inhibitor. Furthermore, erythromycin may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
    Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as ranolazine, should be done with caution and close monitoring. In addition, escitalopram may inhibit the CYP2D6 metabolism of ranolazine and ranolazine may inhibit the CYP3A4 metabolism of escitalopram. If ranolazine and escitalopram are coadministered, monitor the clinical effects of both medications.
    Eslicarbazepine: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers. In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Although not specifically mentioned by the manufacturer, coadministration of ranolazine with eslicarbazepine may result in decreased ranolazine plasma concentrations and decreased efficacy.
    Estazolam: (Moderate) CYP3A4 inhibitors, like ranolazine, may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
    Ethinyl Estradiol: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Ethinyl Estradiol; Desogestrel: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Ethinyl Estradiol; Etonogestrel: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Ethinyl Estradiol; Levonorgestrel: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Ethinyl Estradiol; Norelgestromin: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Ethinyl Estradiol; Norethindrone: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Ethinyl Estradiol; Norgestimate: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Ethinyl Estradiol; Norgestrel: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
    Ethosuximide: (Moderate) Ranolazine inhibits CYP3A isoenzymes and may theoretically increase the plasma concentrations of ethosuximide.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with ranolazine. In vitro, ranolazine is a weak inhibitor of CYP3A4 as well as a P-glycoprotein (P-gp) inhibitor; etoposide, VP-16 is a CYP3A4 and P-gp substrate. Coadministration may cause accumulation of etoposide and decreased metabolism, resulting in increased etoposide concentrations.
    Etravirine: (Moderate) Etravirine is a CYP3A4 inducer/substrate and a P-glycoprotein (PGP) inhibitor. Ranolazine is a CYP3A4 substrate/inhibitor and PGP substrate/inhibitor. Caution is warranted if these drugs are coadministered.
    Everolimus: (Moderate) Everolimus is an inhibitor and substrate of CYP3A4 and Pgp and an inhibitor of CYP2D6. Coadminister weak inhibitors of CYP3A4 or Pgp, such as ranolazine, with caution. Patients may experience an increase in systemic exposure to everolimus if these drugs are coadministered. Concurrent administration of ketoconazole, a strong CYP3A4 inhibitor and Pgp inhibitor, and everolimus increased everolimus Cmax and AUC 3.9-fold and 15-fold, respectively. In addition, ranolazine is a substrate of CYP3A4, CYP2D6, and Pgp. The effect of everolimus on ranolazine pharmacokinetics has not been established; however, pharmacokinetic studies showed no significant impact of the coadministration of everolimus with the CYP3A4 and Pgp substrate atorvastatin.
    Ezetimibe; Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking ranolazine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on ranolazine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of ranolazine and simvastatin against the potential risks. Ranolazine increases the simvastatin exposure by approximately 2-fold.
    Ezogabine: (Major) Ezogabine has been associated with QT prolongation. The manufacturer of ezogabine recommends caution during concurrent use of medications known to increase the QT interval, such as ranolazine.
    Famotidine: (Moderate) Coadminister ranolazine and famotidine with caution. Famotidine is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the famotidine dose may be necessary.
    Famotidine; Ibuprofen: (Moderate) Coadminister ranolazine and famotidine with caution. Famotidine is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the famotidine dose may be necessary.
    Fentanyl: (Moderate) Coadministration of fentanyl, a CYP3A4/P-glycoprotein (P-gp) substrate, and ranolazine, a CYP3A4/P-gp inhibitor, may result in increased fentanyl concentrations which may cause prolonged adverse reactions such as increased CNS depression and potentially fatal respiratory depression. If coadministration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved.
    Fesoterodine: (Minor) Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via hepatic CYP3A4. In theory, the CYP3A4 inhibitory effects of ranolazine may result in an increase in plasma concentrations of 5-hydroxymethyltolterodine. The need for fesoterodine doses greater than 4 mg/day should be carefully evaluated prior to increasing the dose during concurrent use of mild to moderate 3A4 inhibitors.
    Fingolimod: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include ranolazine.
    Flecainide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering ranolazine with flecainide. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Flecainide, a Class IC antiarrhythmic, is also associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6, and flecainide is a CYP2D6 substrate. Coadministration may result in elevated flecainide serum concentrations. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during concurrent treatment.
    Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including ranolazine, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
    Fluconazole: (Severe) Although the manufacturer of ranolazine, a CYP3A4 substrate, recommends a dosage limit of 500 mg PO twice daily when coadministered with fluconazole, a moderate CYP3A4 inhibitor, the manufacturer of fluconazole contraindicates this drug combination. According to the manufacturer of fluconazole, fluconazole is contraindicated with drugs that prolong the QT interval and are CYP3A4 substrates.
    Fluoxetine: (Major) In theory, fluoxetine may inhibit both cytochrome P450 pathways for ranolazine metabolism, potentially resulting in large increases ranolazine plasma concentrations and QTc prolongation. In addition, ranolazine may theoretically increase plasma concentrations of drugs that are CYP2D6 substrates such as fluoxetine.
    Fluoxetine; Olanzapine: (Major) In theory, fluoxetine may inhibit both cytochrome P450 pathways for ranolazine metabolism, potentially resulting in large increases ranolazine plasma concentrations and QTc prolongation. In addition, ranolazine may theoretically increase plasma concentrations of drugs that are CYP2D6 substrates such as fluoxetine. (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment. Drugs that are CYP2D6 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include olanzapine.
    Fluphenazine: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously with ranolazine include fluphenazine.
    Flurazepam: (Moderate) CYP3A4 inhibitors, like ranolazine, may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity.
    Fluticasone; Salmeterol: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Vilanterol: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluvoxamine: (Major) According to the manufacturer of ranolazine, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving moderate CYP3A inhibitors. Ranolazine is a primary substrate of CYP3A and fluvoxamine is a moderate CYP3A4 inhibitor. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with ranolazine. Ranolazine is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with ranolazine, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Formoterol: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Formoterol; Mometasone: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fosamprenavir: (Severe) Ranolazine is primarily metabolized by CYP3A, but it is also a substrate of P-glycoprotein. Ranolazine is contraindicated for use with moderate or potent inhibitors of CYP3A isoenzymes, including fosamprenavir. Ranolazine is associated with dose and plasma concentration-related increases in the QTc interval. Coadministration with fosamprenavir may increase the plasma concentrations of ranolazine, thus increasing the risk of drug toxicity and proarrhythmic effects.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as ranolazine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers. Although not specifically mentioned by the manufacturer, coadministration of ranolazine with a CYP3A enzyme inducer such as fosphenytoin may result in decreased ranolazine plasma concentrations and decreased efficacy.
    Gefitinib: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and ranolazine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; ranolazine is a weak CYP3A4 inhibitor in vitro and a moderate inhibitor of CYP2D6. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. In patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated.
    Gemifloxacin: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include gemifloxacin. The maximal change in the QTc interval occurs approximately 5-10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and ranolazine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and ranolazine as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and ranolazine are both substrates and inhibitors of P-glycoprotein (P-gp). (Moderate) Caution is advised with the coadministration of pibrentasvir and ranolazine as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Both pibrentasvir and ranolazine are substrates and inhibitors of P-glycoprotein (P-gp).
    Glipizide; Metformin: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Glyburide; Metformin: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Glycopyrrolate; Formoterol: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Goserelin: (Major) Ranolazine should be used cautiously and with close monitoring with goserelin. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval (see Pharmacokinetics). The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, potentially leading to adverse reactions, such as QT prolongation. Drugs that are CYP3A4 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include granisetron.
    Grapefruit juice: (Major) The dose of ranolazine, a CYP3A4 and P-glycoprotein substrate, should be limited to 500 mg PO twice daily when coadministered with grapefruit juice, a moderate CYP3A inhibitor. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations.
    Guaifenesin; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Halofantrine: (Severe) Halofantrine should be avoided in patients receiving drugs which may induce QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ranolazine. Halogenated anesthetics can prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Haloperidol: (Major) It is prudent to avoid concurrent use of ranolazine and haloperidol if possible, and to evaluate the risks and benefits of alternative treatment options. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs, including haloperidol, may result in additive QT prolongation. In addition, both ranolazine and haloperidol are CYP2D6 substrates and inhibitors. Theoretically, increased plasma concentrations of one or both drugs can occur during co-administration. Elevated haloperidol concentrations occurring through inhibition of CYP2D6 or CYP3A4 may increase the risk of adverse effects, including QT prolongation.
    Halothane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ranolazine. Halogenated anesthetics can prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Homatropine; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Metoprolol is significantly metabolized by CYP2D6 isoenzymes. Coadministration of ranolazine and metoprolol resulted in a 1.8-fold increase in the plasma concentration of metoprolol. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Propranolol is metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ranolazine, could theoretically impair propranolol metabolism. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
    Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Ibuprofen: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Phenylephrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ranolazine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and ranolazine. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Additionally, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Hydroxychloroquine is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include ranolazine.
    Ibuprofen; Oxycodone: (Moderate) Oxycodone is metabolized in part by cytochrome P450 2D6 to oxymorphone, which represents < 15% of the total administered dose. Ranolazine and/or metabolites partially inhibit CYP2D6 isoenzymes based on data available. Although the concomitant use of ranolazine with oxycodone has not been studied, ranolazine may theoretically increase plasma concentrations of oxycodone, Studies of interactions with other CYP2D6 inhibitors and oxycodone have not demonstrated clinical significance.
    Ibutilide: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, such as ibutilide, coadministration may result in additive QT prolongation. Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Idarubicin: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval, such as daunorubicin, doxorubicin, epirubicin, and idarubicin. Acute cardiotoxicity can occur during administration of daunorubicin or doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. In addition, doxorubicin is a CYP3A4 substrate and ritonavir inhibits CYP3A4. Coadministration may result in elevated plasma concentrations of doxorubicin and an added risk of adverse reactions such as QT prolongation.
    Idelalisib: (Severe) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with ranolazine, a CYP3A substrate, as ranolazine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, iloperidone is a substrate for CYP3A4 and CYP2D6 and an inhibitor of P-glycoprotein (P-gp). Ranolazine is an inhibitor of CYP3A4 and CYP2D6 and is a substrate for P-gp. Coadministration may result in increased iloperidone and/or ranolazine concentrations.
    Imatinib: (Severe) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors. Inhibition of ranolazine metabolism could lead to increased ranolazine plasma concentrations and associated QTc prolongation. Although not specifically mentioned by the manufacturer of ranolazine, imatinib, STI-571 is known to be a strong inhibitor of CYP3A4. In addition, ranolazine is metabolized to a lesser extent by CYP2D6; imatinib, STI-571 is a known CYP2D6 inhibitor.
    Indacaterol: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indacaterol; Glycopyrrolate: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indinavir: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including indinavir. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes. In addition, ranolazine may increase the absorption of indinavir via inhibition of P-glycoprotein transport.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with ranolazine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
    Irinotecan Liposomal: (Moderate) Use caution if irinotecan liposomal is coadministered with ranolazine, a weak CYP3A4 inhibitor in vitro, due to a possible increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: (Moderate) In vitro, ranolazine is a moderate inhibitor of P-glycoprotein (P-gp) and a mild CYP3A4 inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Isavuconazonium: (Major) The dose of ranolazine, a CYP3A4 and P-glycoprotein (P-gp) substrate, should be limited to 500 mg PO twice daily when coadministered with isavuconazonium. Isavuconazole, the active moiety of isavuconazonium is a moderate inhibitor of CYP3A4 and an inhibitor of P-gp. Inhibition of ranolazine CYP3A4 metabolism could lead to increased ranolazine plasma concentrations. Serum concentrations of isavuconazole may also be increased as ranolazine is a CYP3A4 inhibitor, while isavuconazole is a sensitive substrate of CYP3A4.
    Isoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ranolazine. Halogenated anesthetics can prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Isoniazid, INH: (Severe) Isoniazid, INH is a potent CYP3A4 inhibitor, and may reduce the hepatic metabolism of CYP3A4 substrates. Moderate or potent CYP3A4 inhibitors, such as isoniazid, are contraindicated for use with ranolazine, a CYP3A4 substrate. In addition, inhibition of ranolazine metabolism could lead to increased ranolazine plasma concentrations and associated QTc prolongation.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Severe) Isoniazid, INH is a potent CYP3A4 inhibitor, and may reduce the hepatic metabolism of CYP3A4 substrates. Moderate or potent CYP3A4 inhibitors, such as isoniazid, are contraindicated for use with ranolazine, a CYP3A4 substrate. In addition, inhibition of ranolazine metabolism could lead to increased ranolazine plasma concentrations and associated QTc prolongation. (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including rifampin. Ranolazine also is a substrate for CYP2D6 and P-glycoprotein. Rifampin potently induces cytochrome P450 enzymes, including CYP3A isoenzymes, and is also an inducer of P-glycoprotein transport. Rifampin (600 mg daily) decreases the plasma concentration of ranolazine (1000 mg twice daily) by approximately 95%, likely due to induction of CYP3A and P-glycoprotein.
    Isoniazid, INH; Rifampin: (Severe) Isoniazid, INH is a potent CYP3A4 inhibitor, and may reduce the hepatic metabolism of CYP3A4 substrates. Moderate or potent CYP3A4 inhibitors, such as isoniazid, are contraindicated for use with ranolazine, a CYP3A4 substrate. In addition, inhibition of ranolazine metabolism could lead to increased ranolazine plasma concentrations and associated QTc prolongation. (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including rifampin. Ranolazine also is a substrate for CYP2D6 and P-glycoprotein. Rifampin potently induces cytochrome P450 enzymes, including CYP3A isoenzymes, and is also an inducer of P-glycoprotein transport. Rifampin (600 mg daily) decreases the plasma concentration of ranolazine (1000 mg twice daily) by approximately 95%, likely due to induction of CYP3A and P-glycoprotein.
    Itraconazole: (Severe) Ranolazine is contraindicated for use during and for 2 weeks after itraconazole therapy. Inhibition of ranolazine CYP3A metabolism by itraconazole could lead to increased ranolazine plasma concentrations, prolonged QTc prolongation, and possibly torsade de pointes.
    Ivabradine: (Moderate) Use caution during coadministration of ivabradine and ranolazine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; ranolazine is a weak inhibitor of CYP3A. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: (Major) Avoid the concomitant use of ivacaftor and ranolazine if possible. Ivacaftor is a CYP3A substrate, and ranolazine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure; however, the clinical impact of this has not yet been determined. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (Pgp); ranolazine is partially metabolized by CYP3A and is a substrate of Pgp. Co-administration may increase ranolazine exposure leading to increased or prolonged therapeutic effects and adverse events, specifically an increased risk for QT prolongation.
    Ixabepilone: (Moderate) Ixabepilone is a CYP3A4 substrate, and concomitant use with mild or moderate CYP3A4 inhibitors such as ranolazine has not been studied. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. Caution is recommended if ixabepilone is coadministered with ranolazine; closely monitor patients for ixabepilone-related toxicities.
    Ketoconazole: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be moderate or potent CYP3A inhibitors including systemic azole antifungal agents. Ketoconazole (200 mg PO twice daily) increases the average steady-state plasma concentrations of ranolazine by 3.2-fold. Avoid coadministering ranolazine with ketoconazole. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, prolonged QTc prolongation, and possibly torsade de pointes.
    Lapatinib: (Major) Lapatinib is a CYP3A4 substrate and a CYP3A4 inhibitor at clinically relevant concentrations in vitro. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (P-gp, ABCB1). Ranolazine is a P-glycoprotein (P-gp) inhibitor, a CYP3A4 substrate, and a CYP3A4 inhibitor. If lapatinib will be coadministered with a CYP3A4 substrate, such as ranolazine, exercise caution and consider dose reduction of ranolazine. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Concurrent administration of lapatinib with a P-gp and CYP3A4 inhibitor such as ranolazine is likely to cause elevated serum lapatinib concentrations, and caution is recommended. In addition to pharmacokinetic interactions, both lapatinib and ranolazine can prolong the QT interval; therefore coadministration may further increase the risk for QT prolongation.
    Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of ranolazine and ledipasvir; sofosbuvir. Both ledipasvir and ranolazine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Lenvatinib: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1,000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Leuprolide: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include ranolazine.
    Leuprolide; Norethindrone: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include ranolazine.
    Levalbuterol: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Levofloxacin: (Major) Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Rare cases of torsade de pointes (TdP) have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. According to the manufacturer, levofloxacin should be avoided in patients taking drugs that can result in prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP include ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Levomethadyl: (Severe) Both ranolazine and levomethadyl are contraindicated in combination with other agents that may prolong the QT interval. Levomethadyl i associated with an established risk of QT prolongation and/or torsades de pointes, particularly at high drug concentrations. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval; the mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported.
    Lidocaine: (Major) Ranolazine is an inhibitor of the cytochrome P450 (CYP) isoenzyme 3A, and lidocaine is a substrate for this pathway. Thus, ranolazine may theoretically reduce lidocaine clearance. If concurrent therapy with ranolazine is necessary, administer lidocaine parenteral infusions with caution and monitor lidocaine serum concentrations.
    Linagliptin; Metformin: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Lithium: (Major) Lithium should be used cautiously and with close monitoring with ranolazine. Lithium has been associated with QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Lomitapide: (Major) Concomitant use of lomitapide and ranolazine may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Ranolazine is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors. In addition, concomitant use may result in increased serum concentrations of ranolazine. According to the manufacturer of lomitapide, dose reduction of ranolazine should be considered during concurrent use. Lomitapide is an inhibitor of P-glycoprotein (P-gp) and ranolazine is a P-gp substrate.
    Long-acting beta-agonists: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loperamide: (Major) Coadministration of loperamide with ranolazine may increase the risk for QT prolongation and torsade de pointes (TdP). At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Ranolazine is also associated with dose- and plasma concentration-related increases in the QTc interval. In addition, the plasma concentrations of loperamide, a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with ranolazine, a CYP3A4, CYP2D6, and P-gp inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Loperamide; Simethicone: (Major) Coadministration of loperamide with ranolazine may increase the risk for QT prolongation and torsade de pointes (TdP). At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Ranolazine is also associated with dose- and plasma concentration-related increases in the QTc interval. In addition, the plasma concentrations of loperamide, a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with ranolazine, a CYP3A4, CYP2D6, and P-gp inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Lopinavir; Ritonavir: (Severe) Ranolazine is primarily metabolized by CYP3A, but it is also a substrate of P-glycoprotein. Ranolazine is contraindicated for use with moderate or potent inhibitors of CYP3A isoenzymes, including the anti-retroviral protease inhibitors. Ranolazine is associated with dose and plasma concentration-related increases in the QTc interval. Coadministration with anti-retroviral protease inhibitors may increase the plasma concentrations of ranolazine, thus increasing the risk of drug toxicity and proarrhythmic effects. In addition, ritonavir and several other anti-retroviral protease inhibitors can increase the absorption of ranolazine via inhibition of P-glycoprotein transport. Furthermore, ritonavir also is associated with QT prolongation; concomitant use increases the risk of QT prolongation. (Severe) Ranolazine is primarily metabolized by CYP3A, but it is also a substrate of P-glycoprotein. Ranolazine is contraindicated for use with moderate or potent inhibitors of CYP3A isoenzymes, including the anti-retroviral protease inhibitors. Ranolazine is associated with dose and plasma concentration-related increases in the QTc interval; lopinavir; ritonavir is also associated with QT prolongation. Coadministration with anti-retroviral protease inhibitors may increase the plasma concentrations of ranolazine, thus increasing the risk of drug toxicity and proarrhythmic effects. In addition, lopinavir; ritonavir and several other anti-retroviral protease inhibitors can increase the absorption of ranolazine via inhibition of P-glycoprotein transport.
    Lovastatin: (Major) The risk of myopathy and rhabdomyolysis may be increased in patients taking ranolazine and lovastatin concurrently; a lovastatin dosage adjustment may be considered. Ranolazine inhibits CYP3A isoenzymes and P-glycoprotein transport. Although not studied, ranolazine may theoretically increase plasma concentrations of CYP3A4 and/or P-glycoprotein substrates such as lovastatin. The plasma concentrations of simvastatin, a CYP3A4 substrate, and its active metabolite are each increased about 2-fold in healthy subjects receiving simvastatin (80 mg once daily) and ranolazine (1000 mg twice daily).The dose of simvastatin may have to be reduced when ranolazine is coadministered. Since lovastatin has a similar drug interaction profile relative to simvastatin, it is prudent to consider using lower doses of lovastatin during ranolazine therapy. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
    Lovastatin; Niacin: (Major) The risk of myopathy and rhabdomyolysis may be increased in patients taking ranolazine and lovastatin concurrently; a lovastatin dosage adjustment may be considered. Ranolazine inhibits CYP3A isoenzymes and P-glycoprotein transport. Although not studied, ranolazine may theoretically increase plasma concentrations of CYP3A4 and/or P-glycoprotein substrates such as lovastatin. The plasma concentrations of simvastatin, a CYP3A4 substrate, and its active metabolite are each increased about 2-fold in healthy subjects receiving simvastatin (80 mg once daily) and ranolazine (1000 mg twice daily).The dose of simvastatin may have to be reduced when ranolazine is coadministered. Since lovastatin has a similar drug interaction profile relative to simvastatin, it is prudent to consider using lower doses of lovastatin during ranolazine therapy. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
    Lumacaftor; Ivacaftor: (Severe) Concomitant use of lumacaftor; ivacaftor and ranolazine is contraindicated. Ranolazine is primarily metabolized by CYP3A and is a substrate of P-glycoprotein (P-gp). Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of ranolazine through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Regardless, FDA-approved labeling for ranolazine contraindicates its use with CYP3A inducers. Rifampin, another strong CYP3A inducer, decreases the plasma concentrations of ranolazine by approximately 95%; however, this interaction may also be influenced by rifampin's induction of P-gp transport. (Major) Avoid the concomitant use of ivacaftor and ranolazine if possible. Ivacaftor is a CYP3A substrate, and ranolazine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure; however, the clinical impact of this has not yet been determined. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (Pgp); ranolazine is partially metabolized by CYP3A and is a substrate of Pgp. Co-administration may increase ranolazine exposure leading to increased or prolonged therapeutic effects and adverse events, specifically an increased risk for QT prolongation.
    Lumacaftor; Ivacaftor: (Severe) Concomitant use of lumacaftor; ivacaftor and ranolazine is contraindicated. Ranolazine is primarily metabolized by CYP3A and is a substrate of P-glycoprotein (P-gp). Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of ranolazine through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Regardless, FDA-approved labeling for ranolazine contraindicates its use with CYP3A inducers. Rifampin, another strong CYP3A inducer, decreases the plasma concentrations of ranolazine by approximately 95%; however, this interaction may also be influenced by rifampin's induction of P-gp transport.
    Lurasidone: (Moderate) Because lurasidone is primarily metabolized by CYP3A4, concurrent use of CYP3A4 inhibitors, such as ranolazine, can theoretically lead to an increased risk of lurasidone-related adverse reactions.
    Maprotiline: (Major) Ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates, such as maprotiline, and could lead to toxicity for drugs that have a narrow therapeutic range. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration. In addition, maprotiline is associated with QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval. The need to coadminister maprotiline with ranolazine should be done with a careful assessment of risk versus benefit; consider alternative therapy to maprotiline.
    Maraviroc: (Moderate) Use caution and careful monitoring with the coadministration of maraviroc and ranolazine as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp) and CYP3A; ranolazine is an inhibitor of P-gp and a weak in vitro inhibitor of CYP3A. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
    Mefloquine: (Major) Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval, such as ranolazine. In addition, mefloquine is metabolized by CYP3A4 and P-glycoprotein (P-gp) and is a P-gp inhibitor. Ranolazine is an inhibitor of CYP3A4 and P-gp and is a substrate for P-gp. Concurrent use may increase the serum concentrations of mefloquine and/or ranolazine, further increasing the risk for QT prolongation.
    Memantine: (Moderate) Coadminister ranolazine and memantine with caution. Memantine is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the memantine dose may be necessary.
    Meperidine; Promethazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of ranolazine with other drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ranolazine include promethazine. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Promethazine is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects
    Mesoridazine: (Severe) Mesoridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Mesoridazine is contraindicated for use along with agents that, when combined with a phenothiazine, may prolong the QT interval, cause orthostatic hypotension, and/or torsade de pointes. Agents which may prolong the QT interval include ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. QT prolonging drugs should be avoided in combination with ranolazine.
    Metaproterenol: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Metformin: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Metformin; Pioglitazone: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Metformin; Repaglinide: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Ranolazine is a mild inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Metformin; Rosiglitazone: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Metformin; Saxagliptin: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Metformin; Sitagliptin: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. At high doses, methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses averaging approximately 400 mg/day. In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concurrent use of methadone with inhibitors of these enzymes may result in increased serum concentrations of methadone. Drugs with a possible risk for QT prolongation and TdP that inhibit CYP3A4, CYP2D6, and P-gp that should be used cautiously with methadone include ranolazine.
    Methamphetamine: (Major) Ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates, such as methamphetamine, and could lead to toxicity for drugs that have a narrow therapeutic range. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
    Metoclopramide: (Moderate) Ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Metoclopramide is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects.
    Metoprolol: (Moderate) Ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Metoprolol is significantly metabolized by CYP2D6 isoenzymes. Coadministration of ranolazine and metoprolol resulted in a 1.8-fold increase in the plasma concentration of metoprolol. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
    Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include ranolazine.
    Mexiletine: (Moderate) Mexiletine is significantly metabolized by CYP2D6 isoenzymes. Moderate CYP2D6 inhibitors, like ranolazine, could impair mexiletine metabolism and increase mexiletine concentrations and the risk for mexiletine-related side effects. Monitor for changes in heart rate and rhythm, as well as gastrointestinal and neurologic tolerance.
    Midazolam: (Moderate) In vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates with a narrow therapeutic index, such as midazolam, potentially leading to adverse reactions. Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent.
    Midostaurin: (Major) The concomitant use of midostaurin and ranolazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Additionally, ranolazine increased the QTc interval compared with placebo in a clinical trial.
    Mifepristone, RU-486: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, mifepristone, RU-486 is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, mifepristone may increase the absorption of ranolazine via P-glycoprotein inhibition.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as ranolazine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and ranolazine. Coadminister with caution. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mitotane: (Severe) The concomitant use of mitotane with ranolazine is contraindicated due to decreased ranolazine exposure and efficacy. Mitotane is a strong CYP3A4 inducer and ranolazine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ranolazine.
    Moxifloxacin: (Major) Prolongation of the QT interval has been reported with administration of moxifloxacin. Post-marketing surveillance has identified very rare cases of ventricular arrhythmias including torsade de pointes (TdP), usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded. According to the manufacturer, moxifloxacin should be avoided in patients taking drugs that can result in prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP include ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions and consider dose reduction of naldemedine if coadministered with ranolazine. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; ranolazine is a moderate P-gp inhibitor in vitro.
    Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with ranolazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as ranolazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with ranolazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as ranolazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Nefazodone: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including nefazodone. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes.
    Nelfinavir: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including nelfinavir. Ranolazine is associated with dose and plasma concentration-related increases in the QTc interval. Coadministration with nelfinavir may increase the plasma concentrations of ranolazine, thus increasing the risk of drug toxicity and proarrhythmic effects. In addition, nelfinavir may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
    Neratinib: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with neratinib is necessary, and titrate the dose of ranolazine based on clinical response. Ranolazine is a P-glycoprotein (P-gp) substrate. Neratinib may inhibit the transport of P-gp substrates.
    Netupitant; Palonosetron: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as ranolazine. The plasma concentrations of ranolazine can increase when co-administered with netupitant, which is a moderate CYP3A4 inhibitor; the inhibitory effect on CYP3A4 can last for multiple days. This might increase the risk for ranolazine-related side effects, such as QT prolongation. Ranolazine is a mild CYP3A4 inhibitor and a CYP2D6 inhbitior, but should not have significant effect on netupitant or palonosetron. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. Co-administration of single dose netupitant 600 mg and palonosetron 1.5 mg had no significant effects on the QTc interval.
    Nevirapine: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers. Although not specifically mentioned by the manufacturer, coadministration of ranolazine with a CYP3A enzyme inducer such as nevirapine may result in decreased ranolazine plasma concentrations and decreased efficacy.
    Niacin; Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking ranolazine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on ranolazine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of ranolazine and simvastatin against the potential risks. Ranolazine increases the simvastatin exposure by approximately 2-fold.
    Nicardipine: (Major) Coadministration of ranolazine with nicardipine may lead to an increase in serum levels of ranolazine.
    Nilotinib: (Severe) Coadministration of nilotinib and ranolazine is contraindicated. First, ranolazine is primarily metabolized by CYP3A4 and is a substrate of P-glycoprotein and of CYP2D6; nilotinib is an inhibitor of CYP3A4, P-glycoprotein (P-gp), and CYP2D6. Ranolazine use is contraindicated with potent inhibitors of CYP3A isoenzymes such as nilotinib. Coadministration would likely increase ranolazine plasma concentrations, thus increasing the risk of drug toxicity and proarrhythmic effects. Second, nilotinib prolongs the QT interval and coadministration with other drugs that prolong the QT interval is not advised; ranolazine is associated with dose and plasma concentration-related increases in the QTc interval. Finally, increased nilotinib concentrations may also occur, as nilotinib is a substrate of CYP3A4 and of P-gp, and ranolazine is an inhibitor of CYP3A4 and of P-gp.
    Nintedanib: (Moderate) In vitro, ranolazine is a moderate inhibitor of P-glycoprotein (P-gp) and a mild CYP3A4 inhibitor; nintedanib is a P-gp substrate as well as a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of ranolazine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Norfloxacin: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include norfloxacin.
    Octreotide: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include octreotide. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy warranting more cautious monitoring during octreotide administration in higher risk patients with cardiac disease.
    Ofloxacin: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include ofloxacin.
    Olanzapine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment. Drugs that are CYP2D6 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include olanzapine.
    Olodaterol: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Coadministration of ranolazine with strong CYP3A inhibitors, such as ritonavir-containing regimens, is contraindicated. Concurrent administration of ranolazine with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is expected to result in elevated plasma concentrations of ranolazine, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Both ritonavir and ranolazine are substrates and inhibitors of CYP3A4, CYP2D6, and P-glycoprotein (P-gp); both drugs are also associated with concentration-dependent QT prolongation. Paritaprevir also inhibits P-gp. Increased plasma concentrations of ranolazine and ritonavir increase the risk of drug toxicity and proarrhythmic effects. Plasma concentrations of the other antiviral agents may also be affected. Paritaprevir and dasabuvir (minor) are metabolized by CYP3A4, and dasabuvir, ombitasvir, and paritaprevir, are all substrates of P-gp. (Severe) Ranolazine is primarily metabolized by CYP3A, but it is also a substrate of P-glycoprotein. Ranolazine is contraindicated for use with moderate or potent inhibitors of CYP3A isoenzymes, including the anti-retroviral protease inhibitors. Ranolazine is associated with dose and plasma concentration-related increases in the QTc interval. Coadministration with anti-retroviral protease inhibitors may increase the plasma concentrations of ranolazine, thus increasing the risk of drug toxicity and proarrhythmic effects. In addition, ritonavir and several other anti-retroviral protease inhibitors can increase the absorption of ranolazine via inhibition of P-glycoprotein transport. Furthermore, ritonavir also is associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    Ondansetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and ranolazine should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ondansetron is a substrate for CYP3A4 and CYP2D6 and P-glycoprotein (P-gp). Ranolazine is an inhibitor of CYP3A4 and CYP2D6 and P-gp. Concurrent administration of ranolazine and ondansetron may result in increased ondansetron concentrations.
    Oritavancin: (Major) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers. Although not specifically mentioned by the manufacturer, coadministration of ranolazine with a CYP3A enzyme inducer such as oritavancin (a weak inducer) may result in decreased ranolazine plasma concentrations and decreased efficacy. Ranolazine is also a substrate of CYP2D6 and oritavancin is a weak CYP2D6 inducer.
    Osimertinib: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ranolazine with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Ranolazine is also associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ranolazine with oxaliplatin is necessary as additive QT prolongation is possible; correct electrolyte abnormalities prior to administration of oxaliplatin. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Oxcarbazepine: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers. Although not specifically mentioned by the manufacturer, coadministration of ranolazine with a CYP3A enzyme inducer such as oxcarbazepine may result in decreased ranolazine plasma concentrations and decreased efficacy.
    Oxycodone: (Moderate) Oxycodone is metabolized in part by cytochrome P450 2D6 to oxymorphone, which represents < 15% of the total administered dose. Ranolazine and/or metabolites partially inhibit CYP2D6 isoenzymes based on data available. Although the concomitant use of ranolazine with oxycodone has not been studied, ranolazine may theoretically increase plasma concentrations of oxycodone, Studies of interactions with other CYP2D6 inhibitors and oxycodone have not demonstrated clinical significance.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, paliperidone is a substrate for CYP3A4 and is an inhibitor and substrate of P-glycoprotein (P-gp). Ranolazine is an inhibitor of CYP3A4 and is a substrate and inhibitor for P-gp. Coadministration may result in increased paliperidone and/or ranolazine concentrations. If coadministration is considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential.
    Panobinostat: (Major) The co-administration of panobinostat with ranolazine is not recommended; QT prolongation has been reported with both agents. Ranolazine is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of ranolazine and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of panobinostat toxicity such as cardiac arrhythmias, diarrhea, bleeding, infection, and hepatotoxicity. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
    Paricalcitol: (Moderate) Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates like paricalcitol, potentially leading to adverse reactions.
    Paroxetine: (Moderate) Monitor for adverse effects of paroxetine (e.g., serotonin syndrome) and ranolazine (e.g., QT prolongation) during coadministration. In theory, ranolazine may reduce the metabolism of paroxetine, and paroxetine may reduce the metabolism of ranolazine, increasing the risk for adverse effects associated with either drug. Both ranolazine and paroxetine are substrates of CYP2D6. Ranolazine is a moderate inhibitor of CYP2D6 and paroxetine is a potent inhibitor of CYP2D6. Because ranolazine is primarily metabolized by CYP3A4, inhibition of a single enzyme, such as CYP2D6, may not significantly decrease ranolazine clearance.
    Pasireotide: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, such as pasireotide, coadministration may result in additive QT prolongation.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and ranolazine have been reported to prolong the QT interval. If pazopanib and ranolazine must be continued, closely monitor the patient for QT interval prolongation. In addition, pazopanib is a weak inhibitor of and substrate for CYP3A4 and a substrate for P-glycoprotein (P-gp). Ranolazine is a substrate for and an inhibitor of CYP3A4 and P-gp. Concurrent administration of ranolazine and pazopanib may result in increased pazopanib concentrations and/or increased ranolazine concentrations. Dose reduction of pazopanib should be considered when coadministration of pazopanib and ranolazine is necessary.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to ranolazine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while ranolazine is partially metabolized by the CYP2D6 isoenzyme.
    Pentamidine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment. Drugs that are CYP2D6 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include pentamidine.
    Perphenazine: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Coadministration of ranolazine with inhibitors of CYP2D6 may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects. Drugs that are CYP2D6 inhibitors that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include perphenazine.
    Perphenazine; Amitriptyline: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Coadministration of ranolazine with inhibitors of CYP2D6 may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects. Drugs that are CYP2D6 inhibitors that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include perphenazine.
    Phenicol Derivatives: (Severe) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors. Although not specifically mentioned by the manufacturer of ranolazine, chloramphenicol is known to be a strong inhibitor of CYP3A4. Inhibition of ranolazine metabolism could lead to increased ranolazine plasma concentrations and associated QTc prolongation. Do not use ranolazine with chloramphenicol due to the potential for reduced metabolism of ranolazine and the risk of QT prolongation.
    Phenylephrine; Promethazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of ranolazine with other drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ranolazine include promethazine. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Promethazine is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects
    Phenytoin: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including phenytoin. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
    Pimavanserin: (Major) Pimavanserin should be avoided in combination with ranolazine. Pimavanserin may cause QT prolongation and ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Pimozide: (Severe) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of ranolazine with pimozide is contraindicated.
    Pindolol: (Moderate) Coadminister ranolazine and pindolol with caution. Pindolol is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the pindolol dose may be necessary.
    Pirbuterol: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Ponatinib: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and ranolazine, a P-gp substrate, may increase the exposure of ranolazine. If these agents are used together, down-titrate ranolazine based on clinical response in patients concomitantly treated with P-gp inhibitors.
    Posaconazole: (Severe) The concurrent use of posaconazole and ranolazine is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Both ranolazine and posaconazole are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of ranolazine. Further, both posaconazole and ranolazine are inhibitors and substrates of the drug efflux protein, P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug. This complex interaction may ultimately result in altered plasma concentrations of both posaconazole and ranolazine. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as ranolazine.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include ranolazine.
    Procainamide: (Moderate) Ranolazine should be used cautiously with procainamide. Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Furthermore, procainamide is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the procainamide dose may be necessary.
    Prochlorperazine: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include prochlorperazine.
    Promethazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of ranolazine with other drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ranolazine include promethazine. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Promethazine is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects
    Propafenone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with ranolazine. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Coadministration of ranolazine with inhibitors of CYP2D6, such as propafenone, may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects.
    Propoxyphene: (Moderate) Ranolazine may theoretically increase plasma concentrations of drugs that are CYP2D6 substrates, like propoxyphene. Lower doses of propoxyphene than are usually prescribed may be needed during therapy with ranolazine. Monitor therapeutic response during coadministration.
    Propranolol: (Moderate) Propranolol is metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ranolazine, could theoretically impair propranolol metabolism. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
    Quazepam: (Moderate) CYP3A4 inhibitors, such as ranolazine, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
    Quetiapine: (Major) Ranolazine may increase plasma concentrations of quetiapine through CYP3A4 inhibition. Avoid co-use if possible, as both drugs have been noted to cause QTc interval prolongation. If co-use is necessary, use the combination with caution. The manufacturer of quetiapine recommends a reduced dosage of quetiapine during concurrent administration of CYP3A4 inhibitors.
    Quinidine: (Severe) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine include ranolazine.
    Quinine: (Major) Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Avoid concurrent use of quinine with other drugs that prolong the QT, such as ranolazine. In addition, quinine is an inhibitor of both CYP3A4 and CYP2D6. Ranolazine is primarily metabolized by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Conversely, ranolazine is a P-glycoprotein (P-gp) and CYP3A inhibitor, and quinine is a substrate for P-gp and CYP3A. Ranolazine may theoretically increase plasma concentrations of quinine and increase the risk for adverse effects, such as QT prolongation.
    Ranitidine: (Moderate) Coadminister ranolazine and ranitidine with caution. Ranitidine is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the ranitidine dose may be necessary.
    Red Yeast Rice: (Moderate) Since certain red yeast rice products (i.e., pre-2005 Cholestin formulations) contain lovastatin, clinicians should use red yeast rice cautiously in combination with drugs known to interact with lovastatin. CYP3A4 inhibitors have been shown to increase HMG-CoA reductase activity and potential for myopathy when coadministered with lovastatin. Because of these potential risks, red yeast rice is best avoided by patients taking CYP3A4 inhibitors. Examples of CYP3A4 inhibitors include ranolazine.
    Regadenoson: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include regadenoson.
    Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Ranolazine is a mild inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Ribociclib: (Major) Avoid coadministration of ribociclib with ranolazine due to an increased risk for QT prolongation. Additionally, the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ribociclib is also extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor; ranolazine is a weak CYP3A4 inhibitor in vitro and CYP3A4 substrate.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with ranolazine due to an increased risk for QT prolongation. Additionally, the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ribociclib is also extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor; ranolazine is a weak CYP3A4 inhibitor in vitro and CYP3A4 substrate.
    Rifabutin: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including rifabutin. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
    Rifampin: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including rifampin. Ranolazine also is a substrate for CYP2D6 and P-glycoprotein. Rifampin potently induces cytochrome P450 enzymes, including CYP3A isoenzymes, and is also an inducer of P-glycoprotein transport. Rifampin (600 mg daily) decreases the plasma concentration of ranolazine (1000 mg twice daily) by approximately 95%, likely due to induction of CYP3A and P-glycoprotein.
    Rifapentine: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including rifapentine. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ranolazine, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Rilpivirine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, potentially leading to adverse reactions, such as QT prolongation. Rilpivirine is a CYP3A4 substrate and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Caution is advised with coadministration.
    Risperidone: (Major) Risperidone and ranolazine have a possible risk for QT prolongation and torsade de pointes (TdP); therefore, caution is recommended during concurrent use. If coadministration is required and the patient has risk factors for cardiac disease or arrhythmias, close monitoring is recommended.
    Ritonavir: (Severe) Ranolazine is primarily metabolized by CYP3A, but it is also a substrate of P-glycoprotein. Ranolazine is contraindicated for use with moderate or potent inhibitors of CYP3A isoenzymes, including the anti-retroviral protease inhibitors. Ranolazine is associated with dose and plasma concentration-related increases in the QTc interval. Coadministration with anti-retroviral protease inhibitors may increase the plasma concentrations of ranolazine, thus increasing the risk of drug toxicity and proarrhythmic effects. In addition, ritonavir and several other anti-retroviral protease inhibitors can increase the absorption of ranolazine via inhibition of P-glycoprotein transport. Furthermore, ritonavir also is associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    Rivaroxaban: (Minor) The coadministration of rivaroxaban and ranolazine should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these two drugs are coadministered to patients with normal renal function. Ranolazine is a combined mild CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
    Rolapitant: (Major) Use caution if ranolazine and rolapitant are used concurrently, and monitor for ranolazine-related adverse effects. Ranolazine is a CYP2D6 and P-glycoprotein (P-gp) substrate and rolapitant is a CYP2D6 and P-gp inhibitor; the inhibitory effect of rolapitant on CYP2D6 lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Romidepsin: (Major) Romidepsin is a substrate for CYP3A4 and P-glycoprotein (P-gp). Ranolazine is a mild inhibitor of CYP3A4 and an inhibitor of P-gp. Concurrent administration of romidepsin with a mild inhibitor of CYP3A4 and an inhibitor of P-gp may cause an increase in systemic romidepsin concentrations. In addition, romidepsin has been reported to prolong the QT interval. Ranolazine may also prolong the QT interval. If romidepsin and ranolazine must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Rufinamide: (Moderate) Shortening of the QT interval has occurred during treatment with rufinamide. Therefore, caution is advisable during co-administration with other drugs associated with QT-shortening including ranolazine.
    Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ranolazine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Salmeterol: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and ranolazine as coadministration may result in increased systemic exposure of ranolazine. Ranolazine is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of ranolazine.
    Saquinavir: (Severe) Concurrent use of ranolazine and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Both saquinavir boosted with ritonavir and ranolazine are inhibitors and substrates of the hepatic isoenzyme CYP3A4. Further, both raolazine and saquinavir are substrates for P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug. This complex interaction may ultimately result in elevated plasma concentrations of both ranolazine and saquinavir, thus increasing the risk of drug toxicity and proarrhythmic effects. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as ranolazine
    Sertraline: (Major) Because both sertraline and ranolazine are associated with a possible risk of QT prolongation and Torsade de Pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, sertraline and ranolazine are partially metabolized by CYP2D6 and both agents are inhibitors of CYP2D6. Increased plasma concentrations of either drug are possible during concurrent use, which may increase the risk of QT prolongation.
    Sevoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ranolazine. Halogenated anesthetics can prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Short-acting beta-agonists: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Sildenafil: (Moderate) Sildenafil is metabolized principally by the hepatic CYP3A4 (major route) and 2C9 (minor route) isoenzymes. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors. Population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors. CYP3A4 inhibitors include ranolazine.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and ranolazine. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by ranolazine may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a P-gp inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of ranolazine, a P-gp and CYP3A4 substrate.
    Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking ranolazine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on ranolazine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of ranolazine and simvastatin against the potential risks. Ranolazine increases the simvastatin exposure by approximately 2-fold.
    Simvastatin; Sitagliptin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking ranolazine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on ranolazine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of ranolazine and simvastatin against the potential risks. Ranolazine increases the simvastatin exposure by approximately 2-fold.
    Sirolimus: (Major) Coadministration of ranolazine and sirolimus may impair the absorption and elimination of sirolimus. In vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, such as sirolimus, potentially leading to adverse reactions, especially for drugs with a narrow therapeutic index. In addition, ranolazine may decrease the absorption of sirolimus via P-glycoprotein inhibition.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with ranolazine. Taking these drugs together may increase the plasma concentrations of both velpatasvir and ranolazine, potentially resulting in adverse events. Both velpatasvir and ranolazine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). Ranolazine is also a weak in vitro inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of ranolazine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently. (Moderate) Use caution when administering velpatasvir with ranolazine. Taking these drugs together may increase the plasma concentrations of both velpatasvir and ranolazine, potentially resulting in adverse events. Both velpatasvir and ranolazine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). Ranolazine is also a weak in vitro inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Solifenacin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering solifenacin with ranolazine. Solifenacin has been associated with dose-dependent prolongation of the QT interval; TdP has been reported during post-marketing use, although causality was not determined. Ranolazine is also associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. In addition, ranolazine may inhibit the CYP3A4 metabolism of solifenacin, resulting in increased serum concentrations of solifenacin. Patients receiving CYP3A4 inhibitors should not receive solifenacin doses greater than 5 mg per day.
    Sorafenib: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include sorafenib. In addition, ranolazine concentrations may also increase with coadministration of sorafenib as ranolazine is a P-glycoprotein (PGP) substrate and sorafenib is a PGP inhibitor in vitro.
    Sotalol: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, such as sotalol, coadministration may result in additive QT prolongation. Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    Sparfloxacin: (Severe) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval such as sparfloxacin.
    St. John's Wort, Hypericum perforatum: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including St. John's wort, Hypericum perforatum. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
    Streptogramins: (Severe) Concomitant medications metabolized by CYP3A4 that may prolong the QT interval should be avoided during dalfopristin; quinupristin. Dalfopristin; quinupristin is a significant CYP3A4 inhibitor, and may reduce the hepatic metabolism of CYP3A4 substrates. Moderate or potent CYP3A4 inhibitors are contraindicated for use with ranolazine, a CYP3A4 substrate. Inhibition of ranolazine metabolism could lead to increased ranolazine plasma concentrations and associated QTc prolongation. Avoid coadministration of ranolazine with dalfopristin; quinupristin due to the potential for reduced metabolism of ranolazine and the risk of QT prolongation.
    Sufentanil: (Moderate) Ranolazine may increase plasma concentrations of sufentanil. In vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, such as sufentanil, potentially leading to adverse reactions, especially for drugs with a narrow therapeutic index.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) have been reported during post-marketing use of sulfamethoxazole; trimethoprim. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sulfamethoxazole; trimethoprim include ranolazine.
    Sunitinib: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include sunitinib.
    Tacrolimus: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, potentially leading to adverse reactions, such as QT prolongation. Drugs that are CYP3A4 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include tacrolimus.
    Tadalafil: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Inhibitors of CYP3A4 may reduce tadalafil clearance. In theory, CYP3A4 inhibitors which may interact with tadalafil include ranolazine. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the 'as needed' dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the 'once-daily' dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
    Tamoxifen: (Major) Concomitant use of tamoxifen and ranolazine may cause an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Ranolazine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4 and CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of ranolazine. Tamsulosin is extensively metabolized by CYP2D6 and CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Therefore, concomitant use with drugs that inhibit both CYP2D6 and CYP3A4, such as ranolazine, should be avoided.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering ranolazine with telaprevir due to an increased potential for ranolazine-related adverse events. If ranolazine dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of ranolazine and telaprevir. Both ranolazine and telaprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4 and the drug efflux transporter, P-glycoprotein (PGP). When used in combination, the plasma concentrations of both medications may be elevated.
    Telavancin: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include telavancin.
    Telithromycin: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including telithromycin. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Telotristat Ethyl: (Severe) Coadministration of telotristat ethyl and ranolazine is contraindicated, as the systemic exposure of ranolazine may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. Ranolazine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Coadministration with a strong CYP3A4 inducer decreased plasma concentrations of ranolazine by approximately 95%. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and ranolazine is a P-gp inhibitor in vitro. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with ranolazine is necessary, and monitor for an increase in temsirolimus- and ranolazine-related adverse reactions. Temsirolimus is a CYP3A4 substrate and ranolazine is a weak CYP3A4 inhibitor in vitro. Additionally, temsirolimus is a P-glycoprotein (P-gp) substrate/inhibitor in vitro, while ranolazine is also a P-gp substrate/inhibitor (in vitro). Coadministration may increase plasma concentrations of both ranolazine and temsirolimus (and active metabolite, sirolimus). Coadministration of temsirolimus with ketoconazole, a strong CYP3A4 inhibitor, had no significant effect on the AUC or Cmax of temsirolimus, but increased the sirolimus AUC and Cmax by 3.1-fold and 2.2-fold, respectively. Coadministration of ranolazine with another CYP3A substrate, simvastatin, increased simvastatin exposure by 100%; ranolazine increased exposure to digoxin, a P-gp substrate, by 50%. Pharmacokinetic data are not available for temsirolimus use with weak CYP3A4 inhibitors or P-gp substrate / inhibitors, or for ranolazine use with P-gp inhibitors.
    Tenofovir Alafenamide: (Minor) Close clinical monitoring is advised when administering ranolazine with tenofovir alafenamide due to an increased potential for adverse events. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Ranolazine is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Coadministration may result in increased tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Terbinafine: (Moderate) Coadministration of terbinafine and ranolazine may result in increased plasma concentrations of ranolazine. Ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Terbinafine is a known CYP2D6 inhibitor. Cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects.The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors.
    Terbutaline: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Testosterone: (Moderate) Testosterone is an inhibitor of P-glycoprotein transport. Ranolazine is a substrate of P-glycoprotein, and inhibitors of P-glycoprotein may increase the absorption of ranolazine. In addition, ranolazine inhibits CYP3A and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4 such as testosterone.
    Tetrabenazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, such as tetrabenazine, coadministration of such drugs may result in additive QT prolongation. The manufacturer of tetrabenazine recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes and tetrabenazine is a substrate. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment.
    Thioridazine: (Severe) Coadministration is contraindicated. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Because of the potential for TdP, coadministration is contraindicated. Additionally, thioridazine is an inhibitor of CYP2D6, and ranolazine is metabolized, to a lesser extent, by CYP2D6. Thioridazine may increase the plasma concentrations of ranolazine.
    Ticagrelor: (Moderate) Coadministration of ticagrelor and ranolazine may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and ranolazine is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Timolol: (Moderate) Timolol is metabolized by CYP2D6 isoenzymes. Ranolazine, a CYP2D6 inhibitor, could theoretically impair timolol metabolism. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
    Tiotropium; Olodaterol: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tipranavir: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, tipranavir is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, tipranavir may decrease the absorption of ranolazine via P-glycoprotein induction.
    Tizanidine: (Major) Ranolazine should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Tolterodine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation, such as tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Tolterodine should be used cautiously and with close monitoring in patients taking other drugs that are associated with QT prolongation. In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed; however, ranolazine is a CYP3A4 inhibitor. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes and tolterodine is a CYP2D6 substrate. Coadministration may result in increased tolterodine serum concentrations.
    Tolvaptan: (Moderate) Administering tolvaptan with ranolazine may result in elevated tolvaptan plasma concentrations. Tolvaptan is a substrate of CYP3A4 and P-gp; ranolazine is an inhibitor of P-gp and is a weak inhibitor of CYP3A4. If these drugs are used together, closely monitor for signs of adverse events.
    Topotecan: (Major) Avoid the concomitant use of ranolazine, an in vitro P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of ranolazine and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Toremifene: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Trabectedin: (Minor) Use caution if coadministration of trabectedin and ranolazine is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, ranolazine is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Tramadol: (Moderate) As ranolazine is a weak to moderate CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Trandolapril; Verapamil: (Major) The dose of ranolazine, a CYP3A4 and P-glycoprotein substrate, should be limited to 500 mg PO twice daily when coadministered with verapamil, a moderate CYP3A inhibitor. Verapamil (120 mg three times daily) causes dose-dependent increases in the average steady-state concentrations of ranolazine by about 2-fold.
    Trazodone: (Major) The manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP).Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. In addition, ranolazine could impair the metabolism of trazodone through inhibition of CYP3A, thereby increasing the risk of trazodone-related adverse effects, including QT prolongation.
    Triazolam: (Moderate) In vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, such as triazolam, potentially leading to adverse reactions, especially for drugs with a narrow therapeutic index.
    Tricyclic antidepressants: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment. Drugs that are CYP2D6 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include tricyclic antidepressants.
    Trifluoperazine: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include trifluoperazine.
    Triptorelin: (Major) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include ranolazine.
    Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and ranolazine is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events. In addition, in vitro data indicate that ulipristal may be an inhibitor of P-glycoprotein (P-gp) at clinically relevant concentrations. Thus, co-administration of ulipristal and P-gp substrates such as ranolazine may increase ranolazine concentrations; use caution. In the absence of clinical data, co-administration of ulipristal (when given daily) and P-gp substrates is not recommended.
    Umeclidinium; Vilanterol: (Moderate) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ranolazine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Vandetanib: (Major) The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval due to an increased risk of QT prolongation and torsade de pointes (TdP); additionally, an increase in ranolazine-related adverse reactions is also possible. Vandetanib can prolong the QT interval in a concentration-dependent manner. TdP and sudden death have been reported in patients receiving vandetanib; ranolazine also has a possible risk for QT prolongation. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose. Additionally, ranolazine is a substrate of P-glycoprotein (P-gp) in vitro. Coadministration with vandetanib increased the Cmax and AUC of another P-gp substrate by 29% and 23%, respectively.
    Vardenafil: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. Drugs that are CYP3A4 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include vardenafil. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).
    Varenicline: (Moderate) Coadminister ranolazine and varenicline with caution. Varenicline is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the varenicline dose may be necessary.
    Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as ranolazine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, ranolazine is a CYP2D6 substrate, a CYP3A4 substrate/inhibitor, and P-glycoprotein (PGP) substrate/inhibitor. Vemurafenib is a weak CYP2D6 inhibitor, a CYP3A4 substrate/inducer, and a PGP substrate/inhibitor. Altered concentrations of both drugs may occur with concomitant use; therefore, monitor the patient for toxicity and efficacy.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and ranolazine; venetoclax is a substrate of P-glycoprotein (P-gp) and ranolazine is an inhibitor of P-gp. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day). If ranolazine is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    Venlafaxine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include venlafaxine. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates, such as venlafaxine, and could lead to toxicity for drugs that have a narrow therapeutic range.
    Verapamil: (Major) The dose of ranolazine, a CYP3A4 and P-glycoprotein substrate, should be limited to 500 mg PO twice daily when coadministered with verapamil, a moderate CYP3A inhibitor. Verapamil (120 mg three times daily) causes dose-dependent increases in the average steady-state concentrations of ranolazine by about 2-fold.
    Vinblastine: (Moderate) Use ranolazine and Vinca alkaloids together with caution; concomitant use may result in increased vinblastine plasma concentrations and increased vinblastine toxicity. Ranolazine is a weak CYP3A4 inhibitor and a moderate P-glycoprotein inhibitor (P-gp); vinca alkaloids are CYP3A4 and P-gp substrates.
    Vinca alkaloids: (Moderate) Use ranolazine and Vinca alkaloids together with caution; concomitant use may result in increased vinblastine plasma concentrations and increased vinblastine toxicity. Ranolazine is a weak CYP3A4 inhibitor and a moderate P-glycoprotein inhibitor (P-gp); vinca alkaloids are CYP3A4 and P-gp substrates.
    Vincristine Liposomal: (Moderate) Use ranolazine and Vinca alkaloids together with caution; concomitant use may result in increased vinblastine plasma concentrations and increased vinblastine toxicity. Ranolazine is a weak CYP3A4 inhibitor and a moderate P-glycoprotein inhibitor (P-gp); vinca alkaloids are CYP3A4 and P-gp substrates.
    Vincristine: (Moderate) Use ranolazine and Vinca alkaloids together with caution; concomitant use may result in increased vinblastine plasma concentrations and increased vinblastine toxicity. Ranolazine is a weak CYP3A4 inhibitor and a moderate P-glycoprotein inhibitor (P-gp); vinca alkaloids are CYP3A4 and P-gp substrates.
    Vinorelbine: (Moderate) Use ranolazine and Vinca alkaloids together with caution; concomitant use may result in increased vinblastine plasma concentrations and increased vinblastine toxicity. Ranolazine is a weak CYP3A4 inhibitor and a moderate P-glycoprotein inhibitor (P-gp); vinca alkaloids are CYP3A4 and P-gp substrates.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and ranolazine. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ranolazine, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including voriconazole. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes.
    Vorinostat: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Vorinostat therapy is associated with a risk of QT prolongation and should be used cautiously with ranolazine.
    Zafirlukast: (Major) Coadministration of ranolazine with CYP3A4 inhibitors like zafirlukast could lead to an increase in ranolazine serum concentrations, with potential to result in QTc prolongation and torsade de pointes.
    Ziprasidone: (Severe) According to the manufacturer, ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine. Given the potential for QT prolongation, ziprasidone is contraindicated for use with drugs that are known to cause QT prolongation with potential for torsades de pointes including ranolazine.
    Zolpidem: (Moderate) In vitro studies indicate that ranolazine and its O-demethylated metabolite are inhibitors of CYP3A isoenzymes. In theory, ranolazine may inhibit zolpidem CYP3A4 metabolism, potentially leading to increased zolpidem plasma concentrations. Although not studied, excessive sedation and possible respiratory depression may occur.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ranolazine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no data on the use of ranolazine during pregnancy to inform any drug-associated risks. Animal studies have shown fetal toxicity (decreased fetal weight and reduced ossification) and maternal weight loss at doses 4 times the maximum recommended human dose (MRHD). No adverse effects were observed when animals were administered doses equal to the MRHD.

    There are no data on the presence of ranolazine in human milk, the effects on the breast-fed infant, or the effects on milk production. Ranolazine is present in rat milk. Adult female rats were administered ranolazine from gestation through postnatal day 20. At maternally toxic doses, male and female pups exhibited increased mortality and decreased body weight, and female pups showed increased motor activity. The pups were potentially exposed to low amounts of ranolazine via maternal milk. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for ranolazine and any potential adverse effects on the breast-fed infant from ranolazine or from the underlying maternal condition.

    MECHANISM OF ACTION

    Mechanism of Action: Ranolazine is a piperazine compound that belongs in a group known as partial fatty-acid oxidation (PFox) inhibitors. The exact mechanism of action is not clear. Initially, the main anti-anginal effects of ranolazine were thought to be related to the actions of ranolazine to shift adenosine triphosphate (ATP) production away from fatty acid oxidation toward glycolysis. Recent evidence suggests ranolazine is an inhibitor of the late sodium current which results in a reduction of the intracellular sodium and calcium overload in ischemic cardiac myocytes. Ranolazine does not possess negative chronotropic or inotropic effects, and has had minimal effects on heart rate and blood pressure during clinical trials in patients with angina and CHF NYHA Class I or II, and also in a study of 85 patients with CHF NYHA Class III or IV. In contrast, traditional antianginal agents reduce myocardial oxygen demand by lowering blood pressure and/or heart rate. Heart rate and arterial pressure at rest and at peak exercise are unchanged after ranolazine (240 mg single dose). Given the absence of hemodynamic effects, this drug can be safely added to traditional antianginal therapy if there are no other significant drug interactions (see Drug Interactions).Ranolazine has been associated with a significant dose and concentration-related prolongation of the QT interval. These effects are believed to be caused by ranolazine and not by its metabolites. The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of I(Kr), which prolongs the ventricular action potential.The effects of ranolazine on angina frequency and exercise tolerance are considerably smaller in women than in men. In the CARISA trial, the improvement in Exercise Tolerance Test (ETT) in females was about 33% of that in males at the 1000 mg twice daily dosage. In the ERICA trial, the mean reduction in weekly anginal attacks was 0.3 for females and 1.3 for males. The mechanism for the reduced antianginal benefits in females is not known.In addition to comparable antianginal efficacy for diabetic vs. nondiabetic patients, preliminary data suggest that ranolazine may have a slight benefit on HbA1c values in diabetic patients. The mechanism of this effect is under investigation. One hundred and thirty one diabetic patients were placed on placebo or ranolazine 750 mg or 1000 mg PO twice daily. The HbA1c values were compared before and after 12 weeks of treatment. The HbA1c decreased significantly from 7.65 to 7.14 (p = 0.0008) in the ranolazine 750-mg group and 7.92 to 6.93 (p = 0.0002) in the ranolazine 1000-mg group. Additional prospective data from the MERLIN TIMI-36 trial provide further evidence supporting this theory. Among 4306 patients undergoing treatment for ACS in which serial data are available, those treated with ranolazine experienced a significant reduction in HbA1c compared with placebo. Patients diagnosed with diabetes mellitus treated with ranolazine were more likely to achieve a HbA1c <7% at 4 months compared to those patients treated with placebo (59% vs. 49%, p < 0.001).

    PHARMACOKINETICS

    Ranolazine is administered orally. Ranolazine is approximately 62% bound to plasma proteins. Following absorption, ranolazine is rapidly and extensively metabolized within the liver and intestine by hepatic cytochrome P450 (CYP) isoenzymes. Ranolazine is metabolized by numerous drug elimination pathways, forming an abundant number of metabolites (at least twelve), with four main metabolites having exposure (AUC) at least 10% relative to the parent compound. Ranolazine is primarily metabolized by CYP3A isoenzymes and to a lesser extent by CYP2D6 isoenzymes. It is also a substrate of P-glycoprotein (P-gp). Drugs that affect these isoenzymes may alter the response to ranolazine. According to the manufacturer, ranolazine is specifically contraindicated for use with inducers or potent inhibitors of CYP3A. In addition, inhibitors of P-gp (e.g., cyclosporine) may increase drug absorption.
     
    Approximately 75% of an oral dose of ranolazine is excreted in urine; 25% is excreted in feces. Less than 5% is excreted unchanged in the urine and feces. The apparent terminal half-life of ranolazine is 7 hours. Steady-state for the parent drug is generally achieved within 3 days of twice daily dosing. After dosing to steady-state with 500 mg to 1500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about 5 to 33% that of ranolazine. The half-lives of the metabolites range from 6 to 22 hours; the time to steady-state for the longest-acting metabolite is expected to be longer than for the parent drug (steady-state is generally reached by 5 times the half-life), especially for patients with renal or hepatic impairment. The pharmacologic activity of the metabolites has not been well characterized. The drug-induced QT prolonging effects are believed to be caused by ranolazine and not by its metabolites.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP2D6, P-gp, OCT2
    In vitro studies indicate that ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A and moderate inhibitors of CYP2D6 and P-gp in addition to being inhibitors of OCT2 (Organic Cation Transporter 2). Also in vitro, ranolazine is a substrate of CYP3A and, to a lesser extent, CYP2D6 in addition to being a substrate for P-gp.

    Oral Route

    After oral administration, peak plasma concentrations of ranolazine are attained within 2—5 hours. Following administration of an oral solution of radiolabeled ranolazine, 73% of the dose is systemically available as parent drug or metabolites. Compared to the oral solution, the relative bioavailability of ranolazine extended-release tablets (Ranexa) is about 76%. Food has no important effect on the Cmax or AUC.
     
    Due to extensive and rapid gut and liver metabolism, the systemic availability of ranolazine is highly variable. For example, at a oral dose of 1000 mg twice daily the mean steady-state Cmax is 2569 ng/ml, with 95% of Cmax values ranging between 420 and 6080 ng/ml. The variability has clinical relevance since ranolazine is associated with dose and plasma concentration-dependent increases in QTc prolongation. At steady-state, ranolazine Cmax and AUC increase slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively, over the therapeutic range (500 to 1000 mg PO twice daily). With twice daily dosing, the trough to peak ratio of the ranolazine plasma concentration is 0.3—0.6. The relationship between ranolazine plasma concentrations and QTc remains linear over a concentration range up to several-fold greater than the concentrations produced by the maximum recommended dosage (1000 mg PO twice daily), and is not affected by changes in heart rate. Age, weight, gender, race, heart rate, CHF NYHA Class I to IV, and diabetes have no significant effect on the relationship between ranolazine plasma concentration and the increase in QTc interval.