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  • CLASSES

    Small Molecule Antineoplastic Cyclin-Dependent Kinase (CDK) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral, selective inhibitor of cyclin-dependent kinases (CDKs) 4 and 6
    Used for the initial endocrine-based treatment of hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor in postmenopausal women
    Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions

    COMMON BRAND NAMES

    KISQALI

    HOW SUPPLIED

    KISQALI/Ribociclib Oral Tab: 200mg

    DOSAGE & INDICATIONS

    For the treatment of breast cancer.
    For the first-line treatment of HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy, in combination with an aromatase inhibitor.
    Oral dosage
    Adult females

    600 mg orally once daily, preferably in the morning, on days 1 to 21, followed by 7 days of rest, repeated every 28 days; administer in combination with an aromatase inhibitor at its recommended dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Pre- or perimenopausal women should also be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards. In a randomized, double-blind clinical trial (MONALEESA-7), treatment with ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) and goserelin significantly improved the median progression-free survival (PFS) in previously untreated pre- and perimenopausal women with HR-positive, HER2-negative advanced breast cancer compared with placebo plus an NSAI and goserelin (27.5 months vs. 13.8 months). The median overall survival could not be estimated in patients who received ribociclib plus an NSAI or tamoxifen and goserelin compared with 40.9 months in those who received placebo/NSAI or tamoxifen/goserelin. Estimated overall survival at 42 months was significantly improved in the subgroup of patients receiving ribociclib/NSAI/goserelin compared with placebo/NSAI/goserelin (69.7% vs. 43%).[61816] [64287]After a median follow-up of 26.4 months, ribociclib plus letrozole also significantly improved PFS in postmenopausal women with HR-positive, HER2-negative advanced breast cancer compared with placebo plus letrozole (25.3 months vs. 16 months) in another randomized, double-blind clinical trial (MONALEESA-2); the overall response rate in patients with measurable disease was 54.5% versus 38.8%, respectively, in this trial. Median overall survival was not reached in the combination therapy arm compared with 33 months in patients who received placebo plus letrozole.[61816] [63747]

    For the first-line treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy, in combination with fulvestrant.
    Oral dosage
    Postmenopausal females

    600 mg orally once daily, preferably in the morning, on days 1 to 21, followed by 7 days of rest, repeated every 28 days. Administer in combination with fulvestrant 500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area), on days 1, 15, 29 and once monthly thereafter. Give each injection over 1 to 2 minutes.[32947] [61816] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized, double-blind, clinical trial, treatment with ribociclib plus fulvestrant significantly improved investigator-assessed progression-free survival (PFS) compared with placebo plus fulvestrant in postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had received no or only one line of prior endocrine treatment (20.5 months vs. 12.8 months); the overall response rate in patients with measurable disease was 40.9% versus 28.7%, respectively.[61816]

    For the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer after disease progression on endocrine therapy, in combination with fulvestrant.
    Oral dosage
    Postmenopausal females

    600 mg orally once daily, preferably in the morning, on days 1 to 21, followed by 7 days of rest, repeated every 28 days. Administer in combination with fulvestrant 500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area), on days 1, 15, 29 and once monthly thereafter. Give each injection over 1 to 2 minutes. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized, double-blind, clinical trial, treatment with ribociclib plus fulvestrant significantly improved investigator-assessed progression-free survival (PFS) compared with placebo plus fulvestrant in postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had received no or only one line of prior endocrine treatment (20.5 months vs. 12.8 months); the overall response rate in patients with measurable disease was 40.9% versus 28.7%, respectively.

    MAXIMUM DOSAGE

    Adults

    600 mg PO once daily.

    Geriatric

    600 mg PO once daily.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment:
    Mild hepatic impairment (Child-Pugh class A): No dosage adjustment necessary.
    Moderate to severe hepatic impairment (Child-Pugh class B or C): Reduce the starting dose of ribociclib to 400 mg orally once daily. Recommendations for patients who have grade 3 or higher elevations in AST/ALT at baseline have not been established.
     
    Treatment-Related Hepatotoxicity:
    AST/ALT up to 3 times the upper limit of normal (ULN) (grade 1); total bilirubin less than 2 times ULN: No dosage adjustment necessary.
    AST/ALT 3.01 to 5 times ULN (grade 2); total bilirubin LESS than 2 times ULN: If baseline hepatic impairment was grade 2, continue treatment with ribociclib; more frequent monitoring of LFTs is recommended. If baseline was grade 0 or 1, hold ribociclib therapy. For the first occurrence of grade 2 hepatotoxicity, resume treatment at original dose level when AST/ALT resolve to less than or equal to baseline. For recurrent grade 2 hepatotoxicity, resume therapy at the next lower dose level (reduce 600 mg to 400 mg; reduce 400 mg to 200 mg). More frequent monitoring of LFTs is recommended. If further dose reduction below 200 mg per day is required, discontinue treatment.
    AST/ALT 3.01 to 5 times ULN (grade 2); total bilirubin GREATER than 2 times ULN (irrespective of baseline; in the absence of cholestasis): Discontinue ribociclib therapy.
    AST/ALT 5.01 to 20 times ULN (grade 3); total bilirubin LESS than 2 times ULN: Hold ribociclib therapy. For the first occurrence of grade 3 hepatotoxicity, resume therapy at the next lower dose level when AST/ALT recover to baseline grade or lower (reduce 600 mg to 400 mg; reduce 400 mg to 200 mg). More frequent monitoring of LFTs is recommended. If further dose reduction below 200 mg per day is required, discontinue treatment. Discontinue ribociclib for recurrent grade 3 hepatotoxicity.
    AST/ALT 5.01 to 20 times ULN (grade 3); total bilirubin GREATER than 2 times ULN (irrespective of baseline; in the absence of cholestasis): Discontinue ribociclib therapy.
    AST/ALT greater than 20 times ULN (grade 4): Discontinue ribociclib therapy.

    Renal Impairment

    Baseline Renal Insufficiency
    Mild to moderate renal impairment (CrCL 30 to 90 mL/min): No dosage adjustment is necessary.
    Severe renal impairment (CrCL less than 30 mL/min): The recommended starting dose of ribociclib is 200 mg PO once daily.

    ADMINISTRATION

    Take with or without food.
    Take ribociclib at approximately the same time each day, preferably in the morning.
    If a dose is missed or the patient vomits, do not take any additional doses that day. Take the next prescribed dose at the usual time.
    Swallow tablets whole; do not crush, break, or chew. Do not take any tablet that is broken, cracked, or otherwise not intact.

    STORAGE

    KISQALI:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Hepatic disease, hepatotoxicity

    Use ribociclib with caution in patients with baseline hepatic disease; a dose reduction is necessary in patients with baseline Child-Pugh class B or C hepatic disease. Hepatotoxicity, including elevated transaminases with or without an elevation in total bilirubin, has been reported in patients receiving therapy with ribociclib in combination with either letrozole or fulvestrant. The median time to onset of grade 3 or higher transaminase elevations was 85 days, with a median time to resolution to grade 2 or less of 22 days. Monitor liver function tests prior to initiating therapy with ribociclib, every 2 weeks for the first 2 cycles, prior to the next 4 cycles, and then as clinically indicated. A dose interruption, reduction, or discontinuation of therapy may be necessary.

    Bone marrow suppression, neutropenia

    Bone marrow suppression is commonly reported with ribociclib plus letrozole therapy, with neutropenia being the most frequently reported adverse reaction. The median time to onset of grade 2 or higher neutropenia was 16 days, with the median time to resolution (to normalization or below grade 3) of 12 days. Monitor a complete blood count (CBC) prior to initiating therapy with ribociclib, every 2 weeks for the first 2 cycles, prior to the next 4 cycles, and then as clinically indicated. A dose interruption, reduction, or discontinuation of therapy may be necessary for patients with an absolute neutrophil count (ANC) less than 1,000 cells/mm3.

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

    Avoid the use of ribociclib in patients with long QT syndrome, uncontrolled or significant cardiac disease including cardiac arrhythmias, recent myocardial infarction, congestive heart failure, unstable angina and bradycardia or bradyarrhythmias, electrolyte imbalance (hypomagnesemia, hypokalemia, hypocalcemia), or in patients receiving medications known to prolong the QT interval or strongly inhibit CYP3A4 as this may lead to prolongation of the QTcF interval. Use ribociclib with caution in patients with other conditions that may increase the risk of QT prolongation including hypertension, coronary artery disease, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation. Assess ECG prior to starting therapy; do not initiate treatment in patients with a QTcF greater than 450 msec. Repeat ECG at approximately day 14 of the first cycle, at the beginning of the second cycle, and then as clinically indicated. Prolongation of the QTcF interval may require interruption of therapy, dose reduction, or discontinuation of therapy. Monitor serum electrolytes (including potassium, calcium, phosphorous and magnesium) prior to beginning therapy with ribociclib, at the beginning of the first 6 cycles, and as clinically indicated; correct any electrolyte imbalance before starting ribociclib therapy. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; these ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. There are no reported cases of Torsades de Pointes (TdP).

    Chronic lung disease (CLD), pneumonitis

    Use ribociclib with caution in patients who have a history of pre-existing chronic lung disease (CLD); severe pneumonitis/interstitial lung disease (ILD) has been reported in patients treated with ribociclib when taken in combination with endocrine therapy. Advise patients to immediately report any new or worsening respiratory symptoms including hypoxia, cough, or dyspnea. Immediately interrupt ribociclib in patients with new or worsening respiratory symptoms indicative of ILD/pneumonitis and exclude other causes. Permanently discontinue ribociclib in patients with recurrent symptomatic or severe ILD/pneumonitis.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during ribociclib treatment and for at least 3 weeks after the last dose. Although there are no available human data, ribociclib can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving ribociclib should be apprised of the potential hazard to the fetus. When given to pregnant rats at exposures approximately 0.6 times what would be achieved at the recommended human dose, reduced maternal body weight gain and reduced fetal weights were accompanied by skeletal changes related to the lower fetal weights. Increased incidences of fetal abnormalities (malformations and external, visceral, and skeletal variants) as well as lower fetal weights occurred in rabbits treated at exposures of 1.5 times what would be achieved at the recommended human dose; there was no maternal toxicity at this dose. Fetal abnormalities included reduced/small lung lobes, additional vessel on the descending aorta, additional vessel on the aortic arch, small eyes, diaphragmatic hernia, absent accessory lobe or (partly) fused lung lobes, reduced/small accessory lung lobe, extra/rudimentary 13th ribs, misshapen hyoid bone, bent hyoid bone alae, and reduced number of phalanges in the pollex; there was not an increased incidence of embryo-fetal mortality.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during ribociclib treatment. Ribociclib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception (resulting in less than 1% pregnancy rates) during and for at least 3 weeks after treatment with ribociclib. Females of reproductive potential should undergo pregnancy testing prior to initiation of ribociclib. Women who become pregnant while receiving ribociclib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of ribociclib on human fertility, male infertility has been observed in animal studies.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from ribociclib, advise women to discontinue breast-feeding during treatment and for 3 weeks after the final dose. It is not known whether ribociclib is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 53.0-65.0
    leukopenia / Delayed / 12.0-36.0
    lymphopenia / Delayed / 7.0-15.0
    elevated hepatic enzymes / Delayed / 5.0-11.0
    QT prolongation / Rapid / 1.0-6.0
    hypophosphatemia / Delayed / 2.0-6.0
    infection / Delayed / 1.0-5.0
    anemia / Delayed / 0-4.0
    vomiting / Early / 1.0-4.0
    fatigue / Early / 0-3.0
    renal failure (unspecified) / Delayed / 0-3.0
    thrombocytopenia / Delayed / 0-2.0
    anorexia / Delayed / 0-2.0
    nausea / Early / 0-2.0
    dyspnea / Early / 0-2.0
    back pain / Delayed / 0-2.0
    hypokalemia / Delayed / 0-2.0
    abdominal pain / Early / 0-1.0
    constipation / Delayed / 0-1.0
    stomatitis / Delayed / 0-1.0
    diarrhea / Early / 0-1.0
    pruritus / Rapid / 0-1.0
    rash / Early / 0-1.0
    headache / Early / 0-1.0
    insomnia / Early / 0-1.0
    fever / Early / 0-1.0
    arthralgia / Delayed / 0-1.0
    hypoglycemia / Early / 0-1.0
    dizziness / Early / 0-1.0
    pulmonary fibrosis / Delayed / 0-0.6
    pneumonitis / Delayed / 0.4-0.4
    interstitial lung disease / Delayed / 0.4-0.4
    acute respiratory distress syndrome (ARDS) / Early / 0-0.2

    Moderate

    peripheral edema / Delayed / 12.0-14.0
    hypoalbuminemia / Delayed / 0-12.0
    erythema / Early / 0-4.0
    hypocalcemia / Delayed / 2.0-4.0

    Mild

    alopecia / Delayed / 19.0-33.0
    cough / Delayed / 15.0-22.0
    asthenia / Delayed / 12.0-14.0
    dyspepsia / Early / 5.0-10.0
    xerosis / Delayed / 0-8.0
    dysgeusia / Early / 0-7.0
    xerostomia / Early / 0-5.0
    xerophthalmia / Early / 0-5.0
    vertigo / Early / 0-5.0
    lacrimation / Early / 0-4.0
    syncope / Early / 0.4-3.0

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Use caution if coadministration of ribociclib with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
    Abemaciclib: (Major) If coadministration with ribociclib is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If ribociclib is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of ribociclib. Abemaciclib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and ribociclib; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong CYP3A inhibitor for 5 days.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with ribociclib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ribociclib is a strong inhibitor of CYP3A4.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with ribociclib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ribociclib is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with ribociclib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ribociclib is a strong inhibitor of CYP3A4.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ribociclib is necessary. If ribociclib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ribociclib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ribociclib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Acetaminophen; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with ribociclib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of ribociclib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Aclidinium; Formoterol: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as formoterol as compared to short-acting beta-agonists.
    Ado-Trastuzumab emtansine: (Major) Avoid coadministration of ribociclib with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until ribociclib has cleared from the circulation (approximately 3 half-lives of ribociclib) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; ribociclib is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Albuterol: (Minor) Coadministration may result in additive effects on the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval such as ribociclib. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol; Ipratropium: (Minor) Coadministration may result in additive effects on the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval such as ribociclib. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of ribociclib is necessary. If ribociclib is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ribociclib can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If ribociclib is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
    Alfuzosin: (Severe) Alfuzosin is contraindicated for use with ribociclib due to the potential for serious/life-threatening reactions, including hypotension. Additive effects on the QT interval may also occur. Alfuzosin is a CYP3A4 substrate that may prolong the QT interval in a dose-dependent manner. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner. Concomitant use may increase the risk for QT prolongation.
    Aliskiren; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ribociclib is necessary; adjust the dose of amlodipine as clinically appropriate. Ribociclib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ribociclib is necessary; adjust the dose of amlodipine as clinically appropriate. Ribociclib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with ribociclib is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and ribociclib should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
    Alosetron: (Moderate) Concomitant use of alosetron with ribociclib may result in increased serum concentrations of alosetron and increase the risk for adverse reactions. Caution and close monitoring are advised if these drugs are used together. Alosetron is a substrate of hepatic isoenzyme CYP3A4; ribociclib is a strong inhibitor of this enzyme. In a study of healthy female subjects, another strong CYP3A4 inhibitor increased mean alosetron AUC by 29%.
    Alprazolam: (Major) Avoid coadministration of alprazolam and ribociclib due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ribociclib, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold.
    Amiodarone: (Major) Avoid coadministration of ribociclib with amiodarone due to an increased risk for QT prolongation and torsade de pointes (TdP). The systemic exposure to amiodarone may also increase resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Amiodarone, a Class III antiarrhythmic agent, is a CYP3A4 substrate that is also associated with a well-established risk of QT prolongation; although the frequency is less with amiodarone than with other Class III agents, amiodarone is additionally 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.
    Amitriptyline: (Major) Avoid coadministration of ribociclib with amitriptyline due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Concomitant use may increase the risk for QT prolongation.
    Amitriptyline; Chlordiazepoxide: (Major) Avoid coadministration of ribociclib with amitriptyline due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Concomitant use may increase the risk for QT prolongation. (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with ribociclib is necessary; adjust the dose of chlordiazepoxide if necessary. Ribociclib is a strong CYP3A4 inhibitor and chlordiazepoxide is a CYP3A4 substrate.
    Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ribociclib is necessary; adjust the dose of amlodipine as clinically appropriate. Ribociclib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Atorvastatin: (Major) If concomitant use of atorvastatin with ribociclib is necessary, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Ribociclib is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ribociclib is necessary; adjust the dose of amlodipine as clinically appropriate. Ribociclib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ribociclib is necessary; adjust the dose of amlodipine as clinically appropriate. Ribociclib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ribociclib is necessary; adjust the dose of amlodipine as clinically appropriate. Ribociclib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ribociclib is necessary; adjust the dose of amlodipine as clinically appropriate. Ribociclib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ribociclib is necessary; adjust the dose of amlodipine as clinically appropriate. Ribociclib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Telmisartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ribociclib is necessary; adjust the dose of amlodipine as clinically appropriate. Ribociclib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ribociclib is necessary; adjust the dose of amlodipine as clinically appropriate. Ribociclib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of ribociclib with clarithromycin due to the potential for additive effects on the QT interval and significantly increased exposure to ribociclib. Ribociclib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor that has an established risk for QT prolongation and torsade de pointes (TdP). Concomitant use may increase the risk for QT prolongation.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of ribociclib with clarithromycin due to the potential for additive effects on the QT interval and significantly increased exposure to ribociclib. Ribociclib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor that has an established risk for QT prolongation and torsade de pointes (TdP). Concomitant use may increase the risk for QT prolongation.
    Anagrelide: (Major) Avoid coadministration of ribociclib with anagrelide due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ventricular tachycardia and TdP have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Concomitant use may increase the risk for QT prolongation.
    Apalutamide: (Major) Avoid coadministration of ribociclib with apalutamide, as the systemic exposure of ribociclib may be decreased resulting in decreased efficacy; consider an alternative treatment with less potential to induce CYP3A. Exposure to apalutamide may also be increased. Ribociclib is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure by 89%. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively, with this inhibitor. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Apomorphine: (Major) Avoid coadministration of ribociclib with apomorphine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. 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. However, concomitant use may increase the risk for QT prolongation.
    Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of ribociclib with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant. Ribociclib is a strong CYP3A4 inhibitor. Aprepitant is a CYP3A4 substrate; after administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. Coadministration with another strong CYP3A4 inhibitor increased the AUC of aprepitant by approximately 5-fold, and the mean terminal half-life by approximately 3-fold.
    Arformoterol: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as arformoterol as compared to short-acting beta-agonists.
    Aripiprazole: (Major) Avoid coadministration of ribociclib with aripiprazole due to the risk of QT prolongation; exposure to aripiprazole may also increase. Ribociclib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation. Prolongation of the QT interval has also occurred during therapeutic use of aripiprazole, a CYP3A4 substrate, as well as following overdose.
    Arsenic Trioxide: (Major) Avoid coadministration of ribociclib with arsenic trioxide due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Prolongation of the QT interval, TdP, and complete atrioventricular block have been reported with arsenic trioxide use. Concomitant use may increase the risk for QT prolongation.
    Artemether; Lumefantrine: (Major) Avoid coadministration of ribociclib with artemether due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of artemether may also be increased resulting in an increase in artemether-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Artemether is a CYP3A4 substrate that has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased artemether exposure by 2.3-fold. (Major) Avoid coadministration of ribociclib with lumefantrine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of lumefantrine may also be increased resulting in increase in lumefantrine-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Lumefantrine is a CYP3A4 substrate that is also associated with prolongation of the QT interval. Concomitant use may increase the risk for QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold.
    Asenapine: (Major) Avoid coadministration of ribociclib with asenapine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Asenapine has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with ribociclib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ribociclib is a strong inhibitor of CYP3A4.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with ribociclib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ribociclib is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with ribociclib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ribociclib is a strong inhibitor of CYP3A4.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ribociclib is necessary. If ribociclib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ribociclib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ribociclib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Atazanavir: (Severe) Coadministration of ribociclib with atazanavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to atazanavir may also increase. Ribociclib is a strong CYP3A4 inhibitor and is extensively metabolized by CYP3A4; atazanavir is a strong CYP3A4 inhibitor and CYP3A4 substrate.
    Atazanavir; Cobicistat: (Severe) Coadministration of ribociclib with atazanavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to atazanavir may also increase. Ribociclib is a strong CYP3A4 inhibitor and is extensively metabolized by CYP3A4; atazanavir is a strong CYP3A4 inhibitor and CYP3A4 substrate. (Severe) Coadministration of ribociclib with cobicistat is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to cobicistat may also increase. Ribociclib is extensively metabolized by CYP3A4 and is a strong CYP3A4 inhibitor; cobicistat is a strong CYP3A4 inhibitor and CYP3A4 substrate. Coadministration of ribociclib with another strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers.
    Atomoxetine: (Major) Avoid coadministration of ribociclib with atomoxetine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Concomitant use may increase the risk for QT prolongation.
    Atorvastatin: (Major) If concomitant use of atorvastatin with ribociclib is necessary, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Ribociclib is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold.
    Atorvastatin; Ezetimibe: (Major) If concomitant use of atorvastatin with ribociclib is necessary, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Ribociclib is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of phenobarbital with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
    Avanafil: (Major) Do not use avanafil in patients receiving ribociclib due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
    Axitinib: (Major) Avoid coadministration of axitinib with ribociclib due to the increased risk of axitinib-related adverse reactions. If coadministration is necessary, a dose reduction of axitinib by approximately 50% is recommended; subsequent doses may be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib 3 to 5 half-lives after ribociclib is discontinued. Axitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased axitinib exposure by 106%.
    Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and ribociclib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
    Azithromycin: (Major) Avoid coadministration of ribociclib with azithromycin due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. There have been case reports of QT prolongation and TdP with the use of azithromycin in postmarketing reports. Concomitant use may increase the risk for QT prolongation.
    Bedaquiline: (Major) Avoid coadministration of ribociclib with bedaquiline due to an increased risk for QT prolongation. Systemic exposure of bedaquiline may also be increased resulting in an increase in bedaquiline-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Bedaquiline is a CYP3A4 substrate that has been reported to prolong the QT interval. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Severe) Coadministration of ergotamine and ribociclib is contraindicated due to the potential for increased ergotamine exposure resulting in ergotism and other serious vasospastic adverse events. Ergotamine is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. When administered with strong CYP3A4 inhibitors, acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities has occurred, with some cases resulting in amputation. There have also been rare reports of cerebral ischemia, with at least one fatality, in patients receiving concomitant strong CYP3A4 inhibitors. (Major) Avoid coadministration of phenobarbital with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with ribociclib may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of ribociclib in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Ribociclib is an inhibitor of CYP3A4.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Avoid coadministration of ribociclib with metronidazole due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Potential QT prolongation has been reported in limited case reports with metronidazole. Concomitant use may increase the risk for QT prolongation.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Avoid coadministration of ribociclib with metronidazole due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Potential QT prolongation has been reported in limited case reports with metronidazole. Concomitant use may increase the risk for QT prolongation.
    Bortezomib: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of ribociclib is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
    Bosutinib: (Major) Avoid concomitant use of bosutinib and ribociclib; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
    Brentuximab vedotin: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with ribociclib is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and ribociclib is a strong CYp3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.
    Brexpiprazole: (Major) Reduce the brexpiprazole dose to half the usual dose if coadministered with ribociclib. Administer one quarter of the usual brexpiprazole dose if the patient is also receiving a strong or moderate CYP2D6 inhibitor or is a known poor CYP2D6 metabolizer. If ribociclib is discontinued, adjust the brexpiprazole dosage to its original level. Ribociclib is a strong CYP3A4 inhibitor. Brexpiprazole is a CYP3A4 and CYP2D6 substrate. Concomitant use of strong CYP3A4 inhibitors increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
    Brigatinib: (Major) Avoid coadministration of brigatinib with ribociclib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ribociclib, resume the brigatinib dose that was tolerated prior to initiation of ribociclib. Brigatinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with ribociclib ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; ribociclib is a strong inhibitor of CYP3A4.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Budesonide: (Moderate) Avoid coadministration of oral budesonide and ribociclib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
    Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and ribociclib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as formoterol as compared to short-acting beta-agonists.
    Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with ribociclib is necessary. Lidocaine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Buprenorphine: (Major) Avoid coadministration of ribociclib with buprenorphine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of buprenorphine may also be increased, resulting in increased or prolonged opioid effects, particularly when ribociclib is added after a stable buprenorphine dose is achieved. Buprenorphine is a substrate of CYP3A4 that has been associated with QT prolongation and has a possible risk of TdP. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Concomitant use may increase the risk for QT prolongation.
    Buprenorphine; Naloxone: (Major) Avoid coadministration of ribociclib with buprenorphine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of buprenorphine may also be increased, resulting in increased or prolonged opioid effects, particularly when ribociclib is added after a stable buprenorphine dose is achieved. Buprenorphine is a substrate of CYP3A4 that has been associated with QT prolongation and has a possible risk of TdP. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Concomitant use may increase the risk for QT prolongation.
    Buspirone: (Moderate) A low dose of buspirone used cautiously is recommended when coadministered with ribociclib. If a patient has been titrated to a stable dosage of buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone. Administering ribociclib with buspirone may increase buspirone concentration and risk for adverse events. Buspirone is a sensitive substrate of CYP3A4. Ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the buspirone AUC by 19-fold with an increased incidence of buspirone-related adverse effects.
    Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with ribociclib if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and ribociclib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
    Cabozantinib: (Major) Avoid coadministration of cabozantinib with ribociclib due to the risk of increased cabozantinib exposure. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day); for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 100 mg/day or 100 mg/day to 60 mg/day). Resume the cabozantinib dose that was used prior to initiating treatment with ribociclib 2 to 3 days after discontinuation of ribociclib. Cabozantinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased single-dose cabozantinib exposure by 38%.
    Caffeine; Ergotamine: (Severe) Coadministration of ergotamine and ribociclib is contraindicated due to the potential for increased ergotamine exposure resulting in ergotism and other serious vasospastic adverse events. Ergotamine is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. When administered with strong CYP3A4 inhibitors, acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities has occurred, with some cases resulting in amputation. There have also been rare reports of cerebral ischemia, with at least one fatality, in patients receiving concomitant strong CYP3A4 inhibitors.
    Cannabidiol: (Moderate) Consider a dose reduction of cannabidiol if coadministered with ribociclib. Coadministration may increase cannabidiol plasma concentrations increasing the risk of adverse reactions. Cannabidiol is metabolized by CYP3A4; ribociclib is a strong inhibitor of CYP3A4.
    Carbamazepine: (Major) Avoid coadministration of carbamazepine with ribociclib due to decreased ribociclib exposure resulting decreased efficacy; carbamazepine exposure may also increase. Ribociclib is a CYP3A4 substrate and strong inhibitor. Carbamazepine is a CYP3A4 substrate and strong inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Cariprazine: (Major) The dose of cariprazine should be reduced in patients also receiving ribociclib. When ribociclib is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When initiating cariprazine in a patient who is stable on ribociclib, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, and then increased to a maximum dose of 3 mg daily. When ribociclib is withdrawn, the cariprazine dosage may need to be increased. Cariprazine is metabolized by CYP3A4 to its major active metabolite. Ribociclib is a strong CYP3A4 inhibitor. Concurrent use with another strong CYP3A4 inhibitor increased the exposure of cariprazine by about 4-fold; increased the AUC of DDCAR metabolite by about 1.5-fold; and decreased DCAR metabolite AUC by about one-third.
    Ceritinib: (Major) Avoid coadministration of ceritinib with ribociclib due to the risk of QT prolongation and increased ribociclib exposure; plasma concentrations of ceritinib may also increase. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors that are also associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the ceritinib AUC by 2.9-fold and the Cmax by 22%. Coadministration with a strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers.
    Cevimeline: (Moderate) Monitor for an increase in cevimeline-related adverse reactions if coadministration with ribociclib is necessary. Cevimeline is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Chloramphenicol: (Major) Avoid coadministration of chloramphenicol with ribociclib if possible due to increased ribociclib exposure resulting in a risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ribociclib to 400 mg PO once daily; monitor ECGs for QT prolongation and monitor electrolytes. If chloramphenicol is discontinued, the original dose of ribociclib may be resumed after at least 5 half-lives of chloramphenicol. Ribociclib is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ribociclib exposure in healthy subjects by 3.2-fold.
    Chlordiazepoxide: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with ribociclib is necessary; adjust the dose of chlordiazepoxide if necessary. Ribociclib is a strong CYP3A4 inhibitor and chlordiazepoxide is a CYP3A4 substrate.
    Chlordiazepoxide; Clidinium: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with ribociclib is necessary; adjust the dose of chlordiazepoxide if necessary. Ribociclib is a strong CYP3A4 inhibitor and chlordiazepoxide is a CYP3A4 substrate.
    Chloroquine: (Major) Ribociclib should be avoided in patients receiving medications known to prolong the QT interval, such as chloroquine. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. These ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. 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.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with ribociclib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ribociclib is a strong inhibitor of CYP3A4.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with ribociclib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ribociclib is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with ribociclib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ribociclib is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Chlorpromazine: (Major) Avoid coadministration of ribociclib with chlorpromazine due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP. Concomitant use may increase the risk for QT prolongation.
    Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with ribociclib. Monitor for an increase in cilostazol-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Cinacalcet: (Moderate) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with ribociclib; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; ribociclib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Ciprofloxacin: (Major) Avoid coadministration of ribociclib with ciprofloxacin due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Rare cases of QT prolongation and TdP have been reported with ciprofloxacin during postmarketing surveillance. Concomitant use may increase the risk for QT prolongation.
    Cisapride: (Severe) Coadministration of ribociclib with cisapride is contraindicated due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of cisapride may also be increased with concomitant use. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a strong CYP3A4 inhibitor and cisapride is a CYP3A4 substrate.
    Citalopram: (Major) Avoid coadministration of ribociclib with citalopram due to an increased risk for QT prolongation. Both drugs have been shown to prolong the QT interval in a concentration-dependent manner. Concomitant use may increase the risk for QT prolongation.
    Clarithromycin: (Major) Avoid coadministration of ribociclib with clarithromycin due to the potential for additive effects on the QT interval and significantly increased exposure to ribociclib. Ribociclib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor that has an established risk for QT prolongation and torsade de pointes (TdP). Concomitant use may increase the risk for QT prolongation.
    Clofazimine: (Major) Avoid coadministration of clofazimine and ribociclib due to the potential for additive QT prolongation. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications. Ribociclib has also been shown to prolong the QT interval in a concentration-dependent manner.
    Clomipramine: (Major) Avoid coadministration of ribociclib with clomipramine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Concomitant use may increase the risk for QT prolongation.
    Clonazepam: (Moderate) Monitor for an increase in clonazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with ribociclib is necessary. Clonazepam is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Clorazepate: (Moderate) Use caution if coadministration of ribociclib with clorazepate is necessary, as the systemic exposure of the active metabolite of clorazepate may be increased resulting in an increase in treatment-related adverse reactions; adjust the dose of clorazepate if necessary. Ribociclib is a strong CYP3A4 inhibitor. Clorazepate is a pro-drug converted to N-desmethyldiazepam in the GI tract; N-desmethyldiazepam is metabolized by 2C19 and 3A4.
    Clozapine: (Major) Avoid coadministration of ribociclib with clozapine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of clozapine may also be increased resulting in an increase in clozapine-related adverse reactions. Clozapine is a CYP3A4 substrate that has also been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner.
    Cobicistat: (Severe) Coadministration of ribociclib with cobicistat is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to cobicistat may also increase. Ribociclib is extensively metabolized by CYP3A4 and is a strong CYP3A4 inhibitor; cobicistat is a strong CYP3A4 inhibitor and CYP3A4 substrate. Coadministration of ribociclib with another strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers.
    Cobimetinib: (Major) Avoid coadministration of ribociclib with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
    Codeine: (Moderate) Concomitant use of codeine with ribociclib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ribociclib is a strong inhibitor of CYP3A4.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with ribociclib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ribociclib is a strong inhibitor of CYP3A4.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid coadministration of ribociclib with promethazine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Concomitant use may increase the risk for QT prolongation. (Moderate) Concomitant use of codeine with ribociclib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ribociclib is a strong inhibitor of CYP3A4.
    Codeine; Promethazine: (Major) Avoid coadministration of ribociclib with promethazine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Concomitant use may increase the risk for QT prolongation. (Moderate) Concomitant use of codeine with ribociclib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ribociclib is a strong inhibitor of CYP3A4.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and ribociclib 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. Ribociclib can inhibit colchicine's metabolism via 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 a strong CYP3A4 inhibitor like ribociclib 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.
    Colchicine; Probenecid: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and ribociclib 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. Ribociclib can inhibit colchicine's metabolism via 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 a strong CYP3A4 inhibitor like ribociclib 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) Coadministration of conivaptan and ribociclib is contraindicated due to the potential for increased conivaptan exposure; ribociclib exposure may also be increased. Subsequent treatment with ribociclib may be initiated no sooner than 1 week after the infusion of conivaptan is completed. Conivaptan is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; ribociclib is a CYP3A4 substrate and strong CYP3A4 inhibitor. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the exposure of oral conivaptan by 11-fold. The effect on the pharmacokinetics of intravenous conivaptan was not evaluated. Coadministration of a strong CYP3A4 inhibitor increased ribociclib exposure by 3.2-fold.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Avoid coadministration of medroxyprogesterone with ribociclib due to increased plasma concentrations of medroxyprogesterone. Medroxyprogesterone is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Though no formal drug interaction trials have been conducted, concomitant administration of strong CYP3A4 inhibitors is expected to increase medroxyprogesterone exposure.
    Crizotinib: (Major) Avoid coadministration of ribociclib with crizotinib due to increased plasma concentrations of crizotinib and the risk of QT prolongation. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Ribociclib is a strong CYP3A inhibitor that is also associated with concentration-dependent QT prolongation. Coadministration with a strong CYP3A4 inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Cyclosporine: (Moderate) Monitor cyclosporine concentrations if coadministration with ribociclib is necessary; adjust the dose of cyclosporine if necessary. Cyclosporine is a CYP3A4 substrate with a narrow therapeutic index and ribociclib is a strong CYP3A4 inhibitor.
    Dabrafenib: (Major) Avoid coadministration of dabrafenib and ribociclib due to increased dabrafenib exposure. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity. Dabrafenib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%.
    Daclatasvir: (Major) Reduce the daclatasvir dose to 30 mg PO once daily if coadministered with ribociclib due to increased daclatasvir exposure. Daclatasvir is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the daclatasvir AUC by 3-fold.
    Dapagliflozin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with ribociclib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
    Darifenacin: (Major) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with ribociclib due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor.
    Darunavir: (Severe) Coadministration of ribociclib with darunavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to darunavir may also increase. Ribociclib is extensively metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor; exposure to ribociclib may be increased. Additionally, ribociclib is a strong CYP3A4 inhibitor and darunavir is a CYP3A4 substrate.
    Darunavir; Cobicistat: (Severe) Coadministration of ribociclib with cobicistat is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to cobicistat may also increase. Ribociclib is extensively metabolized by CYP3A4 and is a strong CYP3A4 inhibitor; cobicistat is a strong CYP3A4 inhibitor and CYP3A4 substrate. Coadministration of ribociclib with another strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers. (Severe) Coadministration of ribociclib with darunavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to darunavir may also increase. Ribociclib is extensively metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor; exposure to ribociclib may be increased. Additionally, ribociclib is a strong CYP3A4 inhibitor and darunavir is a CYP3A4 substrate.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Severe) Coadministration of ribociclib with cobicistat is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to cobicistat may also increase. Ribociclib is extensively metabolized by CYP3A4 and is a strong CYP3A4 inhibitor; cobicistat is a strong CYP3A4 inhibitor and CYP3A4 substrate. Coadministration of ribociclib with another strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers. (Severe) Coadministration of ribociclib with darunavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to darunavir may also increase. Ribociclib is extensively metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor; exposure to ribociclib may be increased. Additionally, ribociclib is a strong CYP3A4 inhibitor and darunavir is a CYP3A4 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ribociclib with ritonavir due to the potential for significantly increased exposure to ribociclib. If coadministration cannot be avoided, reduce the dose of ribociclib to 400 mg once daily. If ritonavir is discontinued, resume the previous ribociclib dose after at least 5 half-lives of ritonavir. Ribociclib is a CYP3A4 substrate. ritonavir is a strong CYP3A4 inhibitor. Coadministration with a strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with ribociclib is necessary. Paritaprevir is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased paritaprevir exposure by 2.2-fold to 2.9-fold.
    Dasatinib: (Major) Avoid coadministration of ribociclib with dasatinib due to the risk of QT prolongation and increased exposure to dasatinib. Ribociclib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation. Dasatinib is a sensitive substrate of CYP3A4 that also has the potential to prolong the QT interval.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with ribociclib. Concurrent use may significantly increase concentrations of 21-desDFZ , the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; ribociclib is a strong inhibitor of CYP3A4. Administration of deflazacort with another strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    Degarelix: (Major) Avoid coadministration of ribociclib with degarelix due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; QTc prolongation has also been reported with the use of degarelix. Concomitant use may increase the risk for QT prolongation.
    Delavirdine: (Severe) Coadministration of ribociclib with delavirdine is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to delavirdine may also increase. Inhibition of hepatic CYP3A activity by delavirdine is reversible within 1 week after discontinuation. Ribociclib is extensively metabolized by CYP3A4 and delavirdine is a strong CYP3A4 inhibitor; exposure to ribociclib may be increased. Additionally, ribociclib is a strong CYP3A4 inhibitor and delavirdine is a CYP3A4 substrate.
    Desflurane: (Major) Avoid coadministration of ribociclib with halogenated anesthetics due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Halogenated anesthetics can also prolong the QT interval. Concomitant use may increase the risk for QT prolongation.
    Desipramine: (Major) Avoid coadministration of ribociclib with desipramine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Concomitant use may increase the risk for QT prolongation.
    Deutetrabenazine: (Major) Avoid coadministration of deutetrabenazine with ribociclib due the risk of QT prolongation. Clinically relevant QT prolongation may occur with deutetrabenazine. Ribociclib has also been shown to prolong the QT interval in a concentration-dependent manner.
    Dexamethasone: (Moderate) Monitor for an increase in dexamethasone-related adverse reactions if coadministration with ribociclib is necessary. Dexamethasone is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Dexlansoprazole: (Minor) Use caution if coadministration of ribociclib with dexlansoprazole is necessary, as the systemic exposure of dexlansoprazole may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor and dexlansoprazole is a CYP3A4 substrate.
    Dextromethorphan; Promethazine: (Major) Avoid coadministration of ribociclib with promethazine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of ribociclib with quinidine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of quinidine may be increased resulting in an increase in quinidine-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Quinidine is a CYP3A4 substrate that has also been associated with QT prolongation and torsade de pointes (TdP). Concomitant use may increase the risk for QT prolongation.
    Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions if coadministration with ribociclib is necessary; decrease the dose of diazepam if necessary. At low concentrations, diazepam is primarily metabolized by CYP2C19; however, CYP3A4 is also involved at higher concentrations. Ribociclib is a strong CYP3A4 inhibitor.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with ribociclib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ribociclib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ribociclib is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Dihydroergotamine: (Severe) Coadministration of dihydroergotamine with ribociclib is contraindicated due to the potential for elevated dihydroergotamine exposure. Elevated plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues. Ribociclib is a strong inhibitor of CYP3A; dihydroergotamine is a CYP3A4 substrate.
    Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with ribociclib is necessary. Diltiazem is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Disopyramide: (Major) Avoid coadministration of ribociclib with disopyramide due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of disopyramide may also be increased resulting in an increase in disopyramide-related adverse reactions. Disypyramide is a CYP3A4 substrate that has been associated with QT prolongation and TdP; cases of life-threatening interactions have been reported for disopyramide when given with other CYP3A4 inhibitors. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner.
    Docetaxel: (Major) Avoid coadministration of docetaxel with ribociclib if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
    Dofetilide: (Major) Coadministration of dofetilide and ribociclib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption.
    Dolasetron: (Major) Avoid coadministration of ribociclib with dolasetron due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Dolasetron has also been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals. Concomitant use may increase the risk for QT prolongation.
    Dolutegravir: (Moderate) Use caution if coadministration of ribociclib with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
    Dolutegravir; Lamivudine: (Moderate) Use caution if coadministration of ribociclib with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
    Dolutegravir; Rilpivirine: (Major) Avoid coadministration of ribociclib with rilpivirine due to an increased risk for QT prolongation. Systemic exposure of rilpivirine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Supratherapeutic doses of rilpivirine (75 to 300 mg per day), a CYP3A4 substrate, have also caused QT prolongation. Concomitant use may increase the risk for QT prolongation. (Moderate) Use caution if coadministration of ribociclib with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
    Donepezil: (Major) Avoid coadministration of ribociclib with donepezil due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of donepezil may also be increased resulting in increase in treatment-related adverse reactions. Donepezil is a CYP3A4 substrate that has been associated with QT prolongation and TdP in case reports. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner.
    Donepezil; Memantine: (Major) Avoid coadministration of ribociclib with donepezil due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of donepezil may also be increased resulting in increase in treatment-related adverse reactions. Donepezil is a CYP3A4 substrate that has been associated with QT prolongation and TdP in case reports. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner.
    Doravirine: (Minor) Coadministration of doravirine and ribociclib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ribociclib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Minor) Coadministration of doravirine and ribociclib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ribociclib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
    Doxepin: (Major) Avoid coadministration of ribociclib with doxepin due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Concomitant use may increase the risk for QT prolongation.
    Doxorubicin: (Major) Avoid coadministration of ribociclib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronabinol: (Moderate) Monitor for an increase in dronabinol-related adverse reactions if coadministration with ribociclib is necessary. Dronabinol is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Dronedarone: (Severe) Because of the potential for torsade de pointes (TdP), use of ribociclib with dronedarone is contraindicated. Additionally, the systemic exposure of ribociclib may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Both drugs have been shown to prolong the QT interval in a concentration-dependent manner. Although there are no studies examining the effects of dronedarone 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 dronedarone is a moderate CYP3A4 inhibitor. Additionally, ribociclib is a strong CYP3A4 inhibitor and dronedarone is a CYP3A4 substrate.
    Droperidol: (Major) Avoid coadministration of ribociclib with droperidol due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Concomitant use may increase the risk for QT prolongation.
    Drospirenone; Ethinyl Estradiol: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Dutasteride: (Moderate) Monitor for an increase in dutasteride-related adverse reactions if coadministration with ribociclib is necessary. Dutasteride is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Dutasteride; Tamsulosin: (Major) Concurrent use of tamsulosin and ribociclib is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes, and strong inhibitors of CYP3A4 are expected to significantly raise tamsulosin concentrations. Concomitant treatment with another strong CYP3A4 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. (Moderate) Monitor for an increase in dutasteride-related adverse reactions if coadministration with ribociclib is necessary. Dutasteride is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with ribociclib. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; ribociclib is a strong CYP3A inhibitor. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as ribociclib.
    Efavirenz: (Major) Avoid coadministration of ribociclib with efavirenz due to an increased risk for QT prolongation. Additionally, the systemic exposure of efavirenz may be increased resulting in an increase in treatment-related adverse reactions. Efavirenz is a CYP3A4 substrate that has been associated with QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of ribociclib with efavirenz due to an increased risk for QT prolongation. Additionally, the systemic exposure of efavirenz may be increased resulting in an increase in treatment-related adverse reactions. Efavirenz is a CYP3A4 substrate that has been associated with QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of ribociclib with efavirenz due to an increased risk for QT prolongation. Additionally, the systemic exposure of efavirenz may be increased resulting in an increase in treatment-related adverse reactions. Efavirenz is a CYP3A4 substrate that has been associated with QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Elagolix: (Major) Concomitant use of elagolix 200 mg twice daily and ribociclib for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and ribociclib to 6 months. Elagolix is a CYP3A substrate; ribociclib is a strong inhibitor of CYP3A. Coadministration may increase elagolix plasma concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively.
    Elbasvir; Grazoprevir: (Moderate) Monitor for an increase in grazoprevir-related adverse reactions if coadministration with ribociclib is necessary. Grazoprevir is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased grazoprevir exposure by 3-fold. (Moderate) Use caution if ribociclib is coadministered with elbasvir, as the systemic exposure of elbasvir may be increased resulting in adverse reactions. Ribociclib is a strong CYP3A4 inhibitor, and elbasvir is a CYP3A4 substrate.
    Eletriptan: (Severe) Eletriptan is contraindicated with recent use (i.e., within 72 hours) of ribociclib due to the potential for increased eletriptan exposure. Eletriptan is a sensitive substrate of CYP3A4; ribociclib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the Cmax and AUC of eletriptan by 3-fold and 6-fold, respectively.
    Elexacaftor; tezacaftor; ivacaftor: (Major) If ribociclib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor when coadministered with ribociclib; coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 2 elexacaftor/tezacaftor/ivacaftor combination tablets twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive substrate); ribociclib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with ribociclib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, give 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); ribociclib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
    Eliglustat: (Major) Avoid coadministration of eliglustat with ribociclib due to the risk of QT prolongation. Coadministration is contraindicated in intermediate or poor CYP2D6 metabolizers (IMs or PMs), and when concomitantly used with a moderate or strong CYP2D6 inhibitor in all patients. Eliglustat is a CYP3A4 and CYP2D6 substrate that causes PR, QRS, and QT prolongation at elevated plasma concentrations; the risk is highest in CYP2D6 IMs and PMs because a larger portion of the dose is metabolized via CYP3A. Ribociclib is a strong CYP3A4 inhibitor that is also associated with concentration-dependent QT prolongation.
    Eluxadoline: (Moderate) Monitor for an increase in eluxadoline-related adverse reactions including impaired mental or physical abilities if coadministration with ribociclib is necessary. The metabolism of eluxadoline by CYP pathways has not been clearly established, but strong CYP inhibitors such as ribociclib have the potential to increase eluxadoline exposure.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Severe) Coadministration of ribociclib with cobicistat is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to cobicistat may also increase. Ribociclib is extensively metabolized by CYP3A4 and is a strong CYP3A4 inhibitor; cobicistat is a strong CYP3A4 inhibitor and CYP3A4 substrate. Coadministration of ribociclib with another strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Severe) Coadministration of ribociclib with cobicistat is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to cobicistat may also increase. Ribociclib is extensively metabolized by CYP3A4 and is a strong CYP3A4 inhibitor; cobicistat is a strong CYP3A4 inhibitor and CYP3A4 substrate. Coadministration of ribociclib with another strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of ribociclib with rilpivirine due to an increased risk for QT prolongation. Systemic exposure of rilpivirine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Supratherapeutic doses of rilpivirine (75 to 300 mg per day), a CYP3A4 substrate, have also caused QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Avoid coadministration of ribociclib with rilpivirine due to an increased risk for QT prolongation. Systemic exposure of rilpivirine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Supratherapeutic doses of rilpivirine (75 to 300 mg per day), a CYP3A4 substrate, have also caused QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Enalapril; Felodipine: (Moderate) Concurrent use of felodipine and ribociclib should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively.
    Encorafenib: (Major) Avoid coadministration of encorafenib and ribociclib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ribociclib. If unavoidable, monitor ECGs and electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ribociclib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ribociclib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Enflurane: (Major) Avoid coadministration of ribociclib with halogenated anesthetics due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Halogenated anesthetics can also prolong the QT interval. Concomitant use may increase the risk for QT prolongation.
    Entrectinib: (Major) Avoid coadministration of entrectinib with ribociclib due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If ribociclib is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ribociclib. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; ribociclib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Enzalutamide: (Major) Avoid coadministration of ribociclib with enzalutamide, as the systemic exposure of ribociclib may be decreased resulting in decreased efficacy; consider an alternative treatment with less potential to induce CYP3A. Ribociclib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 substrate decreased ribociclib exposure by 89%.
    Eplerenone: (Severe) Eplerenone is contraindicated for use with ribociclib due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Ribociclib is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Erdafitinib: (Major) Avoid coadministration of erdafitinib and ribociclib due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If ribociclib is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. The mean ratios for the Cmax and AUC of erdafitinib were 105% and 134%, respectively, when coadministered with another strong CYP3A4 inhibitor.
    Ergotamine: (Severe) Coadministration of ergotamine and ribociclib is contraindicated due to the potential for increased ergotamine exposure resulting in ergotism and other serious vasospastic adverse events. Ergotamine is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. When administered with strong CYP3A4 inhibitors, acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities has occurred, with some cases resulting in amputation. There have also been rare reports of cerebral ischemia, with at least one fatality, in patients receiving concomitant strong CYP3A4 inhibitors.
    Eribulin: (Major) Avoid coadministration of ribociclib with eribulin due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; eribulin has also been associated with QT prolongation.
    Erlotinib: (Major) Avoid coadministration of erlotinib with ribociclib if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Erythromycin: (Major) Avoid coadministration of ribociclib with erythromycin due to the risk of QT prolongation. Ribociclib causes concentration-dependent QT prolongation. Erythromycin is also associated with QT prolongation and torsade de pointes (TdP).
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of ribociclib with erythromycin due to the risk of QT prolongation. Ribociclib causes concentration-dependent QT prolongation. Erythromycin is also associated with QT prolongation and torsade de pointes (TdP).
    Escitalopram: (Major) Avoid coadministration of ribociclib with escitalopram due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Escitalopram has also been associated with a risk of QT prolongation and TdP. Concomitant use may increase the risk for QT prolongation.
    Estazolam: (Moderate) Use caution if coadministration of ribociclib with estazolam is necessary, as the systemic exposure of estazolam may be increased resulting in an increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of estazolam if necessary. Ribociclib is a strong CYP3A4 inhibitor and estazolam is a CYP3A4 substrate.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Avoid coadministration of medroxyprogesterone with ribociclib due to increased plasma concentrations of medroxyprogesterone. Medroxyprogesterone is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Though no formal drug interaction trials have been conducted, concomitant administration of strong CYP3A4 inhibitors is expected to increase medroxyprogesterone exposure.
    Eszopiclone: (Major) The total dose of eszopiclone should not exceed 2 mg when administered with ribociclib. Coadministration may increase eszopiclone exposure resulting in increased risk of next-day psychomotor or memory impairment and decreased ability to perform tasks requiring full mental alertness such as driving. CYP3A4 is a primary metabolic pathway for eszopiclone; ribociclib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased eszopiclone exposure by 2.2-fold.
    Ethinyl Estradiol: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Desogestrel: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate. (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as ribociclib may increase the serum concentration of etonogestrel.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norethindrone: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norgestimate: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norgestrel: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethosuximide: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with ribociclib is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and ribociclib is a strong CYP3A4 inhibitor.
    Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as ribociclib may increase the serum concentration of etonogestrel.
    Etoposide, VP-16: (Moderate) Monitor for an increase in etoposide-related adverse reactions if coadministration with ribociclib is necessary. Etoposide is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Etravirine: (Moderate) Monitor for an increase in etravirine-related adverse reactions if coadministration with ribociclib is necessary. Etravirine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased etravirine exposure by 1.42-fold.
    Everolimus: (Major) Avoid coadministration of everolimus with ribociclib due to increased exposure to everolimus resulting in an increase of everolimus-related adverse reactions. Re-assess everolimus trough concentrations 2 weeks after discontinuation of ribociclib for indications where therapeutic drug monitoring is necessary. Everolimus is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased everolimus exposure by 15-fold.
    Ezetimibe; Simvastatin: (Severe) Concurrent use of simvastatin and ribociclib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Ezogabine: (Major) Avoid coadministration of ribociclib with ezogabine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ezogabine has been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Fedratinib: (Major) Avoid coadministration of fedratinib with ribociclib as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If ribociclib is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Felodipine: (Moderate) Concurrent use of felodipine and ribociclib should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively.
    Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ribociclib is necessary. If ribociclib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ribociclib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ribociclib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Fingolimod: (Major) Avoid coadministration of ribociclib with fingolimod due to an increased risk for QT prolongation and torsade de pointes (TdP); exposure to fingolimod may also increase. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Fingolimod initiation results in decreased heart rate and may prolong the QT interval; 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. Concomitant use may increase the risk for QT prolongation. Coadministration with another strong CYP3A inhibitor increased fingolimod exposure by 70%.
    Flecainide: (Major) Avoid coadministration of ribociclib with flecainide due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Flecainide is a Class IC antiarrhythmic 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. Concomitant use may increase the risk for QT prolongation.
    Flibanserin: (Severe) The concomitant use of flibanserin and strong CYP3A4 inhibitors such as ribociclib is contraindicated due to increased flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following the use of ribociclib, start flibanserin at least 2 weeks after the last dose of ribociclib. If initiating ribociclib following flibanserin use, begin therapy at least 2 days after the last dose of flibanserin. In cases where the benefit of initiating ribociclib therapy within 2 days of stopping flibanserin clearly outweighs the risk of flibanserin-related hypotension and syncope, monitor the patient for signs of hypotension and syncope.
    Fluconazole: (Severe) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are CYP3A4 substrates, such as ribociclib, is contraindicated. Fluconazole has been associated with QT prolongation. Additionally, the systemic exposure of ribociclib 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; fluconazole also prolongs the QT interval. Concomitant use may increase the risk for QT prolongation. Ribociclib is also extensively metabolized by CYP3A4 and fluconazole is a moderate CYP3A4 inhibitor.
    Fluoxetine: (Major) Avoid coadministration of ribociclib with fluoxetine due to an increased risk for QT prolongation and torsade de pointes (TdP). Additionally, the systemic exposure of ribociclib may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib is a CYP3A4 substrate that has been shown to prolong the QT interval in a concentration-dependent manner. Prolongation of the QT interval and TdP have been reported in patients treated with fluoxetine. While fluoxetine is a weak inhibitor of CYP3A4, its metabolite norfluoxetine is a moderate CYP3A4 inhibitor.
    Fluoxetine; Olanzapine: (Major) Avoid coadministration of ribociclib with fluoxetine due to an increased risk for QT prolongation and torsade de pointes (TdP). Additionally, the systemic exposure of ribociclib may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib is a CYP3A4 substrate that has been shown to prolong the QT interval in a concentration-dependent manner. Prolongation of the QT interval and TdP have been reported in patients treated with fluoxetine. While fluoxetine is a weak inhibitor of CYP3A4, its metabolite norfluoxetine is a moderate CYP3A4 inhibitor. (Major) Avoid coadministration of ribociclib with olanzapine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Concomitant use may increase the risk for QT prolongation.
    Fluphenazine: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as ribociclib.
    Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadminsitration with ribociclib is necessary; adjust the dose of flurazepam if necessary. Flurazepam is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and ribociclib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
    Fluticasone; Salmeterol: (Major) Coadministration of inhaled fluticasone propionate and ribociclib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as salmeterol as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and ribociclib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as vilanterol as compared to short-acting beta-agonists. Ribociclib is also a moderate CYP3A4 inhibitor and vilanterol is a CYP3A4 substrate.
    Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and ribociclib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as vilanterol as compared to short-acting beta-agonists. Ribociclib is also a moderate CYP3A4 inhibitor and vilanterol is a CYP3A4 substrate.
    Fluvoxamine: (Major) Avoid coadministration of ribociclib with fluvoxamine due to the risk of QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Prolongation of the QT interval and torsade de pointes (TdP) have been reported with fluvoxamine use during postmarketing experience.
    Formoterol: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as formoterol as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Coadministration of mometasone with ribociclib may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; ribociclib is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as formoterol as compared to short-acting beta-agonists.
    Fosamprenavir: (Severe) Coadministration of ribociclib with fosamprenavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to fosamprenavir may also increase. Ribociclib is extensively metabolized by CYP3A4. Amprenavir, the active metabolite of fosamprenavir, is a strong CYP3A4 inhibitor that also has the potential to induce CYP3A4; exposure to ribociclib may be increased. Additionally, ribociclib is a strong CYP3A4 inhibitor and fosamprenavir is a CYP3A4 substrate.
    Foscarnet: (Major) Avoid coadministration of ribociclib with foscarnet due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Both QT prolongation and TdP have been reported during postmarketing use of foscarnet. Concomitant use may increase the risk for QT prolongation.
    Fosphenytoin: (Major) Avoid coadministration of fosphenytoin with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
    Fostamatinib: (Moderate) Monitor for an increase in fostamatinib-related adverse reactions if coadministration with ribociclib is necessary. Fostamatinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to R406 (the major active metabolite of fostamatinib) by 102% and increased the Cmax of R406 by 37%.
    Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ribociclib is necessary. Gefitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Gemifloxacin: (Major) Avoid coadministration of ribociclib with gemifloxacin due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin; the likelihood of QTc prolongation may increase with increasing dose of the drug. Concomitant use may increase the risk for QT prolongation.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of gemtuzumab ozogamicin with ribociclib due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Prolongation of the QT has not been reported with gemtuzumab ozogamicin, but it has been reported with other drugs that contain calicheamicin.
    Gilteritinib: (Major) Avoid coadministration of ribociclib with gilteritinib due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Gilteritinib has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Glasdegib: (Major) Consider an alternative to ribociclib during treatment with glasdegib due to the potential for additive QT prolongation and increased glasdegib exposure. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Glycopyrrolate; Formoterol: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as formoterol as compared to short-acting beta-agonists.
    Goserelin: (Major) Avoid coadministration of ribociclib with goserelin due to the risk of QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ribociclib-related ECG changes typically occurred within the first four weeks of treatment and were reversible with dose interruption. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
    Granisetron: (Major) Avoid coadministration of ribociclib with granisetron due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Granisetron has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Grapefruit juice: (Major) Avoid the concomitant use of ribociclib and grapefruit or grapefruit juice; the systemic exposure of ribociclib may be increased resulting in an increase in ribociclib-related adverse reactions. Ribociclib is a CYP3A4 substrate and grapefruit is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ribociclib AUC and Cmax values by 3.2-fold and 1.7-fold, respectively, in healthy volunteers.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Guanfacine: (Major) If coadministration of ribociclib with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If ribociclib is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Ribociclib may significantly increase guanfacine plasma concentrations.
    Halogenated Anesthetics: (Major) Avoid coadministration of ribociclib with halogenated anesthetics due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Halogenated anesthetics can also prolong the QT interval. Concomitant use may increase the risk for QT prolongation.
    Haloperidol: (Major) Avoid coadministration of ribociclib with haloperidol due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of haloperidol may also be increased resulting in an increase in haloperidol-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Haloperidol is a CYP3A4 substrate that has also been associated with QT prolongation and torsade de pointes (TdP). Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Concomitant use may increase the risk for QT prolongation. In clinical trials, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with CYP3A4 inhibitors.
    Halothane: (Major) Avoid coadministration of ribociclib with halogenated anesthetics due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Halogenated anesthetics can also prolong the QT interval. Concomitant use may increase the risk for QT prolongation.
    Histrelin: (Major) Avoid coadministration of ribociclib with histrelin due to the risk of QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ribociclib-related ECG changes typically occurred within the first four weeks of treatment and were reversible with dose interruption. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribociclib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ribociclib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ribociclib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ribociclib is a strong inhibitor of CYP3A4.
    Hydroxychloroquine: (Major) Avoid coadministration of ribociclib with hydroxychloroquine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Hydroxychloroquine has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Hydroxyzine: (Major) Avoid coadministration of ribociclib with hydroxyzine due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Concomitant use may increase the risk for QT prolongation.
    Ibrutinib: (Major) Avoid coadministration of ibrutinib with ribociclib due to the risk of increased ibrutinib-related adverse reactions. Ibrutinib is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ribociclib is necessary. If ribociclib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ribociclib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ribociclib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Ibutilide: (Major) Avoid coadministration of ribociclib with ibutilide due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ibutilide administration can also cause QT prolongation and 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.
    Idelalisib: (Major) Avoid coadministration of idelalisib with ribociclib if possible due to increased ribociclib exposure resulting in a risk of QT prolongation; exposure to idelalisib may also be increased. If concomitant use is unavoidable, reduce the dose of ribociclib to 400 mg PO once daily. Monitor ECGs for QT prolongation and monitor electrolytes; also monitor for idelalisib-related adverse reactions. If idelalisib is discontinued, the original dose of ribociclib may be resumed after at least 5 half-lives of idelalisib. Ribociclib is a CYP3A4 substrate and strong inhibitor that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Idelalisib is also a CYP3A4 substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ribociclib exposure in healthy subjects by 3.2-fold, while another strong CYP3A4 inhibitor increased idelalisib exposure by 1.8-fold.
    Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ribociclib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Ribociclib is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Iloperidone: (Major) Avoid coadministration of ribociclib with iloperidone due to an increased risk for QT prolongation. Systemic exposure of iloperidone may also be increased resulting in increase in treatment-related adverse reactions. Iloperidone is a CYP3A4 substrate that has been associated with QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner. Concomitant use may increase the risk for QT prolongation.
    Imatinib: (Moderate) Monitor for an increase in imatinib-related adverse reactions if coadministration with ribociclib is necessary. Imatinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased imatinib exposure by 40%.
    Imipramine: (Major) Avoid coadministration of ribociclib with imipramine due to the risk of QT prolongation; exposure to imipramine may also increase. Ribociclib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Imipramine is a CYP3A4 substrate. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Indacaterol: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as indacaterol as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as indacaterol as compared to short-acting beta-agonists.
    Indinavir: (Major) Avoid coadministration of indinavir with ribociclib if possible due to increased ribociclib exposure resulting in a risk of QT prolongation; increased indinavir exposure may also occur. If concomitant use is unavoidable, reduce the dose of ribociclib to 400 mg PO once daily; monitor ECGs for QT prolongation and monitor electrolytes. If indinavir is discontinued, the original dose of ribociclib may be resumed after at least 5 half-lives of indinavir. Ribociclib is a CYP3A4 substrate and strong inhibitor that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Indinavir is a sensitive CYP3A4 substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ribociclib exposure in healthy subjects by 3.2-fold.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with ribociclib due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Inotuzumab has been associated with QT interval prolongation. Ribociclib has also been shown to prolong the QT interval in a concentration-dependent manner.
    Irinotecan Liposomal: (Major) Discontinue ribociclib at least 1 week prior to starting irinotecan therapy; do not administer ribociclib with irinotecan unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to both irinotecan and SN-38.
    Irinotecan: (Major) Discontinue ribociclib at least 1 week prior to starting irinotecan therapy; do not administer ribociclib with irinotecan unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to both irinotecan and SN-38.
    Isavuconazonium: (Severe) Coadministration of isavuconazonium with ribociclib is contraindicated due to the risk of increased isavuconazole exposure. Isavuconazole is a sensitive substrate of CYP3A4 and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased isavuconazole exposure by 422%.
    Isoflurane: (Major) Avoid coadministration of ribociclib with halogenated anesthetics due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Halogenated anesthetics can also prolong the QT interval. Concomitant use may increase the risk for QT prolongation.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of rifampin with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased ribociclib exposure in healthy subjects by 89%.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of rifampin with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased ribociclib exposure in healthy subjects by 89%.
    Isradipine: (Moderate) Monitor blood pressure if coadministration of isradipine with ribociclib is necessary. Isradipine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with ribociclib as istradefylline exposure and adverse effects may increase. Ribociclib is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
    Itraconazole: (Major) Avoid coadministration of ribociclib with itraconazole due to the risk of QT prolongation; plasma concentrations of both drugs may increase. Ribociclib is a CYP3A4 substrate and strong inhibitor that is associated with concentration-dependent QT prolongation. Itraconazole is also a CYP3A4 substrate and strong inhibitor that is associated with QT prolongation.
    Ivabradine: (Severe) Coadministration of ribociclib with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold.
    Ivacaftor: (Major) If ribociclib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with ribociclib due to an increased risk of QT prolongation; increased exposure to ivosidenib may also occur. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Coadministration with another strong CYP3A4 inhibitor increased single dose ivosidenib exposure to 269% of control.
    Ixabepilone: (Major) Avoid coadministration of ribociclib with ixabepilone if possible due to increased ixabepilone exposure. If concomitant use is unavoidable, consider reducing the dose of ixabepilone to 20 mg/m2. If ribociclib is discontinued, resume the original dose of ixabepilone after a washout period of approximately 1 week. Ixabepilone is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ixabepilone exposure by 79%.
    Ketoconazole: (Major) Avoid coadministration of ribociclib with ketoconazole due to the potential for additive effects on the QT interval and significantly increased exposure to ribociclib; exposure to ketoconazole may also increase. Both ketoconazole and ribociclib are CYP3A4 substrates and strong inhibitors that have been reported to prolong the QT interval. Concomitant use may increase the risk for QT prolongation.
    Lapatinib: (Major) Avoid coadministration of ribociclib with lapatinib due to an increased risk for QT prolongation; systemic exposure to lapatinib may also be increased resulting in an increase in treatment-related adverse reactions. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner. Concomitant use may increase the risk for QT prolongation.
    Larotrectinib: (Major) Avoid coadministration of larotrectinib with ribociclib due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ribociclib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ribociclib. Larotrectinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Lefamulin: (Major) Avoid coadministration of lefamulin with ribociclib as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
    Lenvatinib: (Major) Avoid coadministration of ribociclib with lenvatinib due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; QT prolongation was also reported during clinical trials of lenvatinib. Concomitant use may increase the risk for QT prolongation.
    Letermovir: (Moderate) Coadministration of letermovir and ribociclib may increase ribociclib exposure. This combination should be avoided in patients also taking cyclosporine, because the magnitude of the interaction may be increased. If the use of ribociclib cannot be avoided in patients receiving both letermovir and cyclosporine, reduce the ribociclib dose to 400 mg once per day. Ribociclib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. The AUC of ribociclib was increased by 3.2-fold when coadministered with a strong CYP3A4 inhibitor. A moderate inhibitor is predicted to increase the ribociclib AUC by 1.9-fold.
    Leuprolide: (Major) Avoid coadministration of ribociclib with leuprolide due to the risk of QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ribociclib-related ECG changes typically occurred within the first four weeks of treatment and were reversible with dose interruption. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of ribociclib with leuprolide due to the risk of QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ribociclib-related ECG changes typically occurred within the first four weeks of treatment and were reversible with dose interruption. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Levalbuterol: (Minor) Coadministration may result in additive effects on the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval such as ribociclib. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Levofloxacin: (Major) Avoid coadministration of ribociclib with levofloxacin due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Levofloxacin has also been associated with a risk of QT prolongation and although extremely rare, TdP has been reported during postmarketing surveillance. Concomitant use may increase the risk for QT prolongation.
    Levomilnacipran: (Major) Do not exceed a levomilnacipran dose of 80 mg once daily if coadministration with ribociclib is necessary. Levomilnacipran is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased levomilnacipran exposure by about 50%.
    Lidocaine: (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with ribociclib is necessary. Lidocaine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Lithium: (Major) Avoid coadministration of ribociclib with lithium due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Lithium has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Lofexidine: (Major) Avoid coadministration of lofexidine and ribociclib due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval; in addition, there are postmarketing reports of torsade de pointes. Ribociclib has also been shown to prolong the QT interval in a concentration-dependent manner.
    Lomitapide: (Severe) Concomitant use of ribociclib and lomitapide is contraindicated; if treatment with ribociclib is unavoidable, lomitapide should be stopped during treatment. Ribociclib is a strong CYP3A4 inhibitor and lomitapide is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased lomitapide exposure approximately 27-fold.
    Loperamide: (Major) Avoid coadministration of ribociclib with loperamide due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of loperamide may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Loperamide is a CYP3A4 substrate that, at high doses, has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Concomitant use may increase the risk for QT prolongation.
    Loperamide; Simethicone: (Major) Avoid coadministration of ribociclib with loperamide due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of loperamide may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Loperamide is a CYP3A4 substrate that, at high doses, has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Concomitant use may increase the risk for QT prolongation.
    Lopinavir; Ritonavir: (Severe) Coadministration of ribociclib with lopinavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to lopinavir may also increase. Ribociclib is a CYP3A4 substrate and strong inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Lopinavir is also a CYP3A4 substrate and strong inhibitor that has been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation. (Major) Avoid coadministration of ribociclib with ritonavir due to the potential for significantly increased exposure to ribociclib. If coadministration cannot be avoided, reduce the dose of ribociclib to 400 mg once daily. If ritonavir is discontinued, resume the previous ribociclib dose after at least 5 half-lives of ritonavir. Ribociclib is a CYP3A4 substrate. ritonavir is a strong CYP3A4 inhibitor. Coadministration with a strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers.
    Lorlatinib: (Major) Avoid coadministration of lorlatinib with ribociclib due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib. If concomitant use is unavoidable, decrease the starting dose of lorlatinib from 100 mg PO once daily to 75 mg PO once daily. In patients who have already had a dose reduction to 75 mg PO once daily due to adverse reactions, reduce the dose of lorlatinib to 50 mg PO once daily. If ribociclib is discontinued, increase the dose of lorlatinib after 3 plasma half-lives of ribociclib to the dose that was used before starting ribociclib. Lorlatinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of lorlatinib by 42% and 24%, respectively.
    Lovastatin: (Severe) Coadministration of lovastatin and ribociclib is contraindicated due to the risk of elevated plasma concentrations of lovastatin leading to myopathy and rhabdomyolysis. Lovastatin is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lovastatin exposure by 11 to 36-fold.
    Lovastatin; Niacin: (Severe) Coadministration of lovastatin and ribociclib is contraindicated due to the risk of elevated plasma concentrations of lovastatin leading to myopathy and rhabdomyolysis. Lovastatin is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lovastatin exposure by 11 to 36-fold.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of lumacaftor; ivacaftor with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%. (Major) If ribociclib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of lumacaftor; ivacaftor with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
    Lurasidone: (Severe) Coadministration of lurasidone with ribociclib is contraindicated due to increased plasma concentrations of lurasidone. Lurasidone is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lurasidone exposure by 9-fold.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as ribociclib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption.
    Macitentan: (Major) Avoid coadministration of macitentan with ribociclib due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
    Maprotiline: (Major) Avoid coadministration of ribociclib with maprotiline due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Concomitant use may increase the risk for QT prolongation.
    Maraviroc: (Major) Reduce the dose of maraviroc when coadministered with strong CYP3A inhibitors such as ribociclib; coadministration of maraviroc with strong CYP3A inhibitors is contraindicated in patients with CrCL less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with ribociclib (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily.
    Medroxyprogesterone: (Major) Avoid coadministration of medroxyprogesterone with ribociclib due to increased plasma concentrations of medroxyprogesterone. Medroxyprogesterone is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Though no formal drug interaction trials have been conducted, concomitant administration of strong CYP3A4 inhibitors is expected to increase medroxyprogesterone exposure.
    Mefloquine: (Major) Avoid coadministration of ribociclib with mefloquine due to an increased risk for QT prolongation. Systemic exposure of mefloquine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Mefloquine is a CYP3A4 substrate. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. 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.
    Meperidine; Promethazine: (Major) Avoid coadministration of ribociclib with promethazine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Mephobarbital: (Major) Avoid coadministration of ribociclib with mephobarbital, as the systemic exposure of ribociclib may be decreased resulting in decreased efficacy; consider an alternative treatment with less potential to induce CYP3A. Ribociclib is extensively metabolized by CYP3A4. Mephobarbital is metabolized to phenobarbital, a strong CYP3A4 inducer.
    Metaproterenol: (Minor) Coadministration may result in additive effects on the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval such as ribociclib. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Metformin; Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with ribociclib is necessary. Repaglinide is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased repaglinide exposure by up to 1.5-fold.
    Metformin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with ribociclib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
    Methadone: (Major) Avoid coadministration of ribociclib with methadone due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of methadone may also be increased resulting in an increase in methadone-related adverse reactions including respiratory depression and sedation. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Methadone is a CYP3A4 substrate that has also been associated with an increased risk of QT prolongation and TdP, especially at higher doses (greater than 200 mg per day but averaging approximately 400 mg per day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Concomitant use may increase the risk for QT prolongation.
    Metronidazole: (Major) Avoid coadministration of ribociclib with metronidazole due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Potential QT prolongation has been reported in limited case reports with metronidazole. Concomitant use may increase the risk for QT prolongation.
    Midazolam: (Moderate) Monitor for an increase in midazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with ribociclib is necessary. Midazolam is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with ribociclib at a reduced dose of 400 mg once daily increased the midazolam AUC by 3.8-fold; coadministration with the recommended dose of ribociclib is predicted to increase midazolam exposure by 5.2-fold.
    Midostaurin: (Major) Avoid coadministration of midostaurin with ribociclib due to the risk of QT prolongation; exposure to midostaurin may also increase. Midostaurin is a sensitive CYP3A4 substrate that has been associated with QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Additive QT prolongation may occur. Coadministration with another strong CYP3A4 inhibitor increased midostaurin exposure by 10.4-fold, and increased concentrations of CGP62221 by 3.5-fold.
    Mifepristone: (Major) Avoid coadministration of ribociclib with mifepristone 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. Both drugs are CYP3A4 substrates and strong inhibitors, and have been shown to prolong the QT interval in a concentration-dependent manner; concomitant use may increase this risk. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mirtazapine: (Major) Avoid coadministration of mirtazapine with ribociclib due to the risk of QT prolongation; mirtazapine plasma concentrations may also increase. Mirtazapine is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; torsade de pointes (TdP) has also been reported in postmarketing experience, primarily in overdose cases or in patients with other risk factors. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Additive QT prolongation may occur. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
    Mitotane: (Major) Avoid coadministration of mitotane with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
    Modafinil: (Moderate) Monitor for an increase in modafinil-related adverse reactions if coadministration with ribociclib is necessary. Modafinil has multiple pathways for metabolism including non-CYP-related pathways; however, due to partial involvement of the CYP3A enzymes, concomitant use of strong CYP3A4 inhibitors such as ribociclib could increase plasma concentrations of modafinil.
    Mometasone: (Moderate) Coadministration of mometasone with ribociclib may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; ribociclib is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
    Moxifloxacin: (Major) Avoid coadministration of ribociclib with moxifloxacin due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory. Concomitant use may increase the risk for QT prolongation.
    Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with ribociclib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor.
    Naloxegol: (Major) Avoid concomitant administration of naloxegol and ribociclib due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; ribociclib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
    Nefazodone: (Major) Avoid coadministration of nefazodone with ribociclib if possible due to increased ribociclib exposure resulting in a risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ribociclib to 400 mg PO once daily; monitor ECGs for QT prolongation and monitor electrolytes. If nefazodone is discontinued, the original dose of ribociclib may be resumed after at least 5 half-lives of nefazodone. Ribociclib is a CYP3A4 substrate and strong inhibitor, that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Nefazodone is a strong CYP3A4 inhibitor as well as a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased ribociclib exposure in healthy subjects by 3.2-fold.
    Nelfinavir: (Severe) Coadministration of ribociclib with nelfinavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to nelfinavir may also increase. Ribociclib is extensively metabolized by CYP3A4 and nelfinavir is a strong CYP3A4 inhibitor. Additionally, ribociclib is a strong CYP3A4 inhibitor and nelfinavir is a CYP3A4 substrate.
    Neratinib: (Major) Avoid concomitant use of ribociclib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 481%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor for an increase in netupitant-related adverse reactions if coadministration with ribociclib is necessary. Netupitant is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%; however, no dosage adjustment is necessary.
    Nevirapine: (Moderate) Monitor for an increase in nevirapine-related adverse reactions if coadministration with ribociclib is necessary. Nevirapine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased nevirapine exposure by 100%; concomitant use with a strong CYP3A4 inhibitor may also increase nevirapine exposure.
    Niacin; Simvastatin: (Severe) Concurrent use of simvastatin and ribociclib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Nifedipine: (Moderate) Monitor blood pressure if coadministration of nifedipine with ribociclib is necessary; consider decreasing the dose of nifedipine if appropriate. Nifedipine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Concomitant use may increase nifedipine exposure.
    Nilotinib: (Major) Avoid coadministration of ribociclib with nilotinib due to an increased risk for QT prolongation. Additionally, the systemic exposure of nilotinib may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Nilotinib is a CYP3A4 substrate that has also been associated with QT prolongation and sudden death. Concomitant use may increase the risk for QT prolongation.
    Nimodipine: (Major) Avoid coadministration of nimodipine with ribociclib due to the risk of significant hypotension. If concomitant use is unavoidable, monitor blood pressure and reduce the dose of nimodipine as clinically appropriate. Nimodipine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with ribociclib due to increased plasma concentrations of nisoldipine. Nisoldipine is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Norfloxacin: (Major) Avoid coadministration of ribociclib with norfloxacin due to the risk of QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Quinolones have also been associated with a risk of QT prolongation. Although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of norfloxacin; these reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Major) Avoid coadministration of ribociclib with nortriptyline due to an increased risk for QT prolongation. Systemic exposure of nortriptyline may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Nortriptyline is a CYP3A4 substrate and tricyclic antidepressant. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Concomitant use may increase the risk for QT prolongation.
    Octreotide: (Major) Avoid coadministration of ribociclib with octreotide due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval. Concomitant use may increase the risk for QT prolongation.
    Ofloxacin: (Major) Avoid coadministration of ribociclib with ofloxacin due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, torsade de pointes has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory. Concomitant use may increase the risk for QT prolongation.
    Olanzapine: (Major) Avoid coadministration of ribociclib with olanzapine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Concomitant use may increase the risk for QT prolongation.
    Olaparib: (Major) Avoid coadministration of olaparib with ribociclib and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC of olaparib by 170%.
    Olodaterol: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as olodaterol as compared to short-acting beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ribociclib with ritonavir due to the potential for significantly increased exposure to ribociclib. If coadministration cannot be avoided, reduce the dose of ribociclib to 400 mg once daily. If ritonavir is discontinued, resume the previous ribociclib dose after at least 5 half-lives of ritonavir. Ribociclib is a CYP3A4 substrate. ritonavir is a strong CYP3A4 inhibitor. Coadministration with a strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with ribociclib is necessary. Paritaprevir is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased paritaprevir exposure by 2.2-fold to 2.9-fold.
    Ondansetron: (Major) Avoid coadministration of ribociclib with ondansetron due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of ondansetron may also be increased resulting in an increase in ondansetron-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Ondansetron is a CYP3A4 substrate that has also been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. Concomitant use may increase the risk for QT prolongation.
    Osimertinib: (Major) Avoid coadministration of ribociclib with osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). Both drugs have been shown to prolong the QT interval in a concentration-dependent manner. For ribociclib, these ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption.
    Ospemifene: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with ribociclib is necessary. Ospemifene is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Oxaliplatin: (Major) Avoid coadministration of ribociclib with oxaliplatin due to the risk of additive QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; these ECG changes typically occurred within the first four weeks of treatment and were reversible with dose interruption. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Oxybutynin: (Moderate) Monitor for an increase in oxybutynin-related adverse reactions if coadministration with ribociclib is necessary. Oxybutynin is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased mean oxybutynin plasma concentrations by approximately 2-fold.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ribociclib is necessary. If ribociclib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ribociclib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ribociclib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration with ribociclib is necessary. Paclitaxel is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Palbociclib: (Major) Avoid coadministration of palbociclib with ribociclib if possible due to the risk of increased palbociclib exposure. If concomitant use is unavoidable, decrease the dose of palbociclib to 75 mg once daily; the original dose of palbociclib may be resumed after 3 to 5 half-lives of the discontinuation of ribociclib. Palbociclib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased palbociclib exposure by 87%.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Paliperidone: (Major) Avoid coadministration of ribociclib with paliperidone due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents that prolong the QT interval. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Panobinostat: (Major) Avoid coadministration of ribociclib with panobinostat due to an increased risk for QT prolongation. Systemic exposure of panobinostat may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Panobinostat is a CYP3A4 substrate that has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Paricalcitol: (Moderate) Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with both paricalcitol and ribociclib, or during periods of dose titration. If hypercalcemia occurs, the dose of paricalcitol should be reduced or withheld until these parameters are normalized. Ribociclib is a strong CYP3A4 inhibitor and paricalcitol is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor approximately doubled the exposure of paricalcitol.
    Pasireotide: (Major) Avoid coadministration of ribociclib with pasireotide due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Pasireotide has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Pazopanib: (Major) Avoid coadministration of ribociclib with pazopanib due to an increased risk for QT prolongation. Additionally, the systemic exposure of pazopanib may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Pazopanib is a CYP3A4 substrate that has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentamidine: (Major) Avoid coadministration of ribociclib with pentamidine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Systemic pentamidine has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ribociclib is necessary; adjust the dose of amlodipine as clinically appropriate. Ribociclib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Perphenazine: (Minor) Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as ribociclib.
    Perphenazine; Amitriptyline: (Major) Avoid coadministration of ribociclib with amitriptyline due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Concomitant use may increase the risk for QT prolongation. (Minor) Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as ribociclib.
    Pexidartinib: (Major) Avoid coadministration of pexidartinib with ribociclib as concurrent use may increase pexidartinib exposure. If concurrent use cannot be avoided, reduce the dose of pexidartinib. If ribociclib is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of ribociclib. Dose adjustments are as follows: 800 mg/day or 600 mg/day of pexidartinib, reduce to 200 mg twice daily; 400 mg/day of pexidartinib, reduce to 200 mg once daily. Pexidartinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased pexidartinib exposure by 70%.
    Phenobarbital: (Major) Avoid coadministration of phenobarbital with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
    Phenylephrine; Promethazine: (Major) Avoid coadministration of ribociclib with promethazine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Phenytoin: (Major) Avoid coadministration of phenytoin with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
    Pimavanserin: (Major) Avoid coadministration of pimavanserin with ribociclib due to the risk of QT prolongation. Plasma concentrations of pimavanserin may also increase, resulting in treatment-related adverse reactions. Pimavanserin is a CYP3A4 substrate that may cause QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Additive QT prolongation may occur.
    Pimozide: (Severe) Because of the potential for torsade de pointes (TdP), use of ribociclib with pimozide is contraindicated. Pimozide is associated with a well-established risk of QT prolongation and TdP. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Additionally, ribociclib is a strong CYP3A4 inhibitor. Pimozide is partially metabolized by CYP3A4, and has a narrow therapeutic window; coadministration may increase systemic exposure to pimozide.
    Pirbuterol: (Minor) Coadministration may result in additive effects on the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval such as ribociclib. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Pitolisant: (Major) Avoid coadministration of pitolisant with ribociclib as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption.
    Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of ribociclib due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; ribociclib is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
    Ponatinib: (Major) Avoid coadministration of ponatinib and ribociclib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to 30 mg PO once daily. Ponatinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Posaconazole: (Severe) The concurrent use of posaconazole with drugs that are associated with QT prolongation and are CYP3A4 substrates, such as ribociclib, is contraindicated. Posaconazole has been associated with QT prolongation and torsade de pointes. Additionally, ribociclib is extensively metabolized by CYP3A4 and posaconazole is a strong CYP3A4 inhibitor.
    Primaquine: (Major) Avoid coadministration of ribociclib with primaquine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Primaquine has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Primidone: (Major) Avoid coadministration of primidone with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
    Procainamide: (Major) Avoid coadministration of ribociclib with procainamide due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Procainamide is also associated with a well-established risk of QT prolongation and TdP. Concomitant use may increase the risk for QT prolongation.
    Prochlorperazine: (Minor) Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as ribociclib.
    Promethazine: (Major) Avoid coadministration of ribociclib with promethazine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Propafenone: (Major) Avoid coadministration of ribociclib with propafenone due to an increased risk for QT prolongation. Systemic exposure of propafenone may also be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Propafenone is a CYP3A4 substrate and Class IC antiarrhythmic that increases the QT interval, but largely due to prolongation of the QRS interval. Concomitant use may increase the risk for QT prolongation.
    Protriptyline: (Major) Avoid coadministration of ribociclib with protriptyline due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Concomitant use may increase the risk for QT prolongation.
    Quazepam: (Moderate) Monitor for an increase in quazepam-related adverse reactions including sedation and respiratory depression if coadministration with ribociclib is necessary; reduce the dose of quazepam if clinically appropriate. Quazepam is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Quetiapine: (Major) Avoid coadministration of ribociclib with quetiapine due to an increased risk for QT prolongation. Systemic exposure of quetiapine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Limited data, including some case reports, suggest that quetiapine, a sensitive CYP3A4 substrate, may also be associated with a significant prolongation of the QTc interval in rare instances. Concomitant use may increase the risk for QT prolongation.
    Quinidine: (Major) Avoid coadministration of ribociclib with quinidine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of quinidine may be increased resulting in an increase in quinidine-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Quinidine is a CYP3A4 substrate that has also been associated with QT prolongation and torsade de pointes (TdP). Concomitant use may increase the risk for QT prolongation.
    Quinine: (Major) Avoid coadministration of ribociclib with quinine due to an increased risk for QT prolongation and torsade de pointes (TdP). Additionally, the systemic exposure of quinine may be increased, resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Quinine is a CYP3A4 substrate that has also been associated with QT prolongation and rare cases of TdP. Concomitant use may increase the risk for QT prolongation.
    Ramelteon: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with ribociclib is necessary. Ramelteon is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
    Ranolazine: (Severe) Coadministration of ranolazine and ribociclib is contraindicated due to elevated ranolazine concentrations and the potential for serious and life threatening reactions, such as cardiac arrhythmias. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Ranolazine is a CYP3A4 substrate that has also been associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of a strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%.
    Regorafenib: (Major) Avoid coadministration of regorafenib with ribociclib due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with ribociclib is necessary. Repaglinide is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased repaglinide exposure by up to 1.5-fold.
    Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as ribociclib, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate.
    Rifabutin: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration is necessary; in some cases, the dose of rifabutin may need to be decreased. Rifabutin is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with CYP3A4 inhibitors may significantly increase the plasma concentration of rifabutin.
    Rifampin: (Major) Avoid coadministration of rifampin with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased ribociclib exposure in healthy subjects by 89%.
    Rilpivirine: (Major) Avoid coadministration of ribociclib with rilpivirine due to an increased risk for QT prolongation. Systemic exposure of rilpivirine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Supratherapeutic doses of rilpivirine (75 to 300 mg per day), a CYP3A4 substrate, have also caused QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Risperidone: (Major) Avoid coadministration of ribociclib with risperidone if possible due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner and risperidone has also been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting.
    Ritonavir: (Major) Avoid coadministration of ribociclib with ritonavir due to the potential for significantly increased exposure to ribociclib. If coadministration cannot be avoided, reduce the dose of ribociclib to 400 mg once daily. If ritonavir is discontinued, resume the previous ribociclib dose after at least 5 half-lives of ritonavir. Ribociclib is a CYP3A4 substrate. ritonavir is a strong CYP3A4 inhibitor. Coadministration with a strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers.
    Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with ribociclib is necessary; carefully weigh the risk against the benefit. Roflumilast is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased roflumilast exposure by 99%.
    Romidepsin: (Major) Avoid coadministration of ribociclib with romidepsin due to an increased risk for QT prolongation; exposure to romidepsin may also increase. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Romidepsin is a CYP3A4 substrate that has also been associated with QT prolongation.
    Ruxolitinib: (Major) Reduce the ruxolitinib dosage during coadministration with ribociclib in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of ribociclib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor.
    Salmeterol: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as salmeterol as compared to short-acting beta-agonists.
    Saquinavir: (Severe) Coadministration of ribociclib with saquinavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to saquinavir may also increase. Both ribociclib and saquinavir prolong the QT interval in a concentration-dependent manner. Both drugs are also CYP3A4 substrates and strong CYP3A4 inhibitors.
    Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with ribociclib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate. (Minor) Coadministration of segesterone, a CYP3A4 substrate and ribociclib, a moderate CYP3A4 inhibitor may increase the serum concentration of segesterone.
    Sertraline: (Major) Avoid coadministration of ribociclib with sertraline due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. QTc prolongation and TdP have been reported during postmarketing use of sertraline; most cases had confounding risk factors. The risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sevoflurane: (Major) Avoid coadministration of ribociclib with halogenated anesthetics due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Halogenated anesthetics can also prolong the QT interval. Concomitant use may increase the risk for QT prolongation.
    Short-acting beta-agonists: (Minor) Coadministration may result in additive effects on the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval such as ribociclib. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Sildenafil: (Major) Coadministration with ribociclib is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving ribociclib. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Ribociclib is a strong CYP3A4 inhibitor and sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Silodosin: (Severe) Concurrent use of silodosin and ribociclib is contraindicated due to increased plasma concentrations of silodosin resulting in an increase of treatment-related adverse reactions. Silodosin is extensively metabolized by CYP3A4 and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased silodosin exposure by 2.9-fold to 3.2-fold.
    Simeprevir: (Major) Coadministration of simeprevir with ribociclib is not recommended due to increased plasma concentrations of simeprevir which increase the risk for treatment-related adverse reactions. Simeprevir is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
    Simvastatin: (Severe) Concurrent use of simvastatin and ribociclib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Simvastatin; Sitagliptin: (Severe) Concurrent use of simvastatin and ribociclib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving ribociclib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Additionally, concomitant use of siponimod and ribociclib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
    Sirolimus: (Major) Avoid coadministration of sirolimus with ribociclib if possible due to increased plasma concentrations of sirolimus resulting in treatment-related adverse reactions. Sirolimus is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Solifenacin: (Major) Avoid coadministration of ribociclib with solifenacin due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of solifenacin may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Solifenacin is a CYP3A4 substrate that has also been associated with dose-dependent prolongation of the QT interval; TdP has been reported with postmarketing use, although causality was not determined. Concomitant use may increase the risk for QT prolongation.
    Sonidegib: (Major) Avoid coadministration of sonidegib with ribociclib due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased sonidegib exposure by 2.2-fold.
    Sorafenib: (Major) Avoid coadministration of ribociclib with sorafenib due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Sorafenib has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Sotalol: (Major) Avoid coadministration of ribociclib with sotalol due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Sotalol administration is also associated with QT prolongation and TdP, with proarrhythmic events anticipated after initiation of therapy and after each upward dosage adjustment. Concomitant use may increase the risk for QT prolongation.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of St. Johns Wort with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. However, the amount of individual constituents in various St. Johns Wort products may alter the inhibiting or inducing effects, making drug interactions unpredictable. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if ribociclib must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of ribociclib is necessary. If ribociclib is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ribociclib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If ribociclib is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Sunitinib: (Major) Avoid coadministration of ribociclib with sunitinib due to the risk of QT prolongation. Increased plasma concentrations of sunitinib may also occur. Both drugs can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP). Ribociclib-related ECG changes generally occurred within the first four weeks of treatment and were reversible with dose interruption. Additionally, sunitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
    Suvorexant: (Major) Coadministration of suvorexant and ribociclib is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold.
    Tacrolimus: (Major) Avoid coadministration of ribociclib with tacrolimus due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of tacrolimus may also be increased resulting in an increase in tacrolimus-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Tacrolimus is a sensitive CYP3A4 substrate that has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Tadalafil: (Major) Avoid coadministration of ribociclib and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ribociclib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the tadalafil AUC after a 20-mg single dose by 312% and Cmax by 22%, relative to the values for tadalafil alone. The same strong inhibitor increased the tadalafil AUC after a 10-mg single dose by 107% and Cmax by 15%, relative to the values for tadalafil alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension, syncope, visual changes, and prolonged erection.
    Tamoxifen: (Major) Avoid coadministration of ribociclib with tamoxifen due to the risk of QT prolongation; an increase in tamoxifen exposure may also occur. Ribociclib is not indicated for concomitant use with tamoxifen. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; these ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. Additionally, data from a clinical trial in patients wtih breast cancer indicated that the Cmax and AUC of tamoxifen increased approximately 2-fold after coadministration of 600 mg of ribociclib.
    Tamsulosin: (Major) Concurrent use of tamsulosin and ribociclib is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes, and strong inhibitors of CYP3A4 are expected to significantly raise tamsulosin concentrations. Concomitant treatment with another strong CYP3A4 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively.
    Telavancin: (Major) Avoid coadministration of ribociclib with telavancin due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Telavancin has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Telithromycin: (Major) Avoid coadministration of ribociclib with telithromycin due to an increased risk for QT prolongation and torsade de pointes (TdP). Additionally, the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a CYP3A4 substrate and strong inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Telithromycin is also a CYP3A4 substrate and strong inhibitor that has been associated with QT prolongation and TdP. Concomitant use may increase the risk for QT prolongation.
    Temsirolimus: (Major) Avoid coadministration of ribociclib with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of ribociclib before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Terbutaline: (Minor) Coadministration may result in additive effects on the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval such as ribociclib. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tetrabenazine: (Major) Avoid coadministration of ribociclib with tetrabenazine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Tetrabenazine causes a small increase in the corrected QT interval (QTc). Concomitant use may increase the risk for QT prolongation.
    Tezacaftor; Ivacaftor: (Major) If ribociclib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with ribociclib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, give 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); ribociclib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
    Thioridazine: (Severe) Because of the potential for torsade de pointes (TdP), use of ribociclib with thioridazine is contraindicated. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Thioridazine is associated with a well-established risk of QT prolongation and TdP. Concomitant use may increase the risk for QT prolongation.
    Thiotepa: (Major) Avoid the concomitant use of thiotepa and ribociclib if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; ribociclib is a strong CYP3A4 inhibitor.
    Ticagrelor: (Major) Avoid coadministration of ticagrelor with ribociclib due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
    Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with ribociclib is necessary. Tinidazole is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Tiotropium; Olodaterol: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as olodaterol as compared to short-acting beta-agonists.
    Tipranavir: (Severe) Coadministration of ribociclib with tipranavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to tipranavir may also increase. Ribociclib is extensively metabolized by CYP3A4 and is a strong CYP3A4 inhibitor; tipranavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased ribociclib exposure in healthy subjects by 3.2-fold.
    Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ribociclib. In patients receiving tofacitinib 5 mg twice daily, reduce to 5 mg once daily; in patients receiving tofacitinib 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving tofacitinib extended-release 11 mg once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Tolterodine: (Major) Avoid coadministration of ribociclib with tolterodine due to an increased risk for QT prolongation. Systemic exposure of tolterodine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Tolterodine is a CYP3A4 substrate that has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Concomitant use may increase the risk for QT prolongation.
    Tolvaptan: (Severe) The concomitant use of tolvaptan and ribociclib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ribociclib is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Toremifene: (Major) Avoid coadministration of ribociclib with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QTc interval in a dose- and concentration-related manner. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Trabectedin: (Major) Avoid the concomitant use of trabectedin with ribociclib due to significantly increased trabectedin exposure. Trabectedin is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the systemic exposure of a single dose of trabectedin by 66%.
    Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with ribociclib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of ribociclib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with ribociclib is necessary. Verapamil is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Trazodone: (Major) Avoid coadministration of ribociclib with trazodone due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of trazodone may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Trazodone is a CYP3A4 substrate that can also prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of TdP. Concomitant use may increase the risk for QT prolongation.
    Triazolam: (Severe) Concomitant use of ribociclib with triazolam is contraindicated due to the risk of serious adverse events, such as prolonged hypnotic and/or sedative effects. Triazolam is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Consider safer alternatives if a benzodiazepine must be administered in combination with ribociclib. Benzodiazepines not metabolized by the CYP3A4 enzyme (e.g., lorazepam, oxazepam) are less likely to be affected by strong CYP3A4 inhibitors.
    Trifluoperazine: (Minor) Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as ribociclib.
    Trimipramine: (Major) Avoid coadministration of ribociclib with trimipramine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Concomitant use may increase the risk for QT prolongation.
    Triptorelin: (Major) Avoid coadministration of ribociclib with triptorelin due to the risk of QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ribociclib-related ECG changes typically occurred within the first four weeks of treatment and were reversible with dose interruption. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Ulipristal: (Moderate) Monitor for an increase in ulipristal-related adverse reactions if coadministration with ribociclib is necessary. Ulipristal is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ulipristal exposure by 5.9-fold and increased the AUC of monodemethyl-ulipristal acetate by 2.4-fold.
    Umeclidinium; Vilanterol: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as vilanterol as compared to short-acting beta-agonists. Ribociclib is also a moderate CYP3A4 inhibitor and vilanterol is a CYP3A4 substrate.
    Upadacitinib: (Moderate) Use upadacitinib with caution in patients receiving chronic treatment with ribociclib as upadacitinib exposure and adverse effects may be increased. Upadacitinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Concurrent use of upadacitinib with a strong inhibitor increased upadacitinib exposure by 75%.
    Valbenazine: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with ribociclib is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
    Vandetanib: (Major) Avoid coadministration of ribociclib with vandetanib due to an increased risk for QT prolongation and torsade de pointes (TdP). Both drugs have been shown to prolong the QT interval in a concentration-dependent manner. Sudden death and TdP have also been reported in patients receiving vandetanib. Concomitant use may increase the risk for QT prolongation.
    Vardenafil: (Major) Avoid coadministration of ribociclib with vardenafil due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of vardenafil may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Vardenafil is a sensitive CYP3A4 substrate also associated with QT prolongation at both therapeutic and supratherapeutic doses. Concomitant use may increase the risk for QT prolongation.
    Vemurafenib: (Major) Avoid coadministration of vemurafenib with ribociclib due to the risk of QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Vemurafenib is a CYP3A4 substrate that has also been associated with QT prolongation. Additive QT prolongation may occur.
    Venetoclax: (Major) Coadministration of ribociclib with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ribociclib. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Venlafaxine: (Major) Avoid coadministration of ribociclib with venlafaxine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of venlafaxine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Venlafaxine is a CYP3A4 substrate that is also associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Concomitant use may increase the risk for QT prolongation.
    Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with ribociclib is necessary. Verapamil is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Vilazodone: (Major) Do not exceed a vilazodone dose of 20 mg once daily if coadministration with ribociclib is necessary; the original dose of vilazodone can be resumed if ribociclib is discontinued. Vilazodone is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vilazodone exposure by 50%.
    Vinblastine: (Moderate) Monitor for increased severity or earlier onset of vinblastine-related adverse reactions if coadministration with ribociclib is necessary. Vinblastine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Vincristine Liposomal: (Major) Avoid coadministration of vincristine with ribociclib due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Vincristine: (Major) Avoid coadministration of vincristine with ribociclib due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Vinorelbine: (Moderate) Monitor for increased severity or earlier onset of vinorelbine-related adverse reactions if coadministration with ribociclib is necessary. Vinorelbine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Vorapaxar: (Major) Avoid coadministration of vorapaxar with ribociclib due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
    Voriconazole: (Major) Avoid coadministration of ribociclib with voriconazole due to an increased risk for QT prolongation and torsade de pointes (TdP). Additionally, the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a CYP3A4 substrate and strong inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Voriconazole is also a CYP3A4 substrate and strong inhibitor that has been associated with QT prolongation and rare cases of TdP. Concomitant use may increase the risk for QT prolongation.
    Vorinostat: (Major) Avoid coadministration of ribociclib with vorinostat due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Vorinostat has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Voxelotor: (Major) Avoid coadministration of voxelotor and ribociclib as concurrent use may increase voxelotor exposure and lead to increased toxicity. If coadministration is unavoidable, reduce voxelotor dosage to 1,000 mg PO once daily. Voxelotor is a substrate of CYP3A4; ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase voxelotor exposure by 42% to 83%.
    Warfarin: (Moderate) Monitor for an increased PT/INR if coadministration of warfarin with ribociclib is necessary. The more potent warfarin S-enantiomer is metabolized by CYP2C9, while the R-enantiomer which has a longer half-life is a CYP3A4 substrate. Ribociclib is a strong CYP3A4 inhibitor. Concomitant use may increase the INR and increase the risk for bleeding.
    Yohimbine: (Moderate) Use caution if coadministration of ribociclib with yohimbine is necessary, as the systemic exposure of yohimbine may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a CYP3A4 inhibitor and yohimbine is a CYP3A4 substrate.
    Zaleplon: (Moderate) Monitor for an increase in zaleplon-related adverse reactions if coadministration with ribociclib is necessary. Zaleplon is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased zaleplon exposure by 20%.
    Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with ribociclib. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of ribociclib, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with another strong CYP3A4 inhibitor.
    Ziprasidone: (Major) Avoid coadministration of ribociclib and ziprasidone due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; the ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption.
    Zolpidem: (Moderate) Monitor for an increase in sedation and other zolpidem-related adverse reactions if coadministration with ribociclib is necessary. Zolpidem is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased zolpidem exposure by 34% to 70%

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during ribociclib treatment and for at least 3 weeks after the last dose. Although there are no available human data, ribociclib can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving ribociclib should be apprised of the potential hazard to the fetus. When given to pregnant rats at exposures approximately 0.6 times what would be achieved at the recommended human dose, reduced maternal body weight gain and reduced fetal weights were accompanied by skeletal changes related to the lower fetal weights. Increased incidences of fetal abnormalities (malformations and external, visceral, and skeletal variants) as well as lower fetal weights occurred in rabbits treated at exposures of 1.5 times what would be achieved at the recommended human dose; there was no maternal toxicity at this dose. Fetal abnormalities included reduced/small lung lobes, additional vessel on the descending aorta, additional vessel on the aortic arch, small eyes, diaphragmatic hernia, absent accessory lobe or (partly) fused lung lobes, reduced/small accessory lung lobe, extra/rudimentary 13th ribs, misshapen hyoid bone, bent hyoid bone alae, and reduced number of phalanges in the pollex; there was not an increased incidence of embryo-fetal mortality.

    Due to the potential for serious adverse reactions in nursing infants from ribociclib, advise women to discontinue breast-feeding during treatment and for 3 weeks after the final dose. It is not known whether ribociclib is present in human milk, although many drugs are excreted in human milk.

    MECHANISM OF ACTION

    Ribociclib is a cyclin-dependent kinase (CDK) 4 and 6 inhibitor. CDK 4 and 6 are activated when binding to D-cyclins. Cyclin D1 and CDK 4/6 are downstream of signaling pathways that lead to cellular proliferation; the cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In vitro, ribociclib decreased pRb phosphorylation leading to arrest in the G1 phase of the cell cycle, reducing cell proliferation in breast cancer cell lines. In a rat xenograft model with human tumor cells, inhibition of pRb phosphorylation by ribociclib monotherapy decreased tumor volumes. The combination of ribociclib and an antiestrogen agent such as letrozole inhibited tumor growth more than either agent alone in studies using patient-derived estrogen receptor positive breast cancer xenograft models.

    PHARMACOKINETICS

    Ribociclib is administered orally. In vitro, ribociclib is approximately 70% protein bound in human plasma, independent of concentration (10 ng/mL to 10,000 ng/mL). The mean in vivo blood-to-plasma ratio was 1.04, indicating equal distribution between red blood cells and plasma. Based on a population pharmacokinetic analysis, the apparent volume of distribution at steady-state (Vss/F) of 1,090 L. The clinical activity and safety profile of ribociclib are primarily due to the parent drug, with little contribution from the circulating metabolites (M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide) which are conjugated via N-acetylation, sulfation, cysteine conjugation, glycosylation and glucuronidation. In patients with advanced cancer, the geometric mean plasma effective half-life was 32 hours (coefficient of variation (CV%), 63%) while the terminal half-life ranged from 29.7 to 54.7 hours in healthy subjects. The geometric mean apparent oral clearance at steady-state (CL/F) was 25.5 L/hr (CV%, 66%) in patients with advanced cancer and 39.9 to 77.5 L/hr in health subjects. Steady-state was generally achieved after 8 days of daily administration of the recommended dose; the geometric mean accumulation ratio was 2.51 (range, 0.972 to 6.40). Ribociclib is extensively metabolized, with unchanged drug accounting for 17% and 12% in feces and urine, respectively. After a single radio-labeled oral dose of ribociclib, 69% of the total dose was recovered in the feces and 23% in the urine.
     
    Affected cytochrome P450 isoenzymes (CYP450) or drug transporters: CYP3A4, CYP1A2, CYP2E1, BCRP, OCT2, MATE1, and human BSEP
    In vitro and in vivo studies indicate that ribociclib is extensively metabolized, primarily via CYP3A4. After a single, radio-labeled, 600 mg dose, the primary metabolic pathway for ribociclib involved combinations of oxidation (dealkylation, C and/or N-oxygenation, oxidation (-2H)). Ribociclib is a reversible and time-dependent strong inhibitor of CYP3A4/5 at clinically relevant concentrations in vitro, as well as a reversible inhibitor of CYP1A2 and CYP2E1 in vitro. However, multiple doses ribociclib decreased the AUC and Cmax of caffeine, a CYP1A2 substrate, by 20% and 10%, respectively. Additionally, it may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations. In vitro, it does not inhibit CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations, nor does it induce CYP1A2, CYP2B6, CYP2C9, or CYP3A4. Ribociclib has a low potential to inhibit P-glycoprotein (P-gp), OATP1B1/B3, OCT1, and MATEK2. Based on in vitro data, oral absorption of ribociclib is unlikely to be affected by P-gp and BCRP mediated transport. It is also not a substrate for OATP1B1/1B3 or OCT-1 in vitro.

    Oral Route

    After both single and repeated doses, ribociclib exhibited over-proportional increases in Cmax and AUC across a dose range of 50 mg to 1,200 mg. The Tmax after oral administration of ribociclib was between 1 and 4 hours. The rate and extent of ribociclib absorption were not affected by administration with a high-fat, high-calorie meal compared to administration in a fasting state, with the geometric mean Cmax of 1 (90% CI, 0.898 to 1.11) and geometric mean AUC of 1.06 (90% CI, 1.01 to 1.12).