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  • CLASSES

    Small Molecule Antineoplastic Multikinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Multi-kinase inhibitor targeting several intracellular and cell surface kinases
    Used for the treatment of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid cancer refractory to radioactive iodine treatment
    Dermatologic toxicities are among the most common adverse reactions associated with sorafenib treatment and may require an interruption of therapy or dose reduction

    COMMON BRAND NAMES

    Nexavar

    HOW SUPPLIED

    Nexavar/Sorafenib tosylate Oral Tab: 200mg

    DOSAGE & INDICATIONS

    For the treatment of advanced renal cell cancer.
    NOTE: Sorafenib has been designated as an orphan drug by the FDA for the treatment of renal cell cancer.
    Oral dosage
    Adults

    400 mg PO twice daily until clinical benefit ceases or unacceptable toxicity occurs. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter,  randomized, double-blind, phase 3 clinical trial, treatment with sorafenib significantly improved median progression-free survival (PFS) compared with placebo in patients with advanced renal cell carcinoma (RCC) who had received one prior systemic therapy (5.5 months vs. 2.8 months). After the first survival analysis, crossover was allowed in the placebo arm. The final survival analysis did not show an overall survival difference with sorafenib; however, censoring the data from placebo-assigned patients who crossed over to receive sorafenib revealed a significant survival advantage in the sorafenib arm (17.8 months vs. 14.3 months).[33032] [36045] [31832] In a second randomized, phase 3 discontinuation trial that enrolled patients with metastatic malignancies including RCC, patients with RCC who were randomized to receive sorafenib had a significantly longer PFS compared with patients who received placebo (163 days vs. 41 days).[31832]

    For the treatment of unresectable hepatocellular cancer (HCC).
    NOTE: Sorafenib has been designated an orphan drug by the FDA for hepatocellular cancer.
    Oral dosage
    Adults

    400 mg PO twice daily until clinical benefit ceases or unacceptable toxicity occurs. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, double-blind, phase 3 clinical trial in patients with previously untreated unresectable hepatocellular carcinoma, treatment with sorafenib significantly improved overall survival (10.7 months vs. 7.9 months) and median time to progression (5.5 months vs. 2.8 months); time to symptomatic progression was not significantly different.

    For the treatment of locally recurrent or metastatic, progressive, differentiated thyroid cancer that is refractory to treatment with radioactive iodine.
    Oral dosage
    Adults

    400 mg PO twice daily until clinical benefit ceases or unacceptable toxicity occurs. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, double-blind clinical trial, treatment with sorafenib significantly improved progression-free survival (PFS) compared with placebo in patients with locally recurrent or metastatic, progressive, differentiated thyroid cancer refractory to radioactive iodine (10.8 months vs. 5.8 months). After disease progression, 77% of patients initially randomized to placebo crossed over to receive open-label sorafenib. Overall survival was not significantly different between groups (42.8 months vs. 39.4 months).[31832]

    For the treatment of advanced malignant melanoma†.
    For the treatment of advanced, including locally unresectable and metastatic, malignant melanoma†.
    Oral dosage
    Adults

    Dosage not established. 400 mg PO twice daily for 12 weeks was studied in 37 patients in a phase II randomized discontinuation trial. After the initial 12-weeks, patient response to therapy was determined. Patients with < 25% change in bi-dimensional tumor measurements were randomized to sorafenib or placebo for an additional 12 weeks. Patients with >= 25% shrinkage in bi-dimensional tumor measurements were continued on open-label sorafenib treatment, and patients with >= 25% growth in bi-dimensional tumor measurements were discontinued from treatment. Of the 34 evaluable patients, 1 patient had >= 25% tumor shrinkage, 6 had < 25% tumor shrinkage, and 27 had >= 25% tumor growth. All 3 patients randomized to further sorafenib treatment progressed by week 24. In another trial of 36 patients (BRAFV600E positive via DNA sequencing, n=6/33; BRAFV600E positive via mutation-specific PCR, n=18/30), sorafenib induced a partial response in 1 patient and stable disease in 3 patients.

    For the treatment of advanced, including locally unresectable and metastatic, malignant melanoma† in combination with carboplatin and paclitaxel.
    Oral dosage
    Adults

    Dosage not established; 400 mg PO twice daily has been studied. In a phase III trial of 270 patients with advanced melanoma that had progressed during or after treatment with either dacarbazine or temozolomide, carboplatin (AUC 6 IV on day 1) and paclitaxel (225 mg/m2 IV on day 1) were given in combination with sorafenib 400 mg PO twice daily on days 2—19 or placebo; cycles were repeated every 3 weeks. Carboplatin and paclitaxel were given until disease progression or unacceptable toxicity, up to a maximum of 10 cycles; sorafenib could be continued beyond 10 cycles in patients with stable disease or better. A mandatory dose reduction of carboplatin (AUC 5 IV on day 1) and paclitaxel (175 mg/m2 IV on day 1) was instituted in cycle 5, unless both doses had been previously reduced. Progression-free survival, the primary endpoint, was not improved with the addition of sorafenib (17.4 weeks with sorafenib v. 17.9 weeks with placebo, p = 0.49). Overall survival was 42 weeks in each arm. Grade 3 and 4 adverse events that occurred more frequently in the sorafenib arm include thrombocytopenia (28% v. 12%), dermatologic adverse events (18% v. 4%), and fatigue (16% v. 10%). These results were confirmed in another phase III trial of 823 chemotherapy-naive patients with metastatic melanoma randomized to receive carboplatin/paclitaxel with or without sorafenib. The primary endpoint, OS, was not significantly different between the treatment arms.

    For the treatment of advanced, including locally unresectable and metastatic, malignant melanoma† in combination with dacarbazine or temozolomide.
    Oral dosage
    Adults

    400 mg PO twice daily has been studied. In a phase II trial of 101 chemotherapy-naive patients, dacarbazine (1000 mg/m2 IV on day 1) was given in combination with sorafenib 400 mg PO twice daily (given continuously) or placebo; cycles were repeated every 3 weeks. Dacarbazine was given up to a maximum of 16 cycles; sorafenib treatment was continued until disease progression or unacceptable toxicity. The primary endpoint, progression-free survival, was improved, although not significantly, in the sorafenib arm (21.1 weeks v. 11.7 weeks, p = 0.068). Time-to-progression (21.1 weeks v. 11.7 weeks, p = 0.039), 6-month PFS (41% v. 19.5%), and 9-month PFS (22.2% v. 12.2%) were all significantly improved in the sorafenib arm. Activity has also been observed with the combination of sorafenib and temozolomide in a phase II trial of 167 patients.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    800 mg/day PO.

    Elderly

    800 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment: No dose adjustment is necessary.
    Severe (Child-Pugh C) hepatic impairment: The pharmacokinetics of sorafenib have not been studied in this population.
     
    Treatment-Related Hepatotoxicity
    Severe drug-induced liver injury, including grade 3 or higher ALT in the absence of other causes; AST/ALT greater than 3 times the upper limit of normal (ULN) with bilirubin greater than 2 times ULN in the absence of another cause; any grade increase in alkaline phosphatase without known bone pathology and grade 2 or worse increase in bilirubin; INR 1.5 or more; ascites and/or encephalopathy in the absence of underlying cirrhosis; other organ failure considered to be due to drug-induced liver injury: Permanently discontinue sorafenib; do not resume therapy.

    Renal Impairment

    Mild (CrCL 50 to 80 mL/min), moderate (CrCL 30 to 49 mL/min), or severe (CrCL less than 30 mL/min) renal impairment: No dose adjustment is necessary.
    Dialysis patients: The pharmacokinetics of sorafenib have not been studied in this population.

    ADMINISTRATION

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 1
    NIOSH (Draft) 2020 List: Table 2
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
    Emetic Risk
    Pediatrics: Doses 150 to 325 mg/m2: Low
    Adults: Minimal/Low
    Administer prn antiemetics as necessary.

    Oral Administration

    Administer sorafenib orally without food (at least 1 hour before or 2 hours after a meal).
    If a dose is missed, the next dose should be taken at the regularly scheduled time; do not administer 2 doses at the same time.

    STORAGE

    Nexavar:
    - Keep away from heat and flame
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in a cool, well ventilated, dry place
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Lung cancer, mortality

    Sorafenib in combination with paclitaxel and carboplatin is contraindicated in patients with squamous cell lung cancer. The use of sorafenib in combination with gemcitabine/cisplatin is not recommended in patients with squamous cell lung cancer. Mortality was increased in patients with squamous cell carcinoma treated with the addition of sorafenib compared with carboplatin/paclitaxel alone (HR 1.81; 95% CI, 1.19 to 2.74) and gemcitabine/cisplatin alone (HR 1.22; 95% CI, 0.82 to 1.8). The safety and efficacy of sorafenib in patients with non-small cell lung cancer has not been established.[31832]

    Bleeding, GI bleeding, intracranial bleeding

    Serious bleeding, including GI bleeding, pulmonary bleeding, and intracranial bleeding, has been reported with sorafenib use. Due to bleeding risk, any tracheal, bronchial, or esophageal infiltration should be treated with local therapy prior to sorafenib therapy in patients with differentiated thyroid cancer. Consider permanent discontinuation of sorafenib therapy in patients who develop bleeding that requires medical intervention.

    Hepatitis, hepatotoxicity

    Severe hepatotoxicity, defined as elevated transaminases above 20 times the upper limit of normal or transaminase elevations with significant clinical sequelae (e.g., elevated INR, ascites, transplantation, or death) has been reported rarely with sorafenib use. Sorafenib-induced hepatitis is characterized by a hepatocellular pattern of liver damage with significant increases of transaminases. Monitor liver function tests regularly. Discontinue sorafenib in patients who develop significantly increased transaminases in the absence of an alternative explanation (e.g., viral hepatitis or progressive underlying malignancy).

    Thyroid cancer

    Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with differentiated thyroid cancer (DTC). Sorafenib interferes with exogenous thyroid suppression. In a randomized, multicenter study of patients with metastatic DTC (n = 207), increases in thyroid stimulating hormone (TSH) above 0.5 mU/L occurred in 41% of sorafenib-treated patients compared to 16% of patients treated with placebo. The median maximal TSH was 1.6 mU/L, with TSH greater than 4.4 mU/L in 25% of patients.[31832]

    Hypertension

    Hypertension may develop with sorafenib use. Monitor blood pressure weekly during the first 6 weeks of therapy and periodically thereafter. Treat hypertension according to standard practice. Temporary or permanent discontinuation of sorafenib should be considered in patients who develop severe or persistent hypertension despite the use of antihypertensive therapy.

    Coronary artery disease, heart failure, myocardial infarction

    Use sorafenib with caution in patients with a history of coronary artery disease, myocardial infarction, or congestive heart failure. The incidence of myocardial infarction/ischemia was increased in patients treated with sorafenib compared with placebo-treated groups in 3 clinical trials; patients with unstable coronary artery disease or recent myocardial infarction were excluded from these studies. Congestive heart failure has also been reported in sorafenib-treated patients across multiple clinical trials. Temporary or permanent discontinuation of therapy should be considered in patients who develop cardiovascular events. Of note, heart failure and myocardial infarction may increase the risk of prolonging the QT interval when using sorafenib.

    Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, females, fever, geriatric, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

    Sorafenib can prolong the QT/QTc interval, which increases the risk for ventricular arrhythmias. Avoid sorafenib treatment in patients with congenital long QT syndrome. Use with caution and monitor electrolytes and ECGs in patients with congestive heart failure, bradyarrhythmias (bradycardia), and in those taking other medications known to prolong the QT interval. Correct any electrolyte abnormalities (e.g., hypomagnesemia, hypokalemia, hypocalcemia); an interruption or discontinuation of therapy may be necessary for QT prolongation. Use sorafenib with caution in patients with conditions that may increase the risk of QT prolongation including AV block, stress-related cardiomyopathy, myocardial infarction, stroke, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

    Surgery

    Impaired wound healing has been reported in patients who received medications that inhibit the vascular endothelial growth factor (VEGF) signaling pathway such as sorafenib. Discontinue sorafenib at least 10 days prior to elective surgery; do not administer sorafenib for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming sorafenib after the resolution of wound healing complications has not been established.

    Skin disease

    Serious skin disease/toxicity, including palmar-plantar erythrodysesthesia (hand and foot syndrome), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), has been reported with sorafenib use. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption, dose modification, or permanent discontinuation of sorafenib. If the dose of sorafenib has been reduced due to dermatologic toxicity, the dose of sorafenib may be increased by one dose level following at least 28 days of treatment at the reduced dose after resolution to grade 1 or less toxicity. Approximately 50% of patients requiring a dose reduction for dermatologic toxicity will meet the criteria for resuming a higher dose, and about half of those patients will tolerate the higher dose. If SJS or TEN is suspected, discontinue sorafenib therapy.

    GI perforation

    GI perforation has been reported infrequently with sorafenib use. Discontinue therapy in patients who develop a GI perforation.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during sorafenib treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant women, sorafenib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving sorafenib should be apprised of the potential hazard to the fetus. In animal reproduction studies, sorafenib was teratogenic and induced embryofetal toxicity (e.g., increased post-implantation loss, resorptions, skeletal retardations, and retarded fetal weight) when administered orally to pregnant rats and rabbits during organogenesis at doses much lower than the recommended human dose (approximately 500 mg/m2 per day). Adverse intrauterine development effects were seen at exposures that were approximately 0.008 times the AUC in patients at the recommended dose (1.2 mg/m2 per day in rats, and 3.6 mg/m2 per day in rabbits).

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during sorafenib treatment. Sorafenib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 6 months after treatment with sorafenib. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential or pregnant partners should use effective contraception during and for at least 3 months after treatment with sorafenib. Females of reproductive potential should undergo pregnancy testing prior to initiation of sorafenib. Women who become pregnant while receiving sorafenib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of sorafenib 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 sorafenib, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether sorafenib is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 6.0-19.0
    lymphopenia / Delayed / 0-13.0
    hypophosphatemia / Delayed / 11.0-13.0
    exfoliative dermatitis / Delayed / 1.0-10.0
    hypertension / Early / 3.0-10.0
    hypocalcemia / Delayed / 2.0-10.0
    diarrhea / Early / 2.0-10.0
    fatigue / Early / 5.0-10.0
    renal failure (unspecified) / Delayed / 1.0-10.0
    abdominal pain / Early / 1.0-9.0
    weight loss / Delayed / 0-6.0
    rash / Early / 0-5.0
    neutropenia / Delayed / 0-5.0
    dyspnea / Early / 0-4.0
    elevated hepatic enzymes / Delayed / 0-4.0
    prolonged bleeding time / Delayed / 0-4.0
    thrombocytopenia / Delayed / 1.0-4.0
    bleeding / Early / 0-3.0
    anorexia / Delayed / 0-3.0
    new primary malignancy / Delayed / 0-3.0
    myocardial infarction / Delayed / 1.9-2.9
    hyperamylasemia / Delayed / 1.0-2.0
    arthralgia / Delayed / 0-2.0
    anemia / Delayed / 0-2.0
    vomiting / Early / 0-2.0
    stomatitis / Delayed / 0-2.0
    heart failure / Delayed / 1.9-1.9
    erythema multiforme / Delayed / 0.1-1.0
    pruritus / Rapid / 0-1.0
    alopecia / Delayed / 0-1.0
    eczema vaccinatum / Delayed / 0.1-1.0
    hypertensive crisis / Early / 0.1-1.0
    intracranial bleeding / Delayed / 0.1-1.0
    hypokalemia / Delayed / 0-1.0
    constipation / Delayed / 0-1.0
    GI perforation / Delayed / 0-1.0
    pancreatitis / Delayed / 0.1-1.0
    headache / Early / 0-1.0
    fever / Early / 0-1.0
    acute respiratory distress syndrome (ARDS) / Early / 0.1-1.0
    cholecystitis / Delayed / 0-1.0
    serious hypersensitivity reactions or anaphylaxis / Rapid / 0.1-1.0
    leukoencephalopathy / Delayed / 0.1-1.0
    nausea / Early / 0-1.0
    xerosis / Delayed / 0-0.5
    dysphonia / Delayed / 0-0.5
    hepatotoxicity / Delayed / 0-0.1
    nephrotic syndrome / Delayed / 0-0.1
    GI bleeding / Delayed / 10.0
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    stroke / Early / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    osteonecrosis / Delayed / Incidence not known
    thrombotic microangiopathy / Delayed / Incidence not known
    aortic dissection / Delayed / Incidence not known

    Moderate

    hypoalbuminemia / Delayed / 0-59.0
    hyponatremia / Delayed / 1.0-10.0
    dysphagia / Delayed / 1.0-10.0
    proteinuria / Delayed / 1.0-10.0
    hypothyroidism / Delayed / 1.0-10.0
    impotence (erectile dysfunction) / Delayed / 1.0-10.0
    depression / Delayed / 1.0-10.0
    dehydration / Delayed / 0-1.0
    pneumonitis / Delayed / 0.1-1.0
    cholangitis / Delayed / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    hyperthyroidism / Delayed / 0-1.0
    gastritis / Delayed / 0.1-1.0
    QT prolongation / Rapid / 0-0.1
    hepatitis / Delayed / 0-0.1
    erythema / Early / 10.0
    leukopenia / Delayed / 10.0
    bone pain / Delayed / 10.0
    jaundice / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    oral ulceration / Delayed / Incidence not known

    Mild

    hyperkeratosis / Delayed / 1.0-10.0
    folliculitis / Delayed / 1.0-10.0
    acne vulgaris / Delayed / 1.0-10.0
    flushing / Rapid / 1.0-10.0
    dysgeusia / Early / 1.0-10.0
    muscle cramps / Delayed / 1.0-10.0
    myalgia / Early / 1.0-10.0
    rhinorrhea / Early / 1.0-10.0
    influenza / Delayed / 0.1-10.0
    gastroesophageal reflux / Delayed / 1.0-10.0
    dyspepsia / Early / 1.0-10.0
    epistaxis / Delayed / 0-7.0
    gynecomastia / Delayed / 0.1-1.0
    tinnitus / Delayed / 0.1-1.0
    asthenia / Delayed / 10.0
    infection / Delayed / 10.0
    urticaria / Rapid / Incidence not known
    xerostomia / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with sorafenib is necessary. Dolutegravir is a P-glycoprotein (P-gp) and UGT1A1 substrate. Sorafenib inhibits both P-gp and UGT1A1 in vitro, and may increase the concentrations of concomitantly administered drugs that are P-gp or UGT1A1 substrates.
    Afatinib: (Moderate) If the concomitant use of sorafenib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of sorafenib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Alfuzosin: (Major) Avoid coadministration of sorafenib with alfuzosin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Alfuzosin may also prolong the QT interval in a dose-dependent manner.
    Amiodarone: (Major) Avoid coadministration of sorafenib with amiodarone due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Sorafenib is also associated with QTc prolongation.
    Amisulpride: (Major) Avoid coadministration of sorafenib with amisulpride due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Amisulpride also causes dose- and concentration-dependent QT prolongation.
    Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sorafenib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of sorafenib with clarithromycin due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Anagrelide: (Major) Do not use anagrelide with sorafenib due to the risk of QT prolongation and torsade de pointes (TdP). Torsade de pointes and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Sorafenib has also been associated with QT prolongation.
    Apalutamide: (Major) Avoid coadministration of sorafenib with apalutamide due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Apomorphine: (Major) Avoid coadministration of sorafenib with apomorphine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Sorafenib is also associated with QTc prolongation.
    Aripiprazole: (Major) Avoid coadministration of sorafenib with aripiprazole due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Sorafenib is also associated with QTc prolongation.
    Arsenic Trioxide: (Major) Avoid coadministration of sorafenib with arsenic trioxide due to the risk of additive QT prolongation. If concomitant use is unavoidable, frequently monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Sorafenib is also associated with QTc prolongation.
    Artemether; Lumefantrine: (Major) Avoid coadministration of sorafenib with artemether; lumefantrine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs are associated with QTc prolongation. (Major) Avoid coadministration of sorafenib with artemether; lumefantrine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. Both drugs are associated with QTc prolongation.
    Asenapine: (Major) Avoid coadministration of asenapine with sorafenib due to the risk of QT prolongation. Both drugs have been associated with QT prolongation.
    Atomoxetine: (Major) Avoid coadministration of sorafenib with atomoxetine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Sorafenib is associated with QTc prolongation.
    Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sorafenib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sorafenib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Azithromycin: (Major) Avoid coadministration of azithromycin with sorafenib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Sorafenib is also associated with QTc prolongation.
    Bedaquiline: (Major) Avoid coadministration of sorafenib with bedaquiline due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of therapy may be necessary if QT prolongation occurs. Bedaquiline prolongs the QT interval. Sorafenib is also associated with QTc prolongation.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of sorafenib with phenobarbital due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking sorafenib. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a P-gp substrate and sorafenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving sorafenib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving sorafenib. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate. Sorafenib inhibits P-gp in vitro, and may increase the concentrations of concomitantly administered drugs that are P-gp substrates. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3 fold.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Buprenorphine: (Major) Avoid coadministration of sorafenib with buprenorphine due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Buprenorphine; Naloxone: (Major) Avoid coadministration of sorafenib with buprenorphine due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Cabotegravir; Rilpivirine: (Major) Avoid coadministration of sorafenib with rilpivirine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Carbamazepine: (Major) Avoid coadministration of sorafenib with carbamazepine due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Ceritinib: (Major) Avoid coadministration of sorafenib with ceritinib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Ceritinib causes concentration-dependent QT prolongation.
    Chloroquine: (Major) Avoid coadministration of chloroquine with sorafenib due to the risk of additive QT prolongation. If concomitant use is unavoidable, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Sorafenib is also associated with QTc prolongation.
    Chlorpromazine: (Major) Avoid coadministration of sorafenib with chlorpromazine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). Sorafenib is also associated with QTc prolongation.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Ciprofloxacin: (Major) Avoid coadministration of sorafenib with ciprofloxacin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of sorafenib with cisapride is contraindicated. Prolongation of the QT interval and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Sorafenib has also been associated with QT prolongation.
    Citalopram: (Major) Avoid coadministration of sorafenib with citalopram due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Citalopram causes dose-dependent QT interval prolongation. Sorafenib is also associated with QTc prolongation.
    Clarithromycin: (Major) Avoid coadministration of sorafenib with clarithromycin due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Clofazimine: (Major) Concomitant use of clofazimine and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Clozapine: (Major) Avoid coadministration of sorafenib with clozapine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Sorafenib is also associated with QTc prolongation.
    Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with sorafenib is necessary. Cobimetinib is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid coadministration of sorafenib with promethazine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Major) Avoid coadministration of sorafenib with promethazine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and sorafenib 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. Sorafenib can inhibit colchicine's metabolism via P-glycoprotein (P-gp), 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 sorafenib 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.
    Crizotinib: (Major) Avoid coadministration of crizotinib with sorafenib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Sorafenib is also associated with QTc prolongation.
    Cyclosporine: (Moderate) Monitor for an increase in cyclosporine plasma concentrations and cyclosporine-related adverse reactions if coadministration with sorafenib is necessary. Cyclosporine is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with sorafenib is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/min. Avoid coadministration in patients with CrCl less than 50 mL/min when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/min in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-glycoprotein substrate and sorafenib is a P-gp inhibitor.
    Darunavir: (Moderate) Monitor for an increase in darunavir-related adverse reactions if coadministration with sorafenib is necessary. Darunavir may be a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Darunavir; Cobicistat: (Moderate) Monitor for an increase in darunavir-related adverse reactions if coadministration with sorafenib is necessary. Darunavir may be a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an increase in darunavir-related adverse reactions if coadministration with sorafenib is necessary. Darunavir may be a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with sorafenib is necessary. Ombitasvir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates. (Major) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with sorafenib is necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates. (Moderate) Monitor for an increase in dasabuvir-related adverse reactions if coadministration with sorafenib is necessary. Dasabuvir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Dasatinib: (Major) Avoid coadministration of sorafenib with dasatinib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. In vitro studies have shown that dasatinib also has the potential to prolong the QT interval.
    Degarelix: (Major) Avoid coadministration of sorafenib with degarelix due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
    Deutetrabenazine: (Major) Avoid coadministration of sorafenib with deutetrabenazine due to the potential risk of QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
    Dexamethasone: (Major) Avoid coadministration of sorafenib with dexamethasone due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and dexamethasone is a CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of sorafenib with quinidine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP). Sorafenib is associated with QTc prolongation.
    Digoxin: (Moderate) Monitor for an increase in digoxin plasma concentrations and digoxin-related adverse reactions if coadministration with sorafenib is necessary. Digoxin is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Disopyramide: (Major) Avoid coadministration of sorafenib with disopyramide due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP). Sorafenib is associated with QTc prolongation.
    Dofetilide: (Major) Coadministration of dofetilide and sorafenib 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 TdP. Sorafenib is associated with QTc prolongation.
    Dolasetron: (Major) Avoid coadministration of sorafenib with dolasetron due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Sorafenib is also associated with QTc prolongation.
    Dolutegravir: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with sorafenib is necessary. Dolutegravir is a P-glycoprotein (P-gp) and UGT1A1 substrate. Sorafenib inhibits both P-gp and UGT1A1 in vitro, and may increase the concentrations of concomitantly administered drugs that are P-gp or UGT1A1 substrates.
    Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with sorafenib is necessary. Dolutegravir is a P-glycoprotein (P-gp) and UGT1A1 substrate. Sorafenib inhibits both P-gp and UGT1A1 in vitro, and may increase the concentrations of concomitantly administered drugs that are P-gp or UGT1A1 substrates.
    Dolutegravir; Rilpivirine: (Major) Avoid coadministration of sorafenib with rilpivirine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with sorafenib is necessary. Dolutegravir is a P-glycoprotein (P-gp) and UGT1A1 substrate. Sorafenib inhibits both P-gp and UGT1A1 in vitro, and may increase the concentrations of concomitantly administered drugs that are P-gp or UGT1A1 substrates.
    Donepezil: (Major) Avoid coadministration of sorafenib with donepezil due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Donepezil; Memantine: (Major) Avoid coadministration of sorafenib with donepezil due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with sorafenib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Doxorubicin Liposomal: (Major) Avoid coadministration of sorafenib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Sorafenib is a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of P-gp. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Doxorubicin: (Major) Avoid coadministration of sorafenib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Sorafenib is a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of P-gp. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronedarone: (Contraindicated) Concurrent use of dronedarone and sorafenib is contraindicated. Sorafenib has been associated with QT prolongation. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. 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.
    Droperidol: (Major) Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as sorafenib. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Sorafenib is also associated with QTc prolongation.
    Edoxaban: (Major) If coadministered with sorafenib, a P-gp inhibitor, dosage reduction of edoxaban, a P-gp substrate, may be necessary for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE). An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with sorafenib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of sorafenib. Increased concentrations of edoxaban may occur during concomitant use of sorafenib; monitor for increased adverse effects of edoxaban.
    Efavirenz: (Major) Avoid coadministration of sorafenib with efavirenz due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. QTc prolongation has also been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of sorafenib with efavirenz due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. QTc prolongation has also been observed with the use of efavirenz. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with sorafenib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of sorafenib with efavirenz due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. QTc prolongation has also been observed with the use of efavirenz. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with sorafenib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Eliglustat: (Major) Avoid coadministration of sorafenib with eliglustat due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Eliglustat is also predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with sorafenib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of sorafenib with rilpivirine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of sorafenib with rilpivirine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with sorafenib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with sorafenib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Encorafenib: (Major) Avoid coadministration of sorafenib with encorafenib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Encorafenib has been associated with dose-dependent QT prolongation. Sorafenib is also associated with QTc prolongation.
    Entrectinib: (Major) Avoid coadministration of sorafenib with entrectinib due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Entrectinib has also been associated with QT prolongation.
    Enzalutamide: (Major) Avoid coadministration of sorafenib with enzalutamide due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Eribulin: (Major) Avoid coadministration of sorafenib with eribulin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs are associated with QTc prolongation.
    Erythromycin: (Major) Avoid coadministration of sorafenib with erythromycin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Erythromycin is associated with QT prolongation and torsade de pointes (TdP). Sorafenib is also associated with QTc prolongation.
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of sorafenib with erythromycin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Erythromycin is associated with QT prolongation and torsade de pointes (TdP). Sorafenib is also associated with QTc prolongation.
    Escitalopram: (Major) Avoid coadministration of sorafenib with escitalopram due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP). Sorafenib is also associated with QTc prolongation.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with sorafenib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Ezogabine: (Major) Avoid coadministration of sorafenib with ezogabine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs have been associated with QT prolongation.
    Fingolimod: (Major) Avoid coadministration of sorafenib with fingolimod due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval; it 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.
    Flecainide: (Major) Avoid coadministration of sorafenib with flecainide due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Major) Avoid coadministration of sorafenib with fluconazole due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Sorafenib is also associated with QTc prolongation.
    Fluoxetine: (Major) Avoid coadministration of sorafenib with fluoxetine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Sorafenib is also associated with QTc prolongation.
    Fluphenazine: (Minor) Use caution if coadministration of sorafenib with fluphenazine is necessary due to the risk of additive QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Sorafenib is also associated with QTc prolongation; the manufacturer of sorafenib recommends avoiding coadministration with other drugs that cause QT prolongation.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with sorafenib is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor in vitro. Coadministration with another P-gp inhibitor increased umeclidinium exposure by 1.4-fold.
    Fluvoxamine: (Major) Avoid coadministration of sorafenib with fluvoxamine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine postmarketing use.
    Foscarnet: (Major) Avoid coadministration of foscarnet with sorafenib due to the risk of QT prolongation. Sorafenib has been associated with QT prolongation. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing experience with foscarnet.
    Fosphenytoin: (Major) Avoid coadministration of sorafenib with fosphenytoin due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Fostemsavir: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of sorafenib with fostemsavir is necessary; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib has been associated with QT prolongation. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gemifloxacin: (Major) Avoid coadministration of sorafenib with gemifloxacin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Gemifloxacin may prolong the QT interval in some patients. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of sorafenib with gemtuzumab due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
    Gilteritinib: (Major) Avoid coadministration of sorafenib with gilteritinib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs are associated with QTc prolongation.
    Glasdegib: (Major) Avoid coadministration of sorafenib with glasdegib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Sorafenib is also associated with QTc prolongation.
    Glecaprevir; Pibrentasvir: (Moderate) Monitor for an increase in glecaprevir-related adverse reactions if coadministration with sorafenib is necessary. Glecaprevir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates. (Moderate) Monitor for an increase in pibrentasvir-related adverse reactions if coadministration with sorafenib is necessary. Pibrentasvir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Glyburide: (Moderate) Monitor for an increase in glyburide-related adverse reactions, including hypoglycemia, if coadministration with sorafenib is necessary. Glyburide is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Glyburide; Metformin: (Moderate) Monitor for an increase in glyburide-related adverse reactions, including hypoglycemia, if coadministration with sorafenib is necessary. Glyburide is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Goserelin: (Major) Avoid coadministration of sorafenib with goserelin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
    Granisetron: (Major) Avoid coadministration of sorafenib with granisetron due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs have been associated with QT prolongation.
    Halogenated Anesthetics: (Major) Avoid coadministration of sorafenib with halogenated anesthetics due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Halogenated anesthetics can also prolong the QT interval.
    Haloperidol: (Major) Avoid coadministration of sorafenib with haloperidol due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment; excessive doses (particularly in the overdose setting) or IV administration may be associated with a higher risk of QT prolongation. Sorafenib is also associated with QTc prolongation.
    Histrelin: (Major) Avoid coadministration of sorafenib with histrelin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and sorafenib due to the risk of increased QT prolongation. If concomitant use is unavoidable, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. Sorafenib is also associated with QTc prolongation.
    Hydroxyzine: (Major) Avoid coadministration of sorafenib with hydroxyzine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Postmarketing data indicate that hydroxyzine also causes QT prolongation and torsade de pointes (TdP).
    Ibutilide: (Major) Avoid coadministration of sorafenib with ibutilide due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Ibutilide administration can cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. Sorafenib is also associated with QTc prolongation.
    Iloperidone: (Major) Avoid coadministration of iloperidone with sorafenib due to the risk of QT prolongation. Both drugs have been associated with QT prolongation.
    Indinavir: (Moderate) Monitor for an increase in indinavir-related adverse reactions if coadministration with sorafenib is necessary. Indinavir is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of sorafenib with inotuzumab due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs have been associated with QT interval prolongation.
    Irinotecan Liposomal: (Major) Avoid administration of sorafenib during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate. Sorafenib inhibits UGT1A1 in vitro and may increase the concentrations of concomitantly administered drugs that are UGT1A1 substrates.
    Irinotecan: (Major) Avoid administration of sorafenib during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate. Sorafenib inhibits UGT1A1 in vitro and may increase the concentrations of concomitantly administered drugs that are UGT1A1 substrates.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of sorafenib with rifampin due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Concomitant use with rifampin decreased sorafenib exposure by 37%.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of sorafenib with rifampin due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Concomitant use with rifampin decreased sorafenib exposure by 37%.
    Itraconazole: (Major) Avoid coadministration of sorafenib with itraconazole due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs have been associated with prolongation of the QT interval.
    Ivosidenib: (Major) Avoid coadministration of sorafenib with ivosidenib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib.
    Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and sorafenib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with sorafenib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of sorafenib with clarithromycin due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Lapatinib: (Major) Avoid coadministration of sorafenib with lapatinib due to the risk of additive QT prolongation; the risk of lapatinib-related adverse reactions may also increase. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is a P-glycoprotein (P-gp) inhibitor that has been associated with QTc prolongation. Lapatinib is a P-gp substrate that has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Lefamulin: (Major) Avoid coadministration of sorafenib with lefamulin due to the risk of additive QT prolongation. The risk of lefamulin-related adverse reactions may also increase if lefamulin is administered orally; an interaction is not expected with intravenous lefamulin. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is a P-glycoprotein (P-gp) inhibitor that is associated with QTc prolongation. Lefamulin is a P-gp substrate 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.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with sorafenib due to the risk of additive QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Sorafenib is also associated with QTc prolongation.
    Leuprolide: (Major) Avoid coadministration of sorafenib with leuprolide due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of sorafenib with leuprolide due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Levofloxacin: (Major) Avoid coadministration of sorafenib with levofloxacin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Levofloxacin has been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of levofloxacin.
    Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and sorafenib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Lithium: (Major) Avoid coadministration of sorafenib with lithium due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs have been associated with QT prolongation.
    Lofexidine: (Major) Avoid coadministration of sorafenib with lofexidine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Lofexidine prolongs the QT interval. Sorafenib is also associated with QTc prolongation.
    Loperamide: (Major) Concomitant use of loperamide and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a P-gp substrate and sorafenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
    Loperamide; Simethicone: (Major) Concomitant use of loperamide and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a P-gp substrate and sorafenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of sorafenib with Lopinavir due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs are associated with QTc prolongation.
    Lorazepam: (Moderate) Monitor for an increase in lorazepam-related adverse reactions and consider reducing the dose of lorazepam if concomitant use of lorazepam and sorafenib is necessary. Avoid lorazepam extended-release capsules and utilize lorazepam immediate-release dosage forms that can be easily titrated. Lorazepam is an UGT substrate and sorafenib is an UGT inhibitor.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of sorafenib with lumacaftor; ivacaftor due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of sorafenib with lumacaftor; ivacaftor due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as sorafenib. 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. Sorafenib has also been associated with QT prolongation.
    Maprotiline: (Major) Avoid coadministration of sorafenib with maprotiline due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Maprotiline has 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 torsade de pointes (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.
    Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with sorafenib is necessary. Maraviroc is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Mefloquine: (Major) Avoid coadministration of sorafenib with mefloquine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. 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.
    Meperidine; Promethazine: (Major) Avoid coadministration of sorafenib with promethazine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Methadone: (Major) Avoid coadministration of sorafenib with methadone due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (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. Sorafenib is also associated with QTc prolongation.
    Metronidazole: (Major) Concomitant use of metronidazole and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Midostaurin: (Major) Avoid coadministration of sorafenib with midostaurin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. QT prolongation was also reported in patients who received midostaurin in clinical trials.
    Mifepristone: (Major) Avoid coadministration of sorafenib with mifepristone due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Mifepristone is associated with dose-related prolongation of the QT interval.
    Mirtazapine: (Major) Avoid coadministration of sorafenib with mirtazapine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation. Sorafenib is also associated with QTc prolongation.
    Mitotane: (Major) Avoid coadministration of sorafenib with mitotane due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Mobocertinib: (Major) Concomitant use of mobocertinib and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Modafinil: (Major) Sorafenib is a CYP3A4 substrate, and concomitant use with a strong CYP3A4 inducer such as modafinil may lead to reduced sorafenib concentrations. For example, concurrent use of sorafenib and the CYP3A4 inducer rifampicin resulted in an average 37% reduction in the sorafenib AUC. Avoid the use of sorafenib with a strong CYP3A4 inducer. If a strong CYP3A4 inducer must be coadministered with sorafenib, consider a sorafenib dose increase.
    Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death, if coadministration with sorafenib is necessary; decrease the dose of morphine as clinically appropriate. Morphine is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates. The concomitant use of P-gp inhibitors can increase the exposure to morphine by about 2-fold.
    Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death, if coadministration with sorafenib is necessary; decrease the dose of morphine as clinically appropriate. Morphine is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates. The concomitant use of P-gp inhibitors can increase the exposure to morphine by about 2-fold.
    Moxifloxacin: (Major) Avoid coadministration of sorafenib with moxifloxacin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. 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 moxifloxacin; these reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with sorafenib. Naldemedine is a P-gp substrate; sorafenib is a P-gp inhibitor in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid coadministration of sirolimus with sorafenib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and sorafenib is a P-gp inhibitor.
    Neomycin: (Moderate) Monitor for decreased clinical response to sorafenib if coadministration with neomycin is necessary. Concomitant administration of oral neomycin and sorafenib decreased the AUC of sorafenib by 54% in healthy volunteers who first received neomycin 1 gm by mouth three times daily for 5 days.
    Nilotinib: (Major) Avoid coadministration of nilotinib with sorafenib due to the risk of QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Sorafenib has also been associated with QT prolongation.
    Octreotide: (Major) Avoid coadministration of sorafenib with octreotide due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (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.
    Ofloxacin: (Major) Avoid coadministration of sorafenib with ofloxacin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Quinolones have also been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, torsade de pointes (TdP) 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.
    Olanzapine: (Major) Avoid coadministration of sorafenib with olanzapine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Olanzapine; Fluoxetine: (Major) Avoid coadministration of sorafenib with fluoxetine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Sorafenib is also associated with QTc prolongation. (Major) Avoid coadministration of sorafenib with olanzapine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Olanzapine; Samidorphan: (Major) Avoid coadministration of sorafenib with olanzapine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with sorafenib is necessary. Ombitasvir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates. (Major) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with sorafenib is necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of sorafenib with rifabutin due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Ondansetron: (Major) Avoid coadministration of sorafenib with ondansetron due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Sorafenib is also associated with QTc prolongation.
    Osilodrostat: (Major) Avoid coadministration of sorafenib with osilodrostat due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Osilodrostat is associated with dose-dependent QT prolongation. Sorafenib is also associated with QTc prolongation.
    Osimertinib: (Major) Avoid coadministration of sorafenib with osimertinib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Sorafenib is associated with QTc prolongation.
    Oxaliplatin: (Major) Avoid coadministration of sorafenib with oxaliplatin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. QT prolongation and ventricular arrhythmias including fatal torsade de pointes (TdP) have been reported with oxaliplatin use in postmarketing experience.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking sorafenib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Sorafenib is associated with QTc prolongation. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia.
    Pacritinib: (Major) Concomitant use of pacritinib and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Paliperidone: (Major) Avoid coadministration of sorafenib with paliperidone due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
    Panobinostat: (Major) Use of panobinostat with sorafenib is not recommended due to the risk of additive QT prolongation. QT prolongation has been reported with panobinostat. Sorafenib is also associated with QTc prolongation.
    Pasireotide: (Major) Avoid coadministration of sorafenib with pasireotide due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Sorafenib is also associated with QTc prolongation.
    Pazopanib: (Major) Coadministration of pazopanib and sorafenib is not advised due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Pazopanib has been reported to prolong the QT interval. Sorafenib is also associated with QTc prolongation.
    Pentamidine: (Major) Avoid coadministration of sorafenib with systemic pentamidine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Systemic pentamidine has also been associated with QT prolongation.
    Perphenazine: (Minor) Use caution if coadministration of sorafenib with perphenazine is necessary due to the risk of additive QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Sorafenib is also associated with QTc prolongation.
    Perphenazine; Amitriptyline: (Minor) Use caution if coadministration of sorafenib with perphenazine is necessary due to the risk of additive QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Sorafenib is also associated with QTc prolongation.
    Pexidartinib: (Major) Avoid coadministration of pexidartinib with sorafenib as concurrent use may increase pexidartinib exposure. If concurrent use cannot be avoided, reduce the dose of pexidartinib. If sorafenib is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of sorafenib. 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 UGT substrate; sorafenib is a UGT inhibitor. Coadministration with another UGT inhibitor increased pexidartinib exposure by 60%.
    Phenobarbital: (Major) Avoid coadministration of sorafenib with phenobarbital due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of sorafenib with phenobarbital due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Phenytoin: (Major) Avoid coadministration of sorafenib with phenytoin due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Pimavanserin: (Major) Avoid coadministration of sorafenib with pimavanserin due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Pimavanserin also prolongs the QT interval.
    Pimozide: (Contraindicated) Because of the potential for TdP, use of sorafenib with pimozide is contraindicated. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Sorafenib has also been associated with QT prolongation.
    Pitolisant: (Major) Avoid coadministration of sorafenib with pitolisant due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Pitolisant also prolongs the QT interval.
    Ponesimod: (Major) Avoid coadministration of sorafenib with ponesimod due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs and for signs and symptoms of infection; correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia.
    Posaconazole: (Major) Avoid coadministration of sorafenib with posaconazole due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes (TdP). Sorafenib is associated with QTc prolongation.
    Primaquine: (Major) Avoid coadministration of sorafenib with primaquine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs are associated with QTc prolongation.
    Primidone: (Major) Avoid coadministration of sorafenib with primidone due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and sorafenib 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. Sorafenib can inhibit colchicine's metabolism via P-glycoprotein (P-gp), 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 sorafenib 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.
    Procainamide: (Major) Avoid coadministration of sorafenib with procainamide due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Sorafenib is associated with QTc prolongation.
    Prochlorperazine: (Minor) Use caution if coadministration of sorafenib with prochlorperazine is necessary due to the risk of additive QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Sorafenib is also associated with QTc prolongation.
    Promethazine: (Major) Avoid coadministration of sorafenib with promethazine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Promethazine; Dextromethorphan: (Major) Avoid coadministration of sorafenib with promethazine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Promethazine; Phenylephrine: (Major) Avoid coadministration of sorafenib with promethazine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Propafenone: (Major) Avoid coadministration of sorafenib with propafenone due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Quetiapine: (Major) Avoid coadministration of sorafenib with quetiapine due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Major) Avoid coadministration of sorafenib with quinidine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP). Sorafenib is associated with QTc prolongation.
    Quinine: (Major) Avoid coadministration of sorafenib with quinine due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Ranolazine: (Major) Avoid coadministration of sorafenib with ranolazine due to the risk of additive QT prolongation; the risk of ranolazine-related adverse reactions may also increase. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Ranolazine is a P-glycoprotein (P-gp) substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Sorafenib is a P-gp inhibitor that is also associated with QTc prolongation.
    Relugolix: (Major) Avoid concomitant use of relugolix and oral sorafenib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects; QT prolongation may also occur. If concomitant use is unavoidable, administer sorafenib at least six hours after relugolix; monitor ECGs for QT prolongation and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Relugolix is a P-gp substrate that may prolong the QT/QTc interval. Sorafenib inhibited P-gp in vitro and may increase the concentrations of P-gp substrates; it is also associated with QTc prolongation.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral sorafenib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects; QT prolongation may also occur. If concomitant use is unavoidable, administer sorafenib at least six hours after relugolix; monitor ECGs for QT prolongation and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Relugolix is a P-gp substrate that may prolong the QT/QTc interval. Sorafenib inhibited P-gp in vitro and may increase the concentrations of P-gp substrates; it is also associated with QTc prolongation.
    Ribociclib: (Major) Avoid coadministration of sorafenib with ribociclib due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner.
    Ribociclib; Letrozole: (Major) Avoid coadministration of sorafenib with ribociclib due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner.
    Rifabutin: (Major) Avoid coadministration of sorafenib with rifabutin due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Rifampin: (Major) Avoid coadministration of sorafenib with rifampin due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Concomitant use with rifampin decreased sorafenib exposure by 37%.
    Rifapentine: (Major) Avoid coadministration of sorafenib with rifapentine due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with sorafenib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and sorafenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
    Rilpivirine: (Major) Avoid coadministration of sorafenib with rilpivirine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with sorafenib; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and sorafenib is a P-gp inhibitor.
    Risperidone: (Major) Avoid coadministration of sorafenib with risperidone due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Sorafenib is also associated with QTc prolongation.
    Romidepsin: (Major) Avoid coadministration of sorafenib with romidepsin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Romidepsin has also been reported to prolong the QT interval.
    Saquinavir: (Contraindicated) Concurrent use of sorafenib and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes (TdP). Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation. Sorafenib is also associated with prolongation of the QT interval. Additionlly, sorafenib inhibits P-glycoprotein (P-gp) in vitro. Concurrent use of sorafenib with a P-gp substrate, such as saquinavir, could increase the concentrations of saquinavir thus increasing the risk of drug toxicity and proarrhythmic effects.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Selpercatinib: (Major) Avoid coadministration of sorafenib with selpercatinib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Sorafenib is also associated with QTc prolongation.
    Sertraline: (Major) Avoid coadministration of sorafenib with sertraline due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Sertraline is also associated with QT prolongation; however, 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).
    Simeprevir: (Moderate) Monitor for an increase in simeprevir-related adverse reactions if coadministration with sorafenib is necessary. Simeprevir is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving sorafenib 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. Sorafenib has been associated with QT prolongation.
    Sirolimus: (Major) Avoid coadministration of sirolimus with sorafenib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and sorafenib is a P-gp inhibitor.
    Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Solifenacin: (Major) Avoid coadministration of sorafenib with solifenacin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Solifenacin has been associated with dose-dependent prolongation of the QT interval; torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined. Sorafenib is also associated with QTc prolongation.
    Sotalol: (Major) Avoid coadministration of sorafenib with sotalol due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sotalol administration is associated with QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. Sorafenib is also associated with QTc prolongation.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of sorafenib with St. John's Wort due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Sunitinib: (Major) Avoid coadministration of sorafenib with sunitinib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs are associated with QTc prolongation.
    Tacrolimus: (Major) Avoid coadministration of sorafenib with tacrolimus due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Sorafenib is also associated with QTc prolongation.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with sorafenib is necessary. Talazoparib is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Tamoxifen: (Major) Concomitant use of tamoxifen and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Telavancin: (Major) Avoid coadministration of sorafenib with telavancin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs are associated with QTc prolongation.
    Telithromycin: (Major) Avoid coadministration of sorafenib with telithromycin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Telithromycin is associated with QT prolongation and torsade de pointes (TdP). Sorafenib is also associated with QTc prolongation.
    Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with sorafenib is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with sorafenib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Tetrabenazine: (Major) Avoid coadministration of tetrabenazine with sorafenib due to the risk of QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). Sorafenib has also been associated with QT prolongation.
    Thioridazine: (Contraindicated) Because of the potential for TdP, use of sorafenib with thioridazine is contraindicated. Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Thioridazine is considered contraindicated for use along with agents that may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Sorafenib has also been associated with QT prolongation.
    Ticagrelor: (Moderate) Monitor for an increase in ticagrelor-related adverse reactions, including bleeding, if coadministration with sorafenib is necessary. Ticagrelor is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Tinzaparin: (Major) Due to the thrombocytopenic effects of sorafenib, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Tipranavir: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with sorafenib is necessary. Tipranavir is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Tolterodine: (Major) Avoid coadministration of sorafenib with tolterodine due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Topotecan: (Major) Avoid coadministration of sorafenib with oral topotecan due to increased topotecan exposure; sorafenib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and sorafenib is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Toremifene: (Major) Avoid coadministration of sorafenib with toremifene due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Sorafenib is also associated with QTc prolongation.
    Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with sorafenib is necessary. Verapamil is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Trazodone: (Major) Concomitant use of trazodone and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Triclabendazole: (Major) Concomitant use of triclabendazole and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Trifluoperazine: (Minor) Use caution if coadministration of sorafenib with trifluoperazine is necessary due to the risk of additive QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Sorafenib is also associated with QTc prolongation; the manufacturer of sorafenib recommends avoiding coadministration with other drugs that cause QT prolongation.
    Triptorelin: (Major) Avoid coadministration of sorafenib with triptorelin due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with sorafenib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the P-gp drug transporter; sorafenib is a P-gp inhibitor.
    Umeclidinium: (Moderate) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with sorafenib is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor in vitro. Coadministration with another P-gp inhibitor increased umeclidinium exposure by 1.4-fold.
    Umeclidinium; Vilanterol: (Moderate) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with sorafenib is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor in vitro. Coadministration with another P-gp inhibitor increased umeclidinium exposure by 1.4-fold.
    Vandetanib: (Major) Avoid coadministration of vandetanib with sorafenib due to an increased risk of additive QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Sorafenib is also associated with QTc prolongation.
    Vardenafil: (Major) Concomitant use of vardenafil and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Vemurafenib: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as sorafenib. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner; these ECG changes occurred within the first month of treatment. Sorafenib is also associated with QTc prolongation.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with sorafenib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of sorafenib. Sorafenib is a P-gp inhibitor in vitro; venetoclax is a P-gp substrate. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Venlafaxine: (Major) Concomitant use of venlafaxine and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with sorafenib is necessary. Verapamil is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Vincristine Liposomal: (Moderate) Monitor for an earlier onset or increased severity of vincristine-related adverse reactions if coadministration with sorafenib is necessary. Vincristine is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor in vitro. The effect of concomitant use of P-gp inhibitors with vincristine has not been investigated; however, it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of vincristine.
    Vincristine: (Moderate) Monitor for an earlier onset or increased severity of vincristine-related adverse reactions if coadministration with sorafenib is necessary. Vincristine is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor in vitro. The effect of concomitant use of P-gp inhibitors with vincristine has not been investigated; however, it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of vincristine.
    Voclosporin: (Major) Avoid concomitant use of sorafenib and voclosporin due to the risk of additive QT prolongation. If concomitant use is necessary, monitor ECGs and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
    Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of sorafenib with clarithromycin due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Voriconazole: (Major) Avoid coadministration of sorafenib with voriconazole due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Sorafenib is also associated with QTc prolongation.
    Vorinostat: (Major) Avoid coadministration of sorafenib with vorinostat due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Vorinostat therapy is associated with a risk of QT prolongation. Sorafenib is also associated with QTc prolongation.
    Warfarin: (Moderate) Monitor for an increased risk of bleeding and regularly monitor the PT/INR of patients taking sorafenib concomitantly with warfarin. Infrequent bleeding or elevations in the INR have been reported in some patients taking warfarin while on sorafenib.
    Ziprasidone: (Major) Concomitant use of ziprasidone and sorafenib should be avoided due to a 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. Sorafenib has also been associated with QT prolongation.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during sorafenib treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant women, sorafenib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving sorafenib should be apprised of the potential hazard to the fetus. In animal reproduction studies, sorafenib was teratogenic and induced embryofetal toxicity (e.g., increased post-implantation loss, resorptions, skeletal retardations, and retarded fetal weight) when administered orally to pregnant rats and rabbits during organogenesis at doses much lower than the recommended human dose (approximately 500 mg/m2 per day). Adverse intrauterine development effects were seen at exposures that were approximately 0.008 times the AUC in patients at the recommended dose (1.2 mg/m2 per day in rats, and 3.6 mg/m2 per day in rabbits).

    Counsel patients about the reproductive risk and contraception requirements during sorafenib treatment. Sorafenib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 6 months after treatment with sorafenib. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential or pregnant partners should use effective contraception during and for at least 3 months after treatment with sorafenib. Females of reproductive potential should undergo pregnancy testing prior to initiation of sorafenib. Women who become pregnant while receiving sorafenib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of sorafenib on human fertility, male infertility has been observed in animal studies.

    MECHANISM OF ACTION

    Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro. It has been shown to inhibit multiple intracellular (c-CRAF, BRAF, and mutant BRAF) and cell surface (KIT, FLT-3, RET, RET/PTC, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-beta) kinases; several of these are thought to be involved in tumor cell signaling, angiogenesis, and apoptosis. Sorafenib inhibited tumor growth of hepatocellular cancer (HCC), renal cell cancer (RCC), and differentiated thyroid cancer (DTC) human tumor xenografts in immunocompromised mice. Reductions in tumor angiogenesis were seen in models of HCC and RCC upon sorafenib treatment, and increases in tumor apoptosis were observed in models of HCC, RCC, and DTC.

    PHARMACOKINETICS

    Sorafenib is administered orally. It is 99.5% bound to human plasma proteins in vitro. The mean elimination half-life of sorafenib is approximately 25 to 48 hours; steady-state plasma concentrations of sorafenib were achieved within 7 days. Sorafenib accounts for approximately 70% to 85% of the circulating analytes in plasma at steady state. Eight metabolites have been identified, 5 of which have been detected in plasma. The main circulating metabolite, the pyridine N-oxide, comprises approximately 9% to 16% of circulating analytes at steady-state and has a similar in vitro potency to sorafenib. Following oral administration, 96% of a single dose was recovered within 14 days; 77% was recovered in the feces (51% as unchanged drug) and 19% in the urine as glucuronidated metabolites (0% as unchanged drug).[31832]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, UGT1A9, UGT1A1, P-glycoprotein (P-gp)
    Sorafenib is a CYP3A4 substrate, undergoing oxidative metabolism; it is also glucuronidated by UGT1A9. Inducers of CYP3A4 activity can decrease the systemic exposure of sorafenib; however, CYP3A4 inhibitors do not impact sorafenib plasma concentrations. Sorafenib inhibits glucuronidation by UGT1A1 and UGT1A9 in vitro and could increase the systemic exposure of concomitantly administered UGT1A1 or UGT1A9 substrates. It also inhibits P-gp in vitro, and could likewise increase the systemic exposure of concomitantly administered P-gp substrates. Sorafenib competitively inhibits CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4; however, steady-state exposure to sorafenib did not increase the systemic exposure of CYP3A4, CYP2D6, or CYP2C19 substrates. While sorafenib is metabolized by CYP3A4, coadministration with CYP3A4 inhibitors is unlikely to alter its metabolism. No clinically relevant change in sorafenib pharmacokinetics and no clinically relevant adverse events or laboratory abnormalities were noted with coadministration of the strong CYP3A4 inhibitor, ketoconazole; the mean systemic exposure in healthy volunteers was unaltered.[31833] [31832]

    Oral Route

    The mean relative bioavailability of sorafenib tablets was 38% to 49% when compared to an oral solution. Following oral administration, sorafenib reached peak plasma levels (Cmax) in approximately 3 hours. The peak-to-trough ratio of mean concentrations at steady-state was less than 2. Mean Cmax and AUC increased less than proportionally beyond oral doses of 400 mg twice daily.[31832]
     
    When administered with a moderate-fat meal (700 calories, 30% fat), the bioavailability of sorafenib was similar to that in the fasted state. With a high-fat meal (900 calories, 50% fat), bioavailability was reduced by 29% compared to that in the fasted state. It is recommended to administer sorafenib without food. The aqueous solubility of sorafenib is pH dependent, with higher pH resulting in lower solubility; however, coadministration with a proton-pump inhibitor for 5 days did not result in a clinically meaningful change in sorafenib single-dose exposure. No dosage adjustment is necessary for sorafenib if coadministration with gastric acid-reducing agents are necessary.[31832]