Stivarga

Drug overview for STIVARGA (regorafenib):

Generic name: REGORAFENIB (RE-goe-RAF-e-nib)
Drug class: Antineoplastic - Protein-Tyrosine Kinase Inhibitors
Therapeutic class: Antineoplastics

Regorafenib, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.

No enhanced Uses information available for this drug.

DRUG IMAGES

STIVARGA 40 MG TABLET

The following indications for STIVARGA (regorafenib) have been approved by the FDA:

Indications:
Gastrointestinal stromal tumor
Liver cell carcinoma
Metastatic colorectal cancer

Professional Synonyms:
Gastrointestinal autonomic nerve tumor
Gastrointestinal pacemaker cell tumor
Gastrointestinal stromal neoplasm
Hepatocarcinoma
Hepatocellular carcinoma

Dosing information for STIVARGA
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
STIVARGA 40 MG TABLET	Maintenance	Adults take 4 tablets (160 mg) by oral route once daily (same time each day) with a low-fat breakfast, on days 1-21 of a 28 day treatment cycle

The following drug interaction information is available for STIVARGA (regorafenib):

Contraindicated
Severe
Moderate

There are 3 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Irinotecan/UGT1A1 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of UGT1A1 may inhibit the metabolism of SN-38, the active metabolite of irinotecan.(1) Atazanavir may inhibit the metabolism of irinotecan by UGT1A1.(1,2) This increases the system exposure to SN-38, the active metabolite of irinotecan.(3) CLINICAL EFFECTS: Concurrent use of UGT1A1 inhibitors may result in increased exposure to and toxicity from irinotecan.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of irinotecan states do not administer UGT1A1 inhibitors with irinotecan unless there are no therapeutic alternatives. The increased exposure to the active metabolite should be taken into consideration when co-administering these agents.(1) The US manufacturer of atazanavir states that concurrent use of irinotecan is contraindicated.(2) The Australian manufacturer of atazanavir states that irinotecan should not be administered with atazanavir.(3) DISCUSSION: Because atazanavir inhibits UGT1A1 at therapeutic concentrations, it is expected to interfere with the metabolism of irinotecan. Therefore, the manufacturer of atazanavir states that irinotecan should not be administered with atazanavir.(1,2) UGT1A1 inhibitors linked to this monograph include: atazanavir, capivasertib, belumosudil, erlotinib, gemfibrozil, lapatinib, nilotinib, pazopanib, probenecid, regorafenib, and sorafenib. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	CAMPTOSAR, IRINOTECAN HCL, ONIVYDE
Live Vaccines; Live BCG/Selected Immunosuppressive Agents SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: A variety of disease modifying agents suppress the immune system. Immunocompromised patients may be at increased risk for uninhibited replication after administration of live, attenuated vaccines or intravesicular BCG. Immune response to vaccines may be decreased during periods of immunocompromise.(1) CLINICAL EFFECTS: The expected serum antibody response may not be obtained and/or the vaccine may result in illness.(1) After instillation of intravesicular BCG, immunosuppression may interfere with local immune response, or increase the severity of mycobacterial infection following inadvertent systemic exposure.(2) PREDISPOSING FACTORS: Immunosuppressive diseases (e.g. hematologic malignancies, HIV disease), treatments (e.g. radiation) and drugs may all increase the magnitude of immunodeficiency. PATIENT MANAGEMENT: The Centers for Disease Control(CDC) Advisory Committee on Immunization Practices (ACIP) states that live-virus and live, attenuated vaccines should not be administered to patients who are immunocompromised. The magnitude of immunocompromise and associated risks should be determined by a physician.(1) For patients scheduled to receive chemotherapy, vaccination should ideally precede the initiation of chemotherapy by 14 days. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy.(1) Patients who receive anti-B cell therapies should not receive live vaccines for at least 6 months after such therapies due to a prolonged duration of immunosuppression. An exception is the Zoster vaccine, which can be given at least 1 month after receipt of anti-B cell therapies.(1) The US manufacturer of abatacept states live vaccines should not be given during or for up to 3 months after discontinuation of abatacept.(2) The US manufacturer of live BCG for intravesicular treatment of bladder cancer states use is contraindicated in immunosuppressed patients.(3) The US manufacturer of daclizumab states live vaccines are not recommended during and for up to 4 months after discontinuation of treatment.(4) The US manufacturer of guselkumab states that live vaccines should be avoided during treatment with guselkumab.(5) The US manufacturer of inebilizumab-cdon states that live vaccines are not recommended during treatment and after discontinuation until B-cell repletion. Administer all live vaccinations at least 4 weeks prior to initiation of inebilizumab-cdon.(6) The US manufacturer of ocrelizumab states that live vaccines are not recommended during treatment and until B-cell repletion occurs after discontinuation of therapy. Administer all live vaccines at least 4 weeks prior to initiation of ocrelizumab.(7) The US manufacturer of ozanimod states that live vaccines should be avoided during and for up to 3 months after discontinuation of ozanimod.(8) The US manufacturer of siponimod states that live vaccines are not recommended during treatment and for up to 4 weeks after discontinuation of treatment.(9) The US manufacturer of ustekinumab states BCG vaccines should not be given in the year prior to, during, or the year after ustekinumab therapy.(10) The US manufacturer of satralizumab-mwge states that live vaccines are not recommended during treatment and should be administered at least four weeks prior to initiation of satralizumab-mwge.(11) The US manufacturer of ublituximab-xiiy states that live vaccines are not recommended during treatment and until B-cell recovery. Live vaccines should be administered at least 4 weeks prior to initiation of ublituximab-xiiy.(12) The US manufacturer of etrasimod states that live vaccines should be avoided during and for 5 weeks after treatment. Live vaccines should be administered at least 4 weeks prior to initiation of etrasimod.(13) The US manufacturer of emapalumab-lzsg states that live vaccines should not be administered to patients receiving emapalumab-lzsg and for at least 4 weeks after the last dose of emapalumab-lzsg. The safety of immunization with live vaccines during or following emapalumab-lzsg therapy has not been studied.(14) DISCUSSION: Killed or inactivated vaccines do not pose a danger to immunocompromised patients.(1) Patients with a history of leukemia who are in remission and have not received chemotherapy for at least 3 months are not considered to be immunocompromised.(1)	ACAM2000 (NATIONAL STOCKPILE), ADENOVIRUS TYPE 4, ADENOVIRUS TYPE 4 AND TYPE 7, ADENOVIRUS TYPE 7, BCG (TICE STRAIN), BCG VACCINE (TICE STRAIN), DENGVAXIA, ERVEBO (NATIONAL STOCKPILE), FLUMIST TRIVALENT 2024-2025, IXCHIQ, M-M-R II VACCINE, PRIORIX, PROQUAD, ROTARIX, ROTATEQ, STAMARIL, VARIVAX VACCINE, VAXCHORA ACTIVE COMPONENT, VAXCHORA VACCINE, VIVOTIF, YF-VAX
Rosuvastatin (Greater Than 10 mg)/Regorafenib SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Rosuvastatin is a substrate for breast cancer resistance protein (BCRP). Regorafenib inhibits intestinal BCRP leading to increased systemic absorption of rosuvastatin.(1,2) CLINICAL EFFECTS: High systemic concentrations of rosuvastatin increase the risk for statin-induced myopathy or rhabdomyolysis.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US manufacturer of rosuvastatin states that the dose of rosuvastatin should not exceed 10 mg daily when used concurrently with regorafenib. Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2) DISCUSSION: In a study of regorafenib 160 mg daily x 14 days followed by rosuvastatin 5 mg single dose, rosuvastatin area-under-curve (AUC) and maximum concentration (Cmax) increased 3.8-fold and 4.6-fold, respectively.(1,2)	CRESTOR, EZALLOR SPRINKLE, ROSUVASTATIN CALCIUM, ROSUVASTATIN-EZETIMIBE, ROSZET

There are 7 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Regorafenib/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Regorafenib and active M2 and M5 metabolites contribute to anticancer activity. Although interpatient variability is high, with repeated dosing the systemic exposure to each component (regorafenib, M2 and M5) is similar. CYP3A4 converts regorafenib to the active M2 metabolite. M2 is subsequently converted, via an unknown pathway, to the active M5 metabolite.(1) Thus, inhibition of CYP3A4 leads to increased serum levels of regorafenib, but decreased levels of both M2 and M5.(1,2) CLINICAL EFFECTS: In an interaction study of regorafenib with a strong CYP3A4 inhibitor, a 33% increase in exposure to regorafenib did not compensate for a 93% decrease in exposure to M2 and M5. Overall, mean exposure to the combination of regorafenib, M2 and M5 decreased by approximately 50 per cent.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of regorafenib states concomitant use with strong inhibitors of CYP3A4 should be avoided. Whenever possible, to assure maximal efficacy of regorafenib it would be prudent to use an alternative agent in place of the strong CYP3A4 inhibitor.(2) The US manufacturer of itraconazole states that concurrent use of regorafenib is not recommended during and two weeks after itraconazole treatment.(4) DISCUSSION: Regorafenib was approved for use prior to completion of an exposure-response analysis or a population pharmacokinetic study.(1) The outcomes of these studies will increase understanding and improve prediction of regorafenib interaction risks. Strong CYP3A4 inhibitors linked to this monograph are: adagrasib, boceprevir, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(3)	CLARITHROMYCIN, CLARITHROMYCIN ER, EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KISQALI, KORLYM, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, NORVIR, NOXAFIL, OMECLAMOX-PAK, PAXLOVID, POSACONAZOLE, PREZCOBIX, RECORLEV, RITONAVIR, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VFEND, VFEND IV, VIRACEPT, VOQUEZNA TRIPLE PAK, VORICONAZOLE, ZYDELIG
Belinostat/UGT1A1 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inhibitors of UGT1A1 may inhibit the metabolism of belinostat.(1) CLINICAL EFFECTS: Concurrent use of UGT1A1 inhibitor may result in increased exposure to and toxicity from belinostat. Toxicities from belinostat include thrombocytopenia, neutropenia, anemia, infections, hepatotoxicity, and gastrointestinal toxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the use of UGT1A1 inhibitors in patients receiving belinostat. If concurrent use cannot be avoided, a dose reduction by 25% is recommended as follows: -If starting dose is 1,000 mg/m2 - reduce dose to 750 mg/m2 -If starting dose is 750 mg/m2 - reduce dose to 562.5 mg/m2 -If starting dose is 500 mg/m2 - interrupt belinostat treatment for the duration of the UGT1A1 inhibitor. After discontinuation of the UGT1A1 inhibitor for 5 half-lives, resume belinostat at the dosage that was taken prior to the UGT1A1 inhibitor.(1) If concurrent use is required, the dose of belinostat may need to be reduced in response to dose-limiting toxicities. The manufacturer of belinostat recommends a 25% dose reduction (to 750 mg/m2) in patients who are homozygous for the UGT1A1*28 allele.(1) DISCUSSION: Belinostat is primarily metabolized by UGT1A1 and inhibitors of UGT1A1 are expected to increase belinostat levels and dose limiting toxicities.(1) In a PKPB model, belinostat half-life increased by 1.5-fold, area-under-curve (AUC) increased by 1.4-fold, concentration maximum (Cmax) decreased by 33%, and renal excretion increased by 2.5-fold following administration with atazanavir (UGT1A1 inhibitor).(1) UGT1A1 inhibitors linked include: atazanavir, belumosudil, capivasertib, erlotinib, gemfibrozil, indinavir, ketoconazole, lapatinib, nilotinib, pazopanib, probenecid, regorafenib, and sorafenib.	BELEODAQ
Regorafenib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of regorafenib via this pathway. Regorafenib and active M2 and M5 metabolites contribute to anticancer activity.(1,2) Although interpatient variability is high, with repeated dosing the systemic exposure to each component (regorafenib, M2 and M5) is similar. CYP3A4 converts regorafenib to the active M2 metabolite. M2 is subsequently converted, via an unknown pathway, to the active M5 metabolite.(2) CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may alter the clinical effectiveness of regorafenib.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of regorafenib with strong CYP3A4 inducers.(1) When possible, select alternative agents in place of the strong CYP3A4 inducer. Monitor patients receiving concurrent therapy for reduced efficacy. DISCUSSION: In an interaction study of rifampin and regorafenib, rifampin was associated with a 50% decrease in exposure to regorafenib and no change in exposure to M2. However, the mean exposure to M5 increased 264%. Due to this large increase in M5, overall exposure to the combination of regorafenib, M2 and M5 was increased by 68%.(2) Regorafenib was approved for use prior to completion of an exposure-response analysis or a population pharmacokinetic study.(2) The outcomes of these studies will increase understanding and improve prediction of regorafenib interaction risks. Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St John's Wort.(3,4)	ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BRAFTOVI, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPITOL, EQUETRO, ERLEADA, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, MYSOLINE, ORKAMBI, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, PRIMIDONE, RIFADIN, RIFAMPIN, SEZABY, TEGRETOL, TEGRETOL XR, TENCON, TIBSOVO, XTANDI
Sacituzumab Govitecan/UGT1A1 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inhibitors of UGT1A1 may inhibit the metabolism of SN-38, the topoisomerase inhibitor which is the antineoplastic component of sacituzumab govitecan.(1) CLINICAL EFFECTS: Concurrent use of UGT1A1 inhibitors may result in increased exposure to and toxicity from sacituzumab govitecan. Toxicities from sacituzumab govitecan include neutropenia, severe diarrhea, nausea, and vomiting.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the use of inhibitors of UGT1A1 in patients receiving sacituzumab govitecan.(1) DISCUSSION: SN-38, the small molecule moiety of sacituzumab govitecan, is metabolized by UGT1A1, and inhibitors of UGT1A1 are expected to increase SN-38 levels and dose limiting toxicities.(1) In a clinical trial, patients homozygous for decreased function UGT1A128 allele had a 26% incidence of Grade 4 neutropenia, compared to 13% of patients heterozygous for the UGT1A128 allele and 11% of patients homozygous for the wild type allele.(1) Coadministration of ketoconazole (a CYP3A4 and UGT1A1 inhibitor) with irinotecan, has been reported to result in increased exposure to SN-38, an active metabolite of irinotecan.(2) UGT1A1 inhibitors linked to this monograph include: atazanavir, belumosudil, capivasertib, erlotinib, gemfibrozil, indinavir, ketoconazole, lapatinib, nilotinib, pazopanib, probenecid, regorafenib, and sorafenib.	TRODELVY
Selected CYP3A4 Substrates/Lonafarnib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lonafarnib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme. Lonafarnib is also an inhibitor of P-glycoprotein (P-gp) and may increase the absorption of sirolimus. CLINICAL EFFECTS: Concurrent use of lonafarnib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway or P-gp.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of lonafarnib states that coadministration of CYP3A4 substrates should be avoided. If concomitant use is unavoidable, monitor for adverse effects and consider dose reduction of the CYP3A4 substrate according to its prescribing information.(1) The manufacturer of lonafarnib states that the dose of P-gp substrates may need to be reduced with coadministration with lonafarnib.(1) DISCUSSION: In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam (3 mg) by 639% and 180%, respectively.(1) In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the AUC and Cmax of single-dose fexofenadine (180 mg) by 24% and 21%, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: bromocriptine, cabergoline, cannabidiol-tetrahydrocannabinol, clonazepam, darolutamide, felodipine, mefloquine, nisoldipine, oliceridine, pomalidomide, regorafenib, sirolimus, and zanubrutinib.(1-3)	ZOKINVY
Sodium Iodide I 131/Myelosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1) DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)	HICON, SODIUM IODIDE I-131
Lorazepam Extended Release/UGT Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inhibitors of UDP-glucuronosyltransferases (UGT) may inhibit the metabolism of lorazepam.(1) CLINICAL EFFECTS: Concurrent use of UGT inhibitors may result in increased exposure to and toxicity from lorazepam, including profound sedation, respiratory depression, and coma.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of lorazepam extended release capsules states the initiating a UGT inhibitor during therapy with lorazepam extended release capsules should be avoided. If a UGT inhibitor is initiated, discontinue lorazepam extended release capsules and switch patient to a reduced dose of lorazepam tablets during concurrent therapy.(1) DISCUSSION: In a study in 8 healthy males, pretreatment with valproate (250 mg twice daily for 3 days) decreased the total clearance of a single dose of lorazepam (2 mg intravenously) by 40% in 6 subjects. The formation rate of lorazepam glucuronide was decreased by 55% in these subjects. Lorazepam concentrations were about 2-fold higher for at least 12 hours post-dose during concurrent valproate.(2,4) In a randomized, double-blind, placebo-controlled study in 16 healthy males, concurrent divalproex (500 mg every 12 hours for 12 days) increased the area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) of lorazepam (1 mg every 12 hours, Days 6-10) by 20%, 8%, and 31%, respectively. Lorazepam clearance was decreased by 31% during concurrent divalproex.(5) There is one case report of coma following the injection of 6 mg of lorazepam over 24 hours in a patient maintained on valproate (1000 mg). The patient remained in a coma for between 48 and 72 hours.(6) In a study in 9 healthy subjects, pretreatment with probenecid (500 mg every 6 hours) increased the half-life (T1/2) of a single intravenous dose of lorazepam (2 mg) by 130%. Lorazepam clearance was decreased by 45%. There was no change in lorazepam apparent volume of distribution.(2,7) UGT inhibitors linked to this monograph include: atazanavir, belumosudil, capivasertib, erlotinib, gemfibrozil, indinavir, ketoconazole, lapatinib, mefenamic acid, nilotinib, pazopanib, probenecid, regorafenib, sorafenib, and valproic acid.	LOREEV XR

There are 3 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Lorazepam; Mexazolam/UGT Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of UDP-glucuronosyltransferases (UGT) may inhibit the metabolism of lorazepam.(1-4) One of the active metabolites of mexazolam is lorazepam. CLINICAL EFFECTS: Concurrent use of UGT inhibitors may increase levels of and clinical effects from lorazepam, including profound sedation, respiratory depression, and coma.(1-4) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturers of lorazepam state that the dosage of lorazepam should be reduced by 50% in patients receiving UGT inhibitors.(1,2) DISCUSSION: In a study in 9 healthy subjects, pretreatment with probenecid (500 mg every 6 hours) increased the half-life (T1/2) of a single intravenous dose of lorazepam (2 mg) by 130%. Lorazepam clearance was decreased by 45%. There was no change in lorazepam apparent volume of distribution.(1,4) In 7 patients given probenecid 1G orally one hour prior to induction anesthesia with midazolam, there was no significant change in plasma protein binding due to probenecid pretreatment. The mean free midazolam fractions were 3.31% prior and 3.34% following pretreatment.(5) UGT inhibitors linked to this monograph include: atazanavir, belumosudil, capivasertib, erlotinib, gemfibrozil, indinavir, ketoconazole, lapatinib, mefenamic acid, nilotinib, pazopanib, probenecid, regorafenib, and sorafenib.	ATIVAN, LORAZEPAM, LORAZEPAM INTENSOL
Rosuvastatin (Less Than or Equal To 10 mg)/Regorafenib SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Rosuvastatin is a substrate for breast cancer resistance protein (BCRP). Regorafenib inhibits intestinal BCRP leading to increased systemic absorption of rosuvastatin.(1,2) CLINICAL EFFECTS: High systemic concentrations of rosuvastatin increase the risk for statin-induced myopathy or rhabdomyolysis.(1) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US manufacturer of rosuvastatin states that the dose of rosuvastatin should not exceed 10 mg daily when used concurrently with regorafenib. Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1,2) DISCUSSION: In a study of regorafenib 160 mg daily x 14 days followed by rosuvastatin 5 mg single dose, rosuvastatin area-under-curve (AUC) and maximum concentration (Cmax) increased 3.8-fold and 4.6-fold, respectively.(1,2)	CRESTOR, EZALLOR SPRINKLE, ROSUVASTATIN CALCIUM, ROSUVASTATIN-EZETIMIBE, ROSZET
Warfarin/Regorafenib SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Regorafenib is a CYP2C9 inhibitor(1) which may decrease the metabolism of the S-enantiomer of warfarin.(2-4) Also, regorafenib and warfarin therapy may both increase the risk of bleeding.(1-2) CLINICAL EFFECTS: Concurrent use of regorafenib may result in elevated levels of warfarin and INR.(1) Concurrent use of warfarin and regorafenib may increase the risk for bleeding. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 1/3, 2/2, 2/3, and 3/3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants. PATIENT MANAGEMENT: Monitor INRs more frequently until stable in patients who start regorafenib therapy.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding. DISCUSSION: In a study of 8 healthy subjects, regorafenib (160 mg once daily) increased the area-under-the-curve (AUC) of a single dose of warfarin by 25%, compared to warfarin alone.(1) In clinical studies, regorafenib increased the risk of hemorrhage, with an overall incidence of hemorrhage Grades 1-5 of 18.2% compared to 9.5% in the placebo group. The incidence of grade 3 or higher hemorrhage was 3% in patients treated with regorafenib, including an incidence of 0.7% of fatal hemorrhagic events.(1) In a case report of a 76 year old man with liver metastasis of colon cancer, three weeks after starting regorafenib therapy the INR increased significantly. The INR before starting regorafenib was 1.26 and significantly increased to 2.1 on day 8, 2.98 on day 15, and 6.4 on day 22. Both regorafenib and warfarin were stopped, and the INR decreased to 1.31 within one week. Warfarin was resumed at a lower dose and titrated based on INR during subsequent regorafenib therapy without further elevation.(5)	JANTOVEN, WARFARIN SODIUM

The following contraindication information is available for STIVARGA (regorafenib):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

*Manufacturer states none known.

There are 4 contraindications. Absolute contraindication.

Contraindication List
Arterial aneurysm
Arterial dissection
Lactation
Surgical wound dehiscence

There are 7 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Acute myocardial infarction
Hemorrhage
Invasive surgical procedure
Myocardial ischemia
Pregnancy
Severe infection
Severe uncontrolled hypertension

There are 1 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Disease of liver

The following adverse reaction information is available for STIVARGA (regorafenib):

Overview
Severe
Less Severe

Adverse reaction overview.

The most common adverse reactions (>=20%) are pain (including GI and abdominal pain), palmar-plantar erythrodysesthesia (hand-foot syndrome), asthenia/fatigue, diarrhea, decreased appetite/food intake, hypertension, infection, dysphonia, hyperbilirubinemia, fever, mucositis, weight loss, rash, and nausea.

There are 30 severe adverse reactions.

More Frequent	Less Frequent
Anemia Elevated serum amylase Elevated serum lipase Hemorrhage Hypocalcemia Hypokalemia Hyponatremia Hypophosphatemia Impaired wound healing Increased alanine transaminase Increased aspartate transaminase Thrombocytopenic disorder	Abnormal hepatic function tests Acute myocardial infarction Hepatic failure Myocardial ischemia Pancreatitis

Rare/Very Rare
Arterial aneurysm Arterial dissection Erythema multiforme Gastrointestinal fistula Gastrointestinal perforation Heart failure Hepatocellular damage Hypersensitivity drug reaction Hypertensive crisis Nephrotic syndrome Posterior reversible encephalopathy syndrome Stevens-johnson syndrome Toxic epidermal necrolysis

There are 23 less severe adverse reactions.

More Frequent	Less Frequent
Acute abdominal pain Anorexia Diarrhea Fatigue Fever General weakness Headache disorder Hyperbilirubinemia Hypertension Infection Nausea Pain Palmar-plantar erythrodysesthesia Proteinuria Skin rash Stomatitis Voice change Weight loss	Alopecia Hypothyroidism Maculopapular rash Muscle rigidity Muscle spasm

Rare/Very Rare
None.

The following precautions are available for STIVARGA (regorafenib):

Pediatric
Pregnant
Lactation
Geriatric

Safety and efficacy of regorafenib have not been established in pediatric patients younger than 18 years of age. Persistent growth and thickening of the femoral epiphyseal growth plate, as well as dose-dependent angiectasis and dentin alteration, have been observed in animals receiving repeated doses of regorafenib at exposure levels lower than those associated with the recommended human dosage.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Regorafenib may cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings.

Regorafenib and its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into milk in humans. Because of the potential for serious adverse reactions to regorafenib in nursing infants, women should be advised to discontinue nursing during regorafenib therapy. The effects of the drug on nursing infants or on milk production are unknown. Women may begin nursing 2 weeks after discontinuance of therapy.

In clinical studies, 40% of patients were 65 years of age or older and 10% were 75 years of age or older. No overall differences in safety and efficacy were observed between geriatric patients and younger adults, but grade 3 or 4 hypertension occurred more frequently in geriatric patients.

The following icd codes are available for STIVARGA (regorafenib)'s list of indications:

Gastrointestinal stromal tumor
C49.A	Gastrointestinal stromal tumor
C49.A0	Gastrointestinal stromal tumor, unspecified site
C49.A1	Gastrointestinal stromal tumor of esophagus
C49.A2	Gastrointestinal stromal tumor of stomach
C49.A3	Gastrointestinal stromal tumor of small intestine
C49.A4	Gastrointestinal stromal tumor of large intestine
C49.A5	Gastrointestinal stromal tumor of rectum
C49.A9	Gastrointestinal stromal tumor of other sites
Liver cell carcinoma
C22.0	Liver cell carcinoma
Metastatic colorectal cancer
C18	Malignant neoplasm of colon
C18.0	Malignant neoplasm of cecum
C18.1	Malignant neoplasm of appendix
C18.2	Malignant neoplasm of ascending colon
C18.3	Malignant neoplasm of hepatic flexure
C18.4	Malignant neoplasm of transverse colon
C18.5	Malignant neoplasm of splenic flexure
C18.6	Malignant neoplasm of descending colon
C18.7	Malignant neoplasm of sigmoid colon
C18.8	Malignant neoplasm of overlapping sites of colon
C18.9	Malignant neoplasm of colon, unspecified
C19	Malignant neoplasm of rectosigmoid junction
C20	Malignant neoplasm of rectum
C21.8	Malignant neoplasm of overlapping sites of rectum, anus and anal canal