Olysio

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Olysio

Classes

NS3/4A Protease Inhibitor Antivirals for Hepatitis C

Administration

 
NOTE: MUST be administered in combination with either sofosbuvir or peginterferon alfa plus ribavirin; never administer as monotherapy.

Oral Administration Oral Solid Formulations

Administer with food.
Swallow capsule whole.

Adverse Reactions
Severe

hepatic failure / Delayed / Incidence not known
hepatitis B exacerbation / Delayed / Incidence not known

Moderate

hyperbilirubinemia / Delayed / 0-27.0
hyperamylasemia / Delayed / 5.0-26.0
dyspnea / Early / 12.0-12.0

Mild

fatigue / Early / 16.0-32.0
photosensitivity / Delayed / 12.0-28.0
rash / Early / 12.0-28.0
headache / Early / 17.0-23.0
pruritus / Rapid / 22.0-22.0
nausea / Early / 13.0-22.0
diarrhea / Early / 6.0-16.0
dizziness / Early / 3.0-16.0
myalgia / Early / 16.0-16.0

Boxed Warning
Hepatitis B exacerbation

Use of direct-acting antivirals (DAA), such as simeprevir, to treat hepatitis C virus (HCV) infections in patients currently or previously infected with hepatitis B virus (HBV) has been associated with reactivation and exacerbation of the HBV infection. Hepatitis B reactivation has also occurred in patients receiving certain immunosuppressive or chemotherapeutic medications; the risk of HBV reactivation associated with DAA treatment may be increased in these patients. To decrease the risk of reactivating a HBV infection, screen all potential drug recipients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc). For those patients whose screening reveals serologic evidence of HBV infection, a baseline HBV DNA concentration should be obtained prior to starting simeprevir. Continue to monitor coinfected patients during and after treatment for clinical and laboratory signs of hepatitis B exacerbation (i.e., HBsAg, HBV DNA, hepatic enzymes, bilirubin). In addition, instruct patients to immediately report any signs of liver toxicity (e.g., yellow eyes or skin, fatigue, weakness, loss of appetite, nausea, vomiting, or light-colored stools) to their health care provider. If a simeprevir recipient develops signs of HBV reactivation, initiate appropriate treatment for HBV infection or consult a physician with expertise in the management of hepatitis infections. The FDA has identified and confirmed 24 cases of hepatitis B exacerbation (including fulminant hepatitis, hepatic failure requiring liver transplant n = 1, and death n = 2) in coinfected patients treated with a DAA-based HCV regimen between November 2013 and July 2016. The exact mechanism is unknown; however, a commonly reported sequence of events included initiation of a DAA-based HCV regimen, rapid drop in HCV RNA to undetectable levels within 1 to 2 weeks of liver enzyme normalization, followed by a rise in HBV DNA (with or without increased transaminases) between treatment weeks 4 and 8. Of the 24 reported cases: 8 discontinued the DAA when transaminases began to rise; 12 received HBV treatment with tenofovir or entecavir; 6 did not receive HBV treatment; and 6 did not report whether HBV treatment was used.

Common Brand Names

Olysio

Dea Class

Rx

Description

Hepatitis C virus NS3/4A protease inhibitor
For treatment of chronic hepatitis C virus infection (genotype 1 and 4) in adults
Must be used with either sofosbuvir or peginterferon plus ribavirin; avoid monotherapy

Dosage And Indications
For the treatment of chronic hepatitis C infection. For the treatment of chronic hepatitis C infection, genotype 1, in patients with or without compensated (Child-Pugh A) hepatic disease. Oral dosage (with sofosbuvir) Treatment-naive and experienced adults WITHOUT cirrhosis

150 mg PO once daily with sofosbuvir for 12 weeks; never administer as monotherapy. If sofosbuvir is discontinued for any reason, then simeprevir must also be discontinued. Once simeprevir is discontinued, it must not be reinitiated. Prior to initiating therapy, screen patients for the presence of NS3 Q80K polymorphism. Efficacy of simeprevir may be substantially reduced in the presence of this polymorphism and an alternative therapy should be considered. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

Treatment-naive and experienced adults WITH compensated (Child-Pugh A) cirrhosis

150 mg PO once daily with sofosbuvir for 24 weeks; never administer as monotherapy. If sofosbuvir is discontinued for any reason, then simeprevir must also be discontinued. Once simeprevir is discontinued, it must not be reinitiated. Prior to initiating therapy, screen patients for the presence of NS3 Q80K polymorphism. Efficacy of simeprevir may be substantially reduced in the presence of this polymorphism and an alternative therapy should be considered. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

Oral dosage (with peginterferon alfa and ribavirin) Treatment-naive and prior relapse adults with or without cirrhosis (Child-Pugh A) who are HIV-negative

150 mg PO once daily with peginterferon alfa and ribavirin, for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 12 weeks of only peginterferon alfa and ribavirin (24 weeks for total course). Monitor HCV RNA at treatment weeks 4 and 12; if concentrations are greater than or equal to 25 International Units/mL, discontinue all 3 drugs. Once simeprevir is discontinued, it must not be reinitiated. If a coadministered antiviral medication is discontinued for any reason, then simeprevir must also be discontinued. Prior to initiating therapy, screen patients for the presence of NS3 Q80K polymorphism. Efficacy of simeprevir, peginterferon alfa, and ribavirin is substantially reduced in the presence of this polymorphism, and an alternative therapy should be considered. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

Treatment-naive and prior relapse adults with HIV coinfection but without cirrhosis

150 mg PO once daily with peginterferon alfa and ribavirin, for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 12 weeks of only peginterferon alfa and ribavirin (24 weeks for total course). Monitor HCV RNA at treatment weeks 4 and 12; if concentrations are greater than or equal to 25 International Units/mL, discontinue all 3 drugs. Once simeprevir is discontinued, it must not be reinitiated. If a coadministered antiviral medication is discontinued for any reason, then simeprevir must also be discontinued. Prior to initiating therapy, screen patients for the presence of NS3 Q80K polymorphism. Efficacy of simeprevir, peginterferon alfa, and ribavirin is substantially reduced in the presence of this polymorphism, and an alternative therapy should be considered. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

Treatment-naive and prior relapse adults with HIV coinfection and compensated (Child-Pugh A) cirrhosis

150 mg PO once daily with peginterferon alfa and ribavirin, for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 36 weeks of only peginterferon alfa and ribavirin (48 weeks for total course). Monitor HCV RNA at treatment weeks 4, 12, and 24; if concentrations are greater than or equal to 25 International Units/mL, discontinue treatment. Once simeprevir is discontinued, it must not be reinitiated. If a coadministered antiviral medication is discontinued for any reason, then simeprevir must also be discontinued. Prior to initiating therapy, screen patients for the presence of NS3 Q80K polymorphism. Efficacy of simeprevir, peginterferon alfa, and ribavirin is substantially reduced in the presence of this polymorphism and an alternative therapy should be considered. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

Adult prior nonresponders (including partial and null responders) with or without compensated (Child-Pugh A) cirrhosis and with or without HIV coinfection

150 mg PO once daily with peginterferon alfa and ribavirin, for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 36 weeks of only peginterferon alfa and ribavirin (48 weeks for total course). Monitor HCV RNA at treatment weeks 4, 12, and 24; if concentrations are greater than or equal to 25 International Units/mL, discontinue treatment. Once simeprevir is discontinued, it must not be reinitiated. If a coadministered antiviral medication is discontinued for any reason, then simeprevir must also be discontinued. Prior to initiating therapy, screen patients for the presence of NS3 Q80K polymorphism. Efficacy of simeprevir, peginterferon alfa, and ribavirin is substantially reduced in the presence of this polymorphism and an alternative therapy should be considered. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

For the treatment of chronic hepatitis C infection, genotype 4, in patients with compensated (Child-Pugh A) hepatic disease. Oral dosage Treatment-naive and prior relapse adults with or without compensated (Child-Pugh A) cirrhosis who are HIV-negative

150 mg PO once daily in combination with peginterferon alfa and ribavirin for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 12 weeks of only peginterferon alfa and ribavirin (24 weeks for total course). Monitor HCV RNA at treatment weeks 4 and 12; if concentrations are greater than or equal to 25 International Units/mL, discontinue all 3 drugs. If peginterferon alfa or ribavirin is discontinued for any reason, then simeprevir must also be discontinued. Once simeprevir is discontinued, it must not be reinitiated. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

Treatment-naive and prior relapse adults with HIV coinfection but without cirrhosis

150 mg PO once daily in combination with peginterferon alfa and ribavirin for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 12 weeks of only peginterferon alfa and ribavirin (24 weeks for total course). Monitor HCV RNA at treatment weeks 4 and 12; if concentrations are greater than or equal to 25 International Units/mL, discontinue all 3 drugs. If peginterferon alfa or ribavirin is discontinued for any reason, then simeprevir must also be discontinued. Once simeprevir is discontinued, it must not be reinitiated. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

Treatment-naive and prior relapse adults with HIV coinfection and compensated (Child-Pugh A) cirrhosis

150 mg PO once daily in combination with peginterferon alfa and ribavirin for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 36 weeks of only peginterferon alfa and ribavirin (48 weeks for total course). Monitor HCV RNA at treatment weeks 4, 12, and 24; if concentrations are greater than or equal to 25 International Units/mL, discontinue treatment. If peginterferon alfa or ribavirin is discontinued for any reason, then simeprevir must also be discontinued. Once simeprevir is discontinued, it must not be reinitiated. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

Adult prior nonresponders (including partial and null responders) with or without compensated (Child-Pugh A) cirrhosis and with or without HIV coinfection

150 mg PO once daily in combination with peginterferon alfa and ribavirin for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 36 weeks of only peginterferon alfa and ribavirin (48 weeks for total course). Monitor HCV RNA at treatment weeks 4, 12, and 24; if concentrations are greater than or equal to 25 International Units/mL, discontinue treatment. If peginterferon alfa or ribavirin is discontinued for any reason, then simeprevir must also be discontinued. Once simeprevir is discontinued, it must not be reinitiated. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

For the treatment of recurrent hepatitis C genotypes 1 and 4 infection in patients after liver transplantation† with or without compensated (Child-Pugh A) cirrhosis. Oral dosage Adults

Guidelines recommend 150 mg PO daily combined with sofosbuvir and with or without weight-based ribavirin for 12 weeks as an alternative regimen.

Dosing Considerations
Hepatic Impairment

No dosage adjustments are needed for mild hepatic impairment (Child-Pugh Class A). Avoid use in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C), as drug exposure and risk of adverse reactions are increased in these patients. In addition, the combined use with peginterferon alfa and ribavirin is contraindicated in decompensated cirrhosis (moderate or severe hepatic impairment).

Renal Impairment

No dosage adjustments are needed in patients with mild, moderate, or severe renal impairment; however, simeprevir has not been studied in patients with end-stage renal disease (ESRD) and those requiring hemodialysis.

Drug Interactions

Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of simeprevir is necessary. If simeprevir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like simeprevir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If simeprevir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Acetaminophen; Tramadol: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tramadol, which is partially metabolized by CYP3A4. Monitor patients for adverse effects of tramadol, such as seizures and serotonin syndrome.
Afatinib: (Moderate) If the concomitant use of simeprevir and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of simeprevir. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and simeprevir is a weak P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Coadministration with simeprevir (150 mg daily for 7 days) increased the Cmax and AUC of another P-gp substrate, digoxin (single dose, 0.5 mg), by 1.31 and 1.39, respectively. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
Aldesleukin, IL-2: (Major) Avoid concurrent use of simeprevir and aldesleukin, IL-2. Inhibition of CYP3A4 by aldesleukine, IL-2 may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Alfentanil: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of alfentanil, which is a CYP3A4 substrate. Monitor patients for adverse effects of alfentanil, such as hypotension, nausea, itching, and respiratory depression.
Alfuzosin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of alfuzosin, which is a CYP3A4 substrate. Monitor patients for adverse effects of alfuzosin, such as dizziness, hypotension, and syncope.
Aliskiren; Amlodipine: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Aliskiren; Valsartan: (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
Almotriptan: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of almotriptan, which is a CYP3A4 substrate. Monitor patients for adverse effects of almotriptan, such as serotonin syndrome.
Alpelisib: (Major) Avoid coadministration of alpelisib with simeprevir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and simeprevir is a BCRP inhibitor.
Alprazolam: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of alprazolam, which is a CYP3A4 substrate. Monitor patients for adverse effects of alprazolam, such as sedation.
Amiodarone: (Major) Use of orally administered amiodarone with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in amiodarone plasma concentrations; monitoring of amiodarone plasma concentrations (if available) is recommended. However, use of amiodarone should be avoided in patients receiving hepatitis C regimens containing both simeprevir and sofosbuvir due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, including cases requiring pacemaker intervention, have been reported when amiodarone is administered concurrenlty with simeprevir and sofosbuvir; additionally, a fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir; sofosbuvir). The mechanism of this effect is unknown. If coadministration of all three medications is required, cardiac monitoring in an inpatient setting for the first 48 hours is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, patients discontinuing amiodarone just prior to starting simeprevir in combination with sofosbuvir should also undergo similar cardiac monitoring as outlined above.
Amitriptyline: (Moderate) Simeprevir, a mild CY1A2 inhibitor and mild intestinal CYP3A4 inhibitor, may increase the side effects of amitriptyline, which is a CYP3A4 and CYP1A2 substrate. Monitor patients for adverse effects of amitriptyline, such as anticholinergic activity, orthostatic hypotension, and sedation.
Amitriptyline; Chlordiazepoxide: (Moderate) Simeprevir, a mild CY1A2 inhibitor and mild intestinal CYP3A4 inhibitor, may increase the side effects of amitriptyline, which is a CYP3A4 and CYP1A2 substrate. Monitor patients for adverse effects of amitriptyline, such as anticholinergic activity, orthostatic hypotension, and sedation.
Amlodipine: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Amlodipine; Atorvastatin: (Major) Do not exceed 40 mg/day of atorvastatin if coadministration with simeprevir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Coadministration of atorvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased atorvastatin plasma concentrations. (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Amlodipine; Benazepril: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Amlodipine; Celecoxib: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together. (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
Amlodipine; Olmesartan: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Amlodipine; Telmisartan: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Amlodipine; Valsartan: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together. (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid concurrent use of simeprevir and clarithromycin; consider use of azithromycin in place of clarithromycin. Inhibition of CYP3A4 by clarithromycin may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concurrent use of simeprevir and clarithromycin; consider use of azithromycin in place of clarithromycin. Inhibition of CYP3A4 by clarithromycin may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Apalutamide: (Major) Coadministration of simeprevir with apalutamide is not recommended as there is a potential for decreased simeprevir concentrations which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Simeprevir is a CYP3A4 and OATP1B1 substrate. Apalutamide is a strong CYP3A4 inducer as well as a weak OATP1B1 inducer.
Aprepitant, Fosaprepitant: (Moderate) Use caution if simeprevir and aprepitant, fosaprepitant are used concurrently and monitor for an increase in simeprevir-related adverse effects for several days after administration of a multi-day aprepitant regimen. Simeprevir is a CYP3A4 substrate in vitro. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of simeprevir. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Simeprevir is also a weak CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
Aripiprazole: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase plasma concentrations of aripiprazole, which is a partial CYP3A4 substrate. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor.
Armodafinil: (Major) Avoid concurrent use of simeprevir and armodafinil. Potential induction of CYP3A4 by armodafinil (an in vitro inducer) may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Artemether; Lumefantrine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of artemether; lumefantrine, which is a CYP3A4 substrate. Monitor patients for adverse effects of artemether; lumefantrine, such as QT prolongation.
Asenapine: (Moderate) Simeprevir, a mild CYP1A2 and a mild intestinal CYP3A4 inhibitor, may increase the side effects of asenapine, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of asenapine, such as extrapyramidal symptoms; however, because asenapine is metabolized by multiple CYP pathways, a clinically significant interaction is less likely to occur.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of simeprevir is necessary. If simeprevir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like simeprevir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If simeprevir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Aspirin, ASA; Pravastatin: (Moderate) Although coadministration of pravastatin with simeprevir has not been studied, use of these drugs together is expected to increase pravastatin exposure. If these drugs are given together, titrate the pravastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Atazanavir: (Major) Avoid concurrent use of simeprevir and atazanavir. Inhibition of CYP3A4 and organic anion transporting polypeptide (OATP1B1) by atazanavir may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Atazanavir; Cobicistat: (Major) Avoid concurrent use of simeprevir and atazanavir. Inhibition of CYP3A4 and organic anion transporting polypeptide (OATP1B1) by atazanavir may increase the plasma concentrations of simeprevir, resulting in adverse effects. (Major) Avoid concurrent use of simeprevir and cobicistat. Inhibition of CYP3A4 by cobicistat may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects. Coadministration with a moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
Atorvastatin: (Major) Do not exceed 40 mg/day of atorvastatin if coadministration with simeprevir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Coadministration of atorvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased atorvastatin plasma concentrations.
Atorvastatin; Ezetimibe: (Major) Do not exceed 40 mg/day of atorvastatin if coadministration with simeprevir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Coadministration of atorvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased atorvastatin plasma concentrations.
Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid concurrent use of simeprevir and phenobarbital as induction of CYP3A4 by phenobarbital may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid concurrent use of simeprevir and phenobarbital as induction of CYP3A4 by phenobarbital may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of ergotamine, which is a CYP3A4 substrate. Monitor patients for adverse effects of ergotamine, such as ergot toxicity.
Bendamustine: (Major) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inhibitor such as simeprevir (a mild inhibitior) may increase bendamustine concentrations in plasma. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with a CYP1A2 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with simeprevir may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of simeprevir in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving simeprevir. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving simeprevir. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; simeprevir inhibits P-gp.
Bexarotene: (Major) Avoid concurrent use of simeprevir and bexarotene. Induction of CYP3A4 by bexarotene may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of systemic bexarotene, which is a CYP3A4 substrate. Monitor patients for adverse effects of bexarotene, such as photosensitivity and hyperlipidemia.
Boceprevir: (Major) Avoid concurrent use of simeprevir and boceprevir. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by boceprivir may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionaly, simeprivir, a P-gp inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of boceprevir, a Pg-p and CYP3A4 substrate.
Bortezomib: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of bortezomib, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of bortezomib, such as peripheral neuropathy, hematologic toxicities, and GI events.
Bosentan: (Major) Avoid concurrent use of simeprevir and bosentan. Induction of CYP3A4 by bosentan may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor and an inhibitor of OATP1B1/3, may increase the side effects of bosentan, which is a CYP3A4 and OATP substrate. Monitor patients for adverse effects of bosentan, such as headache, nausea, vomiting, hyptension, and increased heart rate.
Bosutinib: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of bosutinib, which is a CYP3A4 substrate. Additionally, bosutinib, a P-glycoprotein (P-gp) inhibitor in vitro, may increase plasma concentratins of simeprivier, a P-gp substrate in vitro. FDA-labeling recommends avoiding concomitant moderate and strong CYP3A4 inhibitors with bosutinib. Monitor patients for adverse effects, such as rash, diarrhea, nausea, vomiting, myelosuppresion, and hepatic adverse events.
Brigatinib: (Moderate) Monitor for an increase in simeprevir-related adverse reactions if coadministration with brigatinib is necessary. Simeprevir is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Budesonide: (Minor) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of budesonide, which is a CYP3A4 and P-gp substrate. Monitor patients for adverse effects of budesonide, such as excessive HPA-axis suppresion.
Budesonide; Formoterol: (Minor) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of budesonide, which is a CYP3A4 and P-gp substrate. Monitor patients for adverse effects of budesonide, such as excessive HPA-axis suppresion.
Bupivacaine Liposomal: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of bupivacaine, which is a CYP3A4 substrate. Monitor patients for adverse effects of bupivacaine, such as CNS or respiratory depression.
Bupivacaine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of bupivacaine, which is a CYP3A4 substrate. Monitor patients for adverse effects of bupivacaine, such as CNS or respiratory depression.
Bupivacaine; Lidocaine: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of lidocaine, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of lidocaine, such as CNS and cardiovascular effects. (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of bupivacaine, which is a CYP3A4 substrate. Monitor patients for adverse effects of bupivacaine, such as CNS or respiratory depression.
Buprenorphine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of buprenorphine, which is a CYP3A4 substrate. Monitor patients for adverse effects of buprenorphine, such as CNS or respiratory depression.
Buprenorphine; Naloxone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of buprenorphine, which is a CYP3A4 substrate. Monitor patients for adverse effects of buprenorphine, such as CNS or respiratory depression.
Buspirone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of buspirone, which is a CYP3A4 substrate. Monitor patients for adverse effects of buspirone.
Cabozantinib: (Minor) Monitor for an increase in simeprevir-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of simeprevir may be necessary. Simeprevir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
Caffeine; Ergotamine: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of ergotamine, which is a CYP3A4 substrate. Monitor patients for adverse effects of ergotamine, such as ergot toxicity.
Carbamazepine: (Major) Avoid concurrent use of simeprevir and carbamazepine. Induction of CYP3A4 by carbamazepine may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Carvedilol: (Moderate) Concomitant use of simeprevir and carvedilol may result in increased carvedilol plasma concentrations and side effects. Carvedilol is partially metabolized by P-glycoprotein (P-gp) and simeprevir inhibits P-gp. Monitor patients for adverse events such as cardivascular events.
Ceritinib: (Major) Coadministration of simeprevir with ceritinib is not recommended due to increased plasma concentrations of simeprevir which increase the risk for treatment-related adverse reactions. Simeprevir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
Cerivastatin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of cerivastatin, which is a CYP3A4 substrate. Monitor patients for adverse effects of cerivastatin, such as myopathy and rhabdomyolysis.
Cevimeline: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of cevimeline, which is a CYP3A4 substrate. Monitor patients for adverse effects of cevimeline, such as GI events and hyperhydrosis.
Chloramphenicol: (Major) Avoid concurrent use of simeprevir and chloramphenicol. Inhibition of CYP3A4 by chloramphenicol may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Cilostazol: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of cilostazol, which is a CYP3A4 substrate. Monitor patients for adverse effects of cilostazol, such as increased bleeding.
Cimetidine: (Moderate) Use caution with concurrent use of simeprevir and cimetidine. Cimetidine weakly inhibits CYP3A4 which may increase the plasma concentrations of simeprevir, resulting in adverse effects. The FDA-labeling recommends avoiding moderate and strong CYP3A4 inhibitors.
Cinacalcet: (Moderate) Simeprevir, a mild CYP1A2 and a mild intestinal CYP3A4 inhibitor, may increase the side effects of cinacalcet, which is a CYP1A2 and CYP3A4 substrate. Monitor PTH and calcium concentrations.
Cisapride: (Major) Avoid concurrent use of simeprevir and cisapride. Inhibition of intestinal CYP3A4 by simeprevir may increase the plasma concentrations of cisapride, potentially resulting in adverse events such as cardiac arrhythmias.
Citalopram: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of citalopram, which is a CYP3A4 substrate. Monitor patients for adverse effects of citalopram, such as QT prolongation, serotonin syndrome, and neuroleptic malignant syndrome.
Clarithromycin: (Major) Avoid concurrent use of simeprevir and clarithromycin; consider use of azithromycin in place of clarithromycin. Inhibition of CYP3A4 by clarithromycin may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Clomipramine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of clomipramine, which is a CYP3A4 substrate. Monitor patients for adverse effects of clomipramine, such as QT prolongation.
Clonazepam: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of clonazepam, which is a CYP3A4 substrate. Monitor patients for adverse effects of clonazepam, such as CNS depression.
Clozapine: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of clozapine, which is a CYP1A2 and CYP3A4 substrate. Elevated plasma concentrations of clozapine may increase the risk for QT prolongation, torsade de pointes (TdP), sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 or CYP1A2 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Cobicistat: (Major) Avoid concurrent use of simeprevir and cobicistat. Inhibition of CYP3A4 by cobicistat may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects. Coadministration with a moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
Cobimetinib: (Moderate) If concurrent use of cobimetinib and simeprevir is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro as well as a P-glycoprotein (P-gp) substrate; simeprevir is a weak inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Colchicine: (Major) As colchicine is a CYP3A4 and P-glycoprotein (P-gp) substrate and simepriver is mild intestinal CYP3A4 inhibitor and P-gp inhibitor, increased concentrations of colchicine may occur with concurrent use. Dosage adjustments of colchicine may be required. The increase in colchicine concentrations may be greater in patients with renal or hepatic impairment. Use simeprivir with extreme care, if at all, concomitantly with colchicine.
Colchicine; Probenecid: (Major) As colchicine is a CYP3A4 and P-glycoprotein (P-gp) substrate and simepriver is mild intestinal CYP3A4 inhibitor and P-gp inhibitor, increased concentrations of colchicine may occur with concurrent use. Dosage adjustments of colchicine may be required. The increase in colchicine concentrations may be greater in patients with renal or hepatic impairment. Use simeprivir with extreme care, if at all, concomitantly with colchicine.
Conivaptan: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and simeprevir, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in elevated concentrations of both conivaptan and simeprevir. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
Crizotinib: (Major) Concurrent use of crizotinib with simeprevir is not recommended due to increased plasma concentrations of simeprevir. Simeprevir is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
Cyclophosphamide: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of cyclophosphamide, which is a CYP3A4 substrate. Monitor patients for adverse effects of cyclophosphamide, such as neurotoxicity.
Cyclosporine: (Major) Avoid concurrent use of simeprevir and cyclosporine. Inhibition of the hepatic isoenzyme CYP3A4 and the drug transporters OATP1B1 and P-glycoprotein (P-gp) by cyclosporine causes significant increases in the plasma concentrations of simeprevir. Similarly, the plasma concentrations of cyclosporine are increased when administered with simeprevir. Use of these drugs together may increase the potential for adverse events.
Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with simeprevir, a mild P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like simeprevir in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with simeprevir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Daclatasvir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with simeprevir, a moderate CYP3A4 inhibitor, increases daclatasvir serum concentrations by 94%. In addition, the pharmacokinetic properties (i.e., Cmax, Cmin, and AUC) of simeprevir, a substrate of the drug transporters P-glycoprotein (P-gp) and organic anion transporting polypeptides (OATP), are increased by daclatasvir, a P-gp and OATP inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
Danazol: (Major) Avoid concurrent use of simeprevir and danazol. Inhibition of CYP3A4 by danazol may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Dapsone: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dapsone, which is a CYP3A4 substrate. Monitor patients for adverse effects of dapsone, such as peripheral neuropathy or hematologic changes.
Darifenacin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of darifenacin, which is a CYP3A4 substrate. Monitor patients for adverse effects of darifenacin, such as anticholinergic effects.
Darunavir: (Major) Avoid concurrent use of simeprevir and darunavir boosted with ritonavir. Inhibition of CYP3A4 by darunavir/ritonavir causes increased plasma concentrations of simeprevir, potentially resulting in adverse effects.
Darunavir; Cobicistat: (Major) Avoid concurrent use of simeprevir and cobicistat. Inhibition of CYP3A4 by cobicistat may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects. Coadministration with a moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold. (Major) Avoid concurrent use of simeprevir and darunavir boosted with ritonavir. Inhibition of CYP3A4 by darunavir/ritonavir causes increased plasma concentrations of simeprevir, potentially resulting in adverse effects.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concurrent use of simeprevir and cobicistat. Inhibition of CYP3A4 by cobicistat may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects. Coadministration with a moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold. (Major) Avoid concurrent use of simeprevir and darunavir boosted with ritonavir. Inhibition of CYP3A4 by darunavir/ritonavir causes increased plasma concentrations of simeprevir, potentially resulting in adverse effects.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concurrent use of simeprevir and ritonavir. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by ritonavir causes significantly increased plasma concentrations of simeprevir, potentially resulting in adverse effects. (Major) Avoid the coadministration of simeprevir and dasabuvir; ombitasvir; paritaprevir; ritonavir. The FDA-approved labeling for simeprevir, a CYP3A4 substrate, states that coadministration with strong CYP3A4 inhibitors, including ritonavir, is not recommended as significant increases in simeprevir could result. Additional metabolic interactions are expected which would lead to elevated plasma concentrations of simeprevir, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Simeprevir is a P-glycoprotein (P-gp) substrate/inhibitor, ritonavir is a P-gp substrate/inhibitor, and dasabuvir, ombitasvir, and paritaprevir are P-gp substrates. Simeprevir and paritaprevir are both OATP1B1/3 substrate/inhibitors. Finally, simeprevir is a mild CYP3A4 inhibitor and dasabuvir, paritaprevir, and ritonavir are CYP3A4 substrates. (Major) Avoid the coadministration of simeprevir and dasabuvir; ombitasvir; paritaprevir; ritonavir. The FDA-approved labeling for simeprevir, a CYP3A4 substrate, states that coadministration with strong CYP3A4 inhibitors, including ritonavir, is not recommended as significant increases in simeprevir could result. Additional metabolic interactions are expected which would lead to elevated plasma concentrations of simeprevir, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Simeprevir is a P-glycoprotein (P-gp) substrate/inhibitor, ritonavir is a P-gp substrate/inhibitor, dasabuvir, ombitasvir, and paritaprevir are P-gp substrates, and paritaprevir is a P-gp inhibitor. Simeprevir and paritaprevir are both OATP1B1/3 substrate/inhibitors. Finally, simeprevir is a mild CYP3A4 inhibitor and dasabuvir, paritaprevir, and ritonavir are CYP3A4 substrates.
Delavirdine: (Major) Avoid concurrent use of simeprevir and delavirdine. Inhibition of CYP3A4 by delavirdine may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Dexamethasone: (Major) Avoid concurrent use of simeprevir and systemic dexamethasone. Induction of CYP3A4 by dexamethasone may reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Dexlansoprazole: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dexlansoprazole, which is a CYP3A4 substrate. Monitor patients for adverse effects of dexlansoprazole, such as electroyle changes.
Dextromethorphan; Quinidine: (Moderate) Use of orally administered quinidine with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in quinidine plasma concentrations. If these drugs are administered together, monitoring of quinidine plasma concentrations (if available) is recommended.
Diazepam: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of diazepam, which is a CYP3A4 substrate. Monitor patients for adverse effects of diazepam, such as CNS effects and respiratory depression.
Diclofenac: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of diclofenac, which is a CYP3A4 substrate. Monitor patients for adverse effects of diclofenac, such as bleeding or nephrotoxicity.
Diclofenac; Misoprostol: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of diclofenac, which is a CYP3A4 substrate. Monitor patients for adverse effects of diclofenac, such as bleeding or nephrotoxicity.
Digoxin: (Moderate) Coadministration of digoxin with simeprevir, a P-glycoprotein (P-gp) inhibitor, results in increased digoxin plasma concentrations. If these drugs are administered together, routine monitoring of digoxin plasma concentrations is recommended.
Dihydroergotamine: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dihydroergotamine, which is a CYP3A4 substrate. Monitor patients for adverse effects of dihydroergotamine, such as ergot toxicity.
Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Disopyramide: (Moderate) Coadministration of disopyramide with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in disopyramide plasma concentrations. If these drugs are administered together, monitoring of disopyramide plasma concentrations (if available) is recommended.
Disulfiram: (Minor) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of disulfiram, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of disulfiram.
Docetaxel: (Moderate) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of docetaxel, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of docetaxel, such as myelosuppression and cutaneous reactions.
Dolasetron: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dolasetron, which is a CYP3A4 substrate. Monitor patients for adverse effects of dolasetron, such as QT prolongation.
Donepezil: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of donepezil, which is a CYP3A4 substrate. Monitor patients for adverse effects of donepezil, such as cholinomimetic effects.
Donepezil; Memantine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of donepezil, which is a CYP3A4 substrate. Monitor patients for adverse effects of donepezil, such as cholinomimetic effects.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir, PMPA. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP.
Doxorubicin: (Major) Simeprevir, a breast cancer resistance protein (BCRP) inhibitor, P-glycoprotein inhibitor (P-gp), and a mild intestinal CYP3A4 inhibitor, may increase the side effects of doxorubicin, which is a BCRP, P-gp and CYP3A4 substrate. Avoid coadministration of simeprevir and doxorubicin if possible. If avoidance is not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
Dronedarone: (Major) Avoid concurrent use of simeprevir and dronedarone. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by dronedarone may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionaly, simeprivir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dronedarone, a CYP3A4 substrate.
Dutasteride; Tamsulosin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tamsulosin, which is a CYP3A4 substrate. Monitor patients for adverse effects of tamsulosin, such as hypotension, dizziness, syncope, and vertigo.
Edoxaban: (Moderate) Coadministration of edoxaban and simeprevir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and simeprevir is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of simeprevir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
Efavirenz: (Major) Avoid concurrent use of simeprevir and efavirenz. Induction of CYP3A4 by efavirenz significantly reduces the plasma concentrations of simeprevir, potentially resulting in treatment failure. Concurrent treatment for 14 days has resulted in decreased Cmax, AUC, and Cmin of simeprevir by 51% (90% CI: 46% to 56%), 71% (90% CI: 67% to 74%), and 91% (90% CI: 88% to 92%), respectively.
Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid concurrent use of simeprevir and efavirenz. Induction of CYP3A4 by efavirenz significantly reduces the plasma concentrations of simeprevir, potentially resulting in treatment failure. Concurrent treatment for 14 days has resulted in decreased Cmax, AUC, and Cmin of simeprevir by 51% (90% CI: 46% to 56%), 71% (90% CI: 67% to 74%), and 91% (90% CI: 88% to 92%), respectively. (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir, PMPA. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of simeprevir and efavirenz. Induction of CYP3A4 by efavirenz significantly reduces the plasma concentrations of simeprevir, potentially resulting in treatment failure. Concurrent treatment for 14 days has resulted in decreased Cmax, AUC, and Cmin of simeprevir by 51% (90% CI: 46% to 56%), 71% (90% CI: 67% to 74%), and 91% (90% CI: 88% to 92%), respectively. (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir, PMPA. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP.
Elagolix: (Severe) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as simeprevir is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Simeprevir significantly inhibits all three of these enzymes/drug transporters. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density.
Elbasvir; Grazoprevir: (Major) Concurrent administration of elbasvir with simeprevir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations). Simeprevir is a substrate and inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with simeprevir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Simeprevir is a substrate and inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, simeprevir is a weak inhibitor of the organic anion transporting polypeptide (OATP); grazoprevir is a substrate of OATP1B1/3.
Eletriptan: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of eletriptan, which is a CYP3A4 substrate. Monitor patients for adverse effects of eletriptan, such as cardiovascular events.
Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of simeprevir and eliglustat is not recommended. Simeprevir is a weak CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias) in these patients.
Eluxadoline: (Major) When administered concurrently with simeprevir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); simeprevir is an OATP inhibitor and in vitro substrate. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concurrent use of simeprevir and cobicistat. Inhibition of CYP3A4 by cobicistat may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects. Coadministration with a moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of simeprevir and cobicistat. Inhibition of CYP3A4 by cobicistat may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects. Coadministration with a moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold. (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir, PMPA. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP.
Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir, PMPA. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP.
Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir, PMPA. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP.
Enalapril; Felodipine: (Moderate) Coadministration of felodipine with simeprevir, an inhibitor of intestinal CYP3A4, may result in increased felodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Enzalutamide: (Moderate) Coadministration of simeprevir with enzalutamide is not recommended as there is a potential for decreased simeprevir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Simeprevir is metabolized by CYP3A4 and enzalutamide is a strong CYP3A4 inducer.
Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafte

r. Eplerenone is a CYP3A4 substrate. Simeprevir is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Ergotamine: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of ergotamine, which is a CYP3A4 substrate. Monitor patients for adverse effects of ergotamine, such as ergot toxicity.
Erlotinib: (Major) Avoid coadministration of erlotinib with simeprevir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. Simeprevir is a CYP3A4 and CYP1A2 inhibitor. Coadministration with another moderate CYP3A4/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
Erythromycin: (Major) Avoid concurrent use of simeprevir and erythromycin; consider use of azithromycin in place of erythromycin. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by both drugs results in increased plasma concentrations of simeprevir by 647% and erythromycin by 90%. Administering these drugs together may result in adverse effects.
Erythromycin; Sulfisoxazole: (Major) Avoid concurrent use of simeprevir and erythromycin; consider use of azithromycin in place of erythromycin. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by both drugs results in increased plasma concentrations of simeprevir by 647% and erythromycin by 90%. Administering these drugs together may result in adverse effects.
Escitalopram: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of escitalopram, which is a CYP3A4 substrate. Monitor patients for adverse effects of escitalopram, such as GI effects or serotonin syndrome.
Eslicarbazepine: (Major) Avoid concurrent use of simeprevir and eslicarbazepine. Induction of CYP3A4 by eslicarbazepine may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Estazolam: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of estazolam, which is a CYP3A4 substrate in vitro. Monitor patients for adverse effects of estazolam, such as CNS or respiratory depression.
Eszopiclone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of eszopiclone, which is a CYP3A4 substrate. Monitor patients for adverse effects of eszopiclone, such as prolonged sedative effects.
Ethosuximide: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of ethosuximide, which is a CYP3A4 substrate. Monitor patients for adverse effects of ethosuximide, such as CNS or GI effects.
Etravirine: (Major) Avoid concurrent use of simeprevir and etravirine. Induction of CYP3A4 by etravirine may reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Ezetimibe; Simvastatin: (Moderate) Coadministration of simvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased simvastatin plasma concentrations. If these drugs are given together, titrate the simvastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Fedratinib: (Major) Concurrent use of fedratinib with simeprevir is not recommended due to increased plasma concentrations of simeprevir. Simeprevir is a CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
Felbamate: (Major) Avoid concurrent use of simeprevir and felbamate. Induction of CYP3A4 by felbamate may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Felodipine: (Moderate) Coadministration of felodipine with simeprevir, an inhibitor of intestinal CYP3A4, may result in increased felodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Fentanyl: (Moderate) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of fentanyl, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of fentanyl, such as oversedation, respiratory depression, and hypotension.
Flecainide: (Moderate) Coadministration of flecainide with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in flecainide plasma concentrations. If these drugs are administered together, monitoring of flecainide plasma concentrations (if available) is recommended.
Flibanserin: (Major) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including simeprevir, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
Fluconazole: (Major) Avoid concurrent use of simeprevir and fluconazole. Inhibition of CYP3A4 by fluconazole may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Fluoxetine: (Moderate) Use caution with concurrent use of simeprevir and fluoxetine. Fluoxetine weakly inhibits CYP3A4 which may increase the plasma concentrations of simeprevir, resulting in adverse effects. The FDA-labeling recommends avoiding moderate and strong CYP3A4 inhibitors.
Fluoxetine; Olanzapine: (Moderate) Use caution with concurrent use of simeprevir and fluoxetine. Fluoxetine weakly inhibits CYP3A4 which may increase the plasma concentrations of simeprevir, resulting in adverse effects. The FDA-labeling recommends avoiding moderate and strong CYP3A4 inhibitors. (Minor) Simeprevir is an inhibitor of CYP1A2, which may result in decreased clearance of olanzapine. Decreased metabolism of olanzapine may lead to clinically important adverse reactions such as extrapyramidal symptoms, sedation, or orthostatic hypotension. In addition, olanzapine is associated with a possible risk for QT prolongation and TdP and should be used cautiously with CYP1A2 inhibitors.
Flurazepam: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of flurazepam, which is a CYP3A4 substrate. Monitor patients for adverse effects of flurazepam, such as CNS effects or respiratory depression.
Flutamide: (Major) Avoid concurrent use of simeprevir and flutamide. Induction of CYP3A4 by flutamide (an in vitro inducer) may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor and a mild CYP1A2 inhibitor, may increase the side effects of systemic flutamide, which is primarily metabolized by CYP1A2 with CYP3A4 as a minor metabolic pathway. Monitor patients for adverse effects of flutamide, such as libido decrease, impotence, and hot flashes.
Fluvastatin: (Moderate) Although coadministration of fluvastatin with simeprevir has not been studied, use of these drugs together is expected to increase fluvastatin exposure. If these drugs are given together, titrate the fluvastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Fluvoxamine: (Major) Avoid concurrent use of simeprevir and fluvoxamine. Inhibition of CYP3A4 by fluvoxamine may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a mild CYP1A2 inhibitor, may increase the side effects of fluvoxaine, a CYP1A2 substrate.
Fosamprenavir: (Major) Avoid concurrent use of simeprevir and fosamprenavir (with or without ritonavir). Administration of unboosted fosamprenavir with simeprevir may increase or decrease the plasma concentration of simeprevir. However, when fosamprenavir is boosted with ritonavir, the plasma concentration of simeprevir is expected to increase, and could result in adverse effects.
Fosphenytoin: (Major) Avoid concurrent use of simeprevir and fosphenytoin. Induction of CYP3A4 by phenytoin may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Fostamatinib: (Moderate) Monitor for simeprevir toxicities that may require simeprevir dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a P-gp substrate may increase the concentration of the P-gp substrate. Fostamatinib is a P-gp inhibitor; simeprevir is a substrate for P-gp. Coadministration of fostamatinib with another P-gp substrate increased the P-gp substrate AUC by 37% and Cmax by 70%.
Gemfibrozil: (Minor) Use caution with concurrent use of simeprevir and gemfibrozil. Gemfibrozil is an inhibitor of OAT1B1, which may increase the plasma concentrations of simeprevir, a substrate of OATP1B1/3 in vitro, resulting in adverse effects, such as rash.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and simeprevir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and simeprevir are both substrates and inhibitors of organic anion transporting polypeptide (OATP) 1B1/3 and P-glycoprotein (P-gp). Additionally, glecaprevir is a substrate of breast cancer resistance protein (BCRP) while simeprevir is an inhibitor of BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and simeprevir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Simeprevir is a substrate of of P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3; pibrentasvir is an inhibitor of these drug transporters. Additionally, pibrentasvir is a substrate of P-gp and BCRP while simeprevir is an inhibitor of P-gp and BCRP.
Glyburide: (Moderate) Concomitant use of simeprevir and glyburide may result in increased glyburide plasma concentrations and side effects. Glyburide is metabolized by P-glycoprotein (P-gp) and simeprevir inhibits P-gp. Monitor patients for adverse events such as hypoglycemia.
Glyburide; Metformin: (Moderate) Concomitant use of simeprevir and glyburide may result in increased glyburide plasma concentrations and side effects. Glyburide is metabolized by P-glycoprotein (P-gp) and simeprevir inhibits P-gp. Monitor patients for adverse events such as hypoglycemia.
Grapefruit juice: (Major) Avoid concurrent use of simeprevir and grapefruit juice. Inhibition of CYP3A4 by grapefruit juice may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Haloperidol: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of haloperidol, which is a CYP3A4 substrate. Monitor patients for adverse effects of haloperidol, such as QT prolongation and CNS effects.
Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Concomitant use of simeprevir and triamterene may result in increased triamterene plasma concentrations and side effects. Triamterene is metabolized by CYP1A2 and simeprevir is a mild CYP1A2 inhibitor. Monitor patients for adverse events such as hyperkalemia.
Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
Hydrocodone: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with simeprevir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of simeprevir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If simeprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Simeprevir is a weak inhibitor of CYP3A4.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of simeprevir is necessary. If simeprevir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like simeprevir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If simeprevir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with simeprevir, a CYP3A substrate, as simeprevir toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Imatinib: (Major) Avoid the concomitant use of simeprevir and imatinib; increased plasma concentration of simeprevir and/or imatinib may occur. Simeprivir is CYP3A4 substrate and a breast cancer resistance protein (BCRP) inhibitor; imatinib is a moderate CYP3A4 inhibitor and a BCRP substrate.
Imipramine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of imipramine, which is a CYP3A4 substrate. Monitor patients for adverse effects of imipramine, such as CNS or cardiovascular effects.
Indacaterol: (Moderate) Simeprevir is a P-glycoprotein (P-gp) inhibitor and a CYP3A4 inhibitor, and might increase the concentrations and AUC of indacaterol, which is a P-gp and CYP3A4 substrate. When indacaterol has been administered with dual CYP3A4/P-gp inhibitors, the AUC has increased by 1.4- to 1.9-fold, depending on the agent used. An increase in maximal concentrations may also occur. Monitor patients for adverse effects of indacaterol, such as nervousness, tremor, and increased heart rate.
Indacaterol; Glycopyrrolate: (Moderate) Simeprevir is a P-glycoprotein (P-gp) inhibitor and a CYP3A4 inhibitor, and might increase the concentrations and AUC of indacaterol, which is a P-gp and CYP3A4 substrate. When indacaterol has been administered with dual CYP3A4/P-gp inhibitors, the AUC has increased by 1.4- to 1.9-fold, depending on the agent used. An increase in maximal concentrations may also occur. Monitor patients for adverse effects of indacaterol, such as nervousness, tremor, and increased heart rate.
Indinavir: (Major) Avoid concurrent use of simeprevir and indinavir. Inhibition of CYP3A4 by indinavir may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Isavuconazonium: (Major) Avoid concurrent use of simeprevir and isavuconazonium. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by isavuconazole, the active moiety of isavuconazonium, may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of isavuconazole, a sensitive CYP3A4 substrate.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
Isoniazid, INH; Rifampin: (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
Isradipine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of isradipine, which is a CYP3A4 substrate. Monitor patients for adverse effects of isradipine, such as cardivascular effects, including hypotension.
Itraconazole: (Major) Simeprevir administration is not recommended during or for 2 weeks after itraconazole therapy. Inhibition of CYP3A4 by itraconazole may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects. Itraconazole is a strong CYP3A4 inhibitor; simeprevir is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the AUC of simeprevir by 7-fold.
Ivabradine: (Moderate) Use caution during coadministration of ivabradine and simeprevir as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; simeprevir is a mild inhibitor of CYP3A. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
Ixabepilone: (Moderate) Simeprevir is a mild intestinal CYP3A4 inhibitor. Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with mild or moderate CYP3A4 inhibitors has not been studied. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. Caution is recommended if ixabepilone is coadministered with a mild or moderate CYP3A4 inhibitor; closely monitor patients for ixabepilone-related toxicities, such as periopheral neuropathy, GI effects, and musculoskeletal effects.
Ketoconazole: (Major) Avoid concurrent use of simeprevir and ketoconazole. Inhibition of CYP3A4 by ketoconazole may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir, PMPA. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP.
Lapatinib: (Major) Monitor for an increase in treatment-related adverse reactions if coadministration of simeprevir with lapatinib is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors. Concomitant use may also increase simeprevir exposure.
Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of ledipasvir with simeprevir. Taking these drugs together increases ledipasvir exposure by 92% and simeprevir exposure by 116%. Use of these drugs together increases the risk for adverse effects. (Major) Avoid coadministration of sofosbuvir with simeprevir, a P-glycoprotein (P-gp) inhibitor. Taking these drugs together may increase sofosbuvir plasma concentrations, potentially resulting in adverse effects.
Lefamulin: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with simeprevir as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and simeprevir is a P-gp inhibitor.
Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with simeprevir as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; simeprevir is a weak CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Letermovir: (Major) When possible avoid concurrent administration of simeprevir and letermovir, as taking these drugs together may result in elevated concentrations of both drugs. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs must be used together, closely monitor for adverse events, including tachycardia, atrial fibrillation, and gastrointestinal events. Simeprevir is a substrate and inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and is primarily metabolized by CYP3A4. Letermovir is a substrate and inhibitor of OATP1B1/3, and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In addition, cyclosporine is an OATP1B1 inhibitor, which could further amplify this interaction.
Lidocaine: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of lidocaine, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of lidocaine, such as CNS and cardiovascular effects.
Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with simeprevir, a mild CYP3A4 and P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with simeprevir, a mild CYP3A4 and P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
Lopinavir; Ritonavir: (Major) Avoid concurrent use of simeprevir and lopinavir; ritonavir. Inhibition of CYP3A4, organic anion transporting polypeptide (OATP1B1), and P-glycoprotein (P-gp) by lopinavir; ritonavir may increase the plasma concentrations of simeprevir, resulting in adverse effects. (Major) Avoid concurrent use of simeprevir and ritonavir. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by ritonavir causes significantly increased plasma concentrations of simeprevir, potentially resulting in adverse effects.
Lorlatinib: (Major) Coadministration of simeprevir with lorlatinib is not recommended as there is a potential for decreased simeprevir concentrations which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Simeprevir is metabolized by CYP3A4 and lorlatinib is a moderate CYP3A4 inducer.
Lovastatin: (Moderate) Although coadministration of lovastatin with simeprevir has not been studied, use of these drugs together is expected to increase lovastatin exposure. If these drugs are given together, titrate the lovastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Lovastatin; Niacin: (Moderate) Although coadministration of lovastatin with simeprevir has not been studied, use of these drugs together is expected to increase lovastatin exposure. If these drugs are given together, titrate the lovastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor is expected to alter the systemic exposure of simeprevir; concurrent use is not recommended as it may result in treatment failure. In vitro studies indicate simeprevir is a primary substrate and mild inhibitor of CYP3A and a substrate of the P-glycoprotein (P-gp) efflux transporter. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of simeprevir metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
Lurasidone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of lurasidone, which is a CYP3A4 substrate. Monitor patients for adverse effects of lurasidone, such as dizziness, drowsiness, othorstatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures.
Maraviroc: (Moderate) Use caution and closely monitor for increased adverse effects during concurrent administration of maraviroc and simprevir as increased maraviroc concentrations may occur. Maraviroc is a substrate of CYP3A, P-glycoprotein (P-gp), and organic anion-transporting polypeptide (OATP1B). Simeprevir is a CYP3A4, P-gp, and OATP1B1 inhibitor. Monitor for an increase in adverse effects with concomitant use.
Mefloquine: (Moderate) Use caution with concurrent use of simeprevir and mefloquine as increased plasma concentrations of both drugs may occur. Mefloquine is a substrate of CYP3A4 and P-glycloprotein (P-gp) as well as an inhibitor of P-gp, while simeprevir is a mild intestinal CYP3A4 inhibitor and a substrate of P-gp in vitro. Montior for adverse effects, such as rash, estrapyramidal symptoms, and QT prolongation.
Metformin; Repaglinide: (Moderate) Simeprevir, an inhibitor of OATP1B1/3 and a mild intestinal CYP3A4 inhibitor, may increase the side effects of repaglinide, which is a OATP1B1 and CYP3A4 substrate. Monitor patients for adverse effects of repaglinide, such as hypoglycemia.
Methadone: (Moderate) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of methadone, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of methadone, such as CNS and respiratory depression.
Methotrexate: (Minor) Systemic exposure of methotrexate, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with simeprevir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of methotrexate; monitor patients for potential adverse effects.
Mexiletine: (Moderate) Coadministration of mexiletine with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in mexiletine plasma concentrations. If these drugs are administered together, monitoring of mexiletine plasma concentrations (if available) is recommended.
Midazolam: (Moderate) Coadministration of orally administered midazolam with simeprevir, an intestinal CYP3A4 inhibitor, results in increased midazolam plasma concentrations. Caution is advised if these drugs are administered concurrently.
Mifepristone: (Moderate) Use caution when using mifepristone chronically with simeprevir. Mifepristone may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash, abdominal pain, diarrhea, or headache. Mifepristone is an inhibitor of CYP3A4 and may also inhibit P-glycoprotein (P-gp). When mifepristone is used chronically for hormonal conditions, such as Cushing's syndrome, drug interactions are likely with CYP3A substrates. Simeprevir is primarily metabolized by CYP3A4. Due to the slow elimination of mifepristone from the body, any interaction that occurs may be observed for a prolonged period after mifepristone administration.
Milk Thistle, Silybum marianum: (Major) Avoid concurrent use of simeprevir and milk thistle, Silybum marianum. Inhibition of CYP3A4 by milk thistle may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Mitotane: (Major) Concomitant use of mitotane with simeprevir is not recommended as it could result in decreased plasma concentrations of simeprevir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and simeprevir is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of simeprevir. When coadministered with another strong CYP3A4 inducer (rifampin 600 mg daily; n = 18), the ratio of simeprevir pharmacokinetic parameters was significantly affected as follows (where 1 = no change): Cmax, 1.31 (90% CI, 1.03 to 1.66), AUC, 0.52 (90% CI, 0.41 to 0.67), and Cmin, 0.08 (90% CI, 0.06 to 0.11).
Mitoxantrone: (Moderate) Use mitoxantrone and simeprevir together with caution; increased systemic exposure of mitoxantrone may occur resulting in increased mitoxantrone adverse effects. If these drugs are taken together, monitor patients for signs of mitoxantrone adverse effects. Mitoxantrone is a substrate of the breast cancer resistance protein (BCRP) drug transporter and simeprevir may inhibit BCRP.
Modafinil: (Major) Avoid concurrent use of simeprevir and modafinil. Induction of CYP3A4 by modafinil may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of modafinil, which is a CYP3A4 substrate. Monitor patients for adverse effects of modafinil, such as CNS effects.
Morphine: (Moderate) Concomitant use of simeprevir and morphine may result in increased morphine plasma concentrations and side effects. Morphine is metabolized by P-glycoprotein (P-gp) and simeprevir inhibits P-gp. Monitor patients for adverse events such as CNS and respiratory depression.
Morphine; Naltrexone: (Moderate) Concomitant use of simeprevir and morphine may result in increased morphine plasma concentrations and side effects. Morphine is metabolized by P-glycoprotein (P-gp) and simeprevir inhibits P-gp. Monitor patients for adverse events such as CNS and respiratory depression.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with simeprevir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; simeprevir is a moderate P-gp inhibitor.
Nebivolol; Valsartan: (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
Nefazodone: (Major) Avoid concurrent use of simeprevir and nefazodone. Inhibition of CYP3A4 by nefazodone may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of nefazodone, a CYP3A4 substrate.
Nelfinavir: (Major) Avoid concurrent use of simeprevir and nelfinavir. Inhibition of CYP3A4 by nelfinavir may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Neratinib: (Moderate) Monitor for an increase in simeprevir-related adverse reactions if coadministration with neratinib is necessary. Simeprevir is a P-glycoprotein (P-gp) substrate. Neratinib may inhibit the transport of P-gp substrates.
Nevirapine: (Major) Avoid concurrent use of simeprevir and nevirapine. Induction of CYP3A4 by nevirapine may reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Niacin; Simvastatin: (Moderate) Coadministration of simvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased simvastatin plasma concentrations. If these drugs are given together, titrate the simvastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Nicardipine: (Moderate) Caution and clinical monitoring are recommended if nicardipine is coadministered with simeprevir due to the potential for increased nicardipine exposure.
Nifedipine: (Moderate) Coadministration of nifedipine with simeprevir, an inhibitor of intestinal CYP3A4, may result in increased nifedipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Nimodipine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of nimodipine, which is a CYP3A4 substrate. Monitor patients for adverse effects of nimodipine, such as hypotension.
Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as simeprevir, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary.Simeprevir is a mild inhibitor of both CYP3A4 and P-gp; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with simeprevir due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and simeprevir is a weak CYP3A4 inhibitor.
Obeticholic Acid: (Minor) Obeticholic acid may increase the exposure to simeprevir. Simeprevir is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if these drugs are used together.
Octreotide: (Major) Avoid concurrent use of simeprevir and octreotide. Octreotide suppresses growth hormone secretion, which may cause a decrease in the metabolic clearance of drugs metabolized by CYP3A4 which may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Olanzapine: (Minor) Simeprevir is an inhibitor of CYP1A2, which may result in decreased clearance of olanzapine. Decreased metabolism of olanzapine may lead to clinically important adverse reactions such as extrapyramidal symptoms, sedation, or orthostatic hypotension. In addition, olanzapine is associated with a possible risk for QT prolongation and TdP and should be used cautiously with CYP1A2 inhibitors.
Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concurrent use of simeprevir and ritonavir. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by ritonavir causes significantly increased plasma concentrations of simeprevir, potentially resulting in adverse effects. (Major) Avoid the coadministration of simeprevir and dasabuvir; ombitasvir; paritaprevir; ritonavir. The FDA-approved labeling for simeprevir, a CYP3A4 substrate, states that coadministration with strong CYP3A4 inhibitors, including ritonavir, is not recommended as significant increases in simeprevir could result. Additional metabolic interactions are expected which would lead to elevated plasma concentrations of simeprevir, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Simeprevir is a P-glycoprotein (P-gp) substrate/inhibitor, ritonavir is a P-gp substrate/inhibitor, and dasabuvir, ombitasvir, and paritaprevir are P-gp substrates. Simeprevir and paritaprevir are both OATP1B1/3 substrate/inhibitors. Finally, simeprevir is a mild CYP3A4 inhibitor and dasabuvir, paritaprevir, and ritonavir are CYP3A4 substrates. (Major) Avoid the coadministration of simeprevir and dasabuvir; ombitasvir; paritaprevir; ritonavir. The FDA-approved labeling for simeprevir, a CYP3A4 substrate, states that coadministration with strong CYP3A4 inhibitors, including ritonavir, is not recommended as significant increases in simeprevir could result. Additional metabolic interactions are expected which would lead to elevated plasma concentrations of simeprevir, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Simeprevir is a P-glycoprotein (P-gp) substrate/inhibitor, ritonavir is a P-gp substrate/inhibitor, dasabuvir, ombitasvir, and paritaprevir are P-gp substrates, and paritaprevir is a P-gp inhibitor. Simeprevir and paritaprevir are both OATP1B1/3 substrate/inhibitors. Finally, simeprevir is a mild CYP3A4 inhibitor and dasabuvir, paritaprevir, and ritonavir are CYP3A4 substrates.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
Oritavancin: (Major) Simeprevir is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of simeprevir may be reduced if these drugs are administered concurrently. Caution is warranted with the concomitant oritavancin and simeprevir. The effects of oritavancin on simeprevir have not been determined; however, the manufacturer warns that coadministration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir and lead to loss of efficacy, which may result in treatment failure.
Osimertinib: (Moderate) Monitor for an increase in simeprevir-related adverse reactions if coadministration with osimertinib is necessary. Simeprevir is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use may increase simeprevir exposure.
Oxcarbazepine: (Major) Avoid concurrent use of simeprevir and oxcarbazepine. Induction of CYP3A4 by oxcarbazepine may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Oxybutynin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of oxybutynin, which is a CYP3A4 substrate. Monitor patients for adverse effects of oxybutynin, such as CNS and anticholinergic effects.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of simeprevir is necessary. If simeprevir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like simeprevir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If simeprevir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Paclitaxel: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of paclitaxel, which is a CYP3A4 substrate. Monitor patients for adverse effects of paclitaxel, such as myelosuppression, myalgia/arthralgia, and peripheral neuropathy.
Paricalcitol: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of paricalcitol, which is a CYP3A4 substrate. Monitor patients for adverse effects of paricalcitol, such as nausea and vomiting. Plasma PTH and serum calcium and phosphorous concentrations should be closely monitored.
Pazopanib: (Moderate) Concurrent administration of simeprevir, a CYP3A4 substrate, with pazopanib, a moderate CYP3A4 inhibitor, may increase simeprevir serum concentrations. In addition, the therapeutic effects of pazopanib, a substrate for CYP3A4, P-glycoprotein (P-gp), and the breast cancer resistant protein (BCRP), may be increased by simeprevir, a P-gp, BCRP, and a mild intestinal CYP3A4 inhibitor. If these drugs are administered together, monitor patients for adverse effects,.
Perampanel: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of perampanel, which is a CYP3A4 substrate. Monitor patients for adverse effects of perampanel, such as CNS and psychiatric events.
Perindopril; Amlodipine: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Perphenazine; Amitriptyline: (Moderate) Simeprevir, a mild CY1A2 inhibitor and mild intestinal CYP3A4 inhibitor, may increase the side effects of amitriptyline, which is a CYP3A4 and CYP1A2 substrate. Monitor patients for adverse effects of amitriptyline, such as anticholinergic activity, orthostatic hypotension, and sedation.
Phenobarbital: (Major) Avoid concurrent use of simeprevir and phenobarbital as induction of CYP3A4 by phenobarbital may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Phentermine; Topiramate: (Major) Avoid concurrent use of simeprevir and topiramate. Induction of CYP3A4 by topiramate may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Phenytoin: (Major) Avoid concurrent use of simeprevir and phenytoin. Induction of CYP3A4 by phenytoin may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Pimozide: (Major) Simeprevir, a mild CYP1A2 and a mild intestinal CYP3A4 inhibitor, may increase the side effects of pimozide, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of pimozide, such as QT prolongation and CNS effects.
Pitavastatin: (Moderate) Although coadministration of pitavastatin with simeprevir has not been studied, use of these drugs together is expected to increase pitavastatin exposure. If these drugs are given together, titrate the pitavastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Porfimer: (Major) Avoid coadministration of porfimer with simeprevir due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like simeprevir may increase the risk of a photosensitivity reaction.
Posaconazole: (Major) Avoid concurrent use of simeprevir and posaconazole. Inhibition of CYP3A4 by posaconazole may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects.
Pravastatin: (Moderate) Although coadministration of pravastatin with simeprevir has not been studied, use of these drugs together is expected to increase pravastatin exposure. If these drugs are given together, titrate the pravastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Prednisolone: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of prednisolone, which is a CYP3A4 substrate. Monitor patients for adverse effects of prednisolone, such as enhanced adrenal suppression.
Prednisone: (Minor) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of prednisone, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of prednisone, such as enhanced adrenal suppression.
Primidone: (Major) Avoid concurrent use of simeprevir and primidone as induction of CYP3A4 by phenobarbital (active metabolite) may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Propafenone: (Moderate) Coadministration of propafenone with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in propafenone plasma concentrations. If these drugs are administered together, monitoring of propafenone plasma concentrations (if available) is recommended.
Quazepam: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of quazepam, which is a CYP3A4 substrate. Monitor patients for adverse effects of quazepam, such as CNS and respiratory depression.
Quetiapine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of quetiapine, which is a CYP3A4 substrate. Monitor patients for adverse effects of quetiapine, such as QT prolongation and GI effects.
Quinidine: (Moderate) Use of orally administered quinidine with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in quinidine plasma concentrations. If these drugs are administered together, monitoring of quinidine plasma concentrations (if available) is recommended.
Quinine: (Major) Interactions between simeprevir and quinine are complicated and coadministration should be avoided. Simeprevir concentrations may be altered as it is a substrate of CYP3A4, while quinine is an inhibitor and an inducer of CYP3A4. Additionally, quinine concentrations may be increased due to inhibition of CYP1A2 and P-glycoprotein (P-gp) as well as mild intestinal CYP3A4 inhibition by simeprevir.
Ramelteon: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of ramelteon, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of ramelteon, such as CNS effects.
Ranolazine: (Major) Avoid concurrent use of simeprevir and ranolazine. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by ranolazine may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a P-gp inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of ranolazine, a P-gp and CYP3A4 substrate.
Rasagiline: (Moderate) Monitor for dopaminergic adverse effects during concurrent use of rasagiline and simeprevir. Coadministration may result in increased rasagiline concentrations. A dose reduction of rasagiline may be necessary. Rasagiline is primarily metabolized by CYP1A2; simeprevir is a weak CYP1A2 inhibitor. When administered with a strong CYP1A2 inhibitor, the AUC of rasagiline was increased by 83%.
Repaglinide: (Moderate) Simeprevir, an inhibitor of OATP1B1/3 and a mild intestinal CYP3A4 inhibitor, may increase the side effects of repaglinide, which is a OATP1B1 and CYP3A4 substrate. Monitor patients for adverse effects of repaglinide, such as hypoglycemia.
Revefenacin: (Major) Coadministration of revefenacin is not recommended with simeprevir because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects.The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; simeprevir is an inhibitor of OATP1B1 and OATP1B3.
Ribociclib: (Major) Coadministration of simeprevir with ribociclib is not recommended due to increased plasma concentrations of simeprevir which increase the risk for treatment-related adverse reactions. Simeprevir is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
Ribociclib; Letrozole: (Major) Coadministration of simeprevir with ribociclib is not recommended due to increased plasma concentrations of simeprevir which increase the risk for treatment-related adverse reactions. Simeprevir is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
Rifabutin: (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
Rifampin: (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
Rifamycins: (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
Rifapentine: (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) and organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with simeprevir, a P-gp and OATP inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp and OATP inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
Ritonavir: (Major) Avoid concurrent use of simeprevir and ritonavir. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by ritonavir causes significantly increased plasma concentrations of simeprevir, potentially resulting in adverse effects.
Rivaroxaban: (Minor) Coadministration of rivaroxaban and simeprevir may result in increases in rivaroxaban exposure and may increase bleeding risk. Simeprevir is a mild inhibitor of P-glycoprotein (P-gp), and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Ropinirole: (Moderate) Simeprevir mildly inhibits CYP1A2, which can potentially lead to increased plasma concentrations of ropinirole. If these drugs are coadministered, adjustment of ropinirole dose may be required.
Ropivacaine: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of ropivacaine, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of ropivacaine, such as hypotension, CNS toxicity, and respiratory depression.
Rosuvastatin: (Moderate) Coadministration of rosuvastatin with simeprevir, an inhibitor of the breast cancer resistance protein (BCRP) and OATP1B1 transporters, results in increased rosuvastatin plasma concentrations. If these drugs are given together, initiate rosuvastatin therapy at 5 mg once daily; do not exceed 10 mg once daily. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Sacubitril; Valsartan: (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and simeprevir as coadministration may result in increased systemic exposure of simeprevir. Simeprevir is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of simeprevir.
Saquinavir: (Major) Avoid concurrent use of simeprevir and saquinavir. Inhibition of CYP3A4 by saquinavir may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Sertraline: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of sertraline, which is a CYP3A4 substrate. Monitor patients for adverse effects of sertraline, such as QT prolongation and CNS and GI effects.
Sibutramine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of sibutramine, which is a CYP3A4 substrate. Although the maginitude of interaction may be small, monitor patients for adverse effects.
Sildenafil: (Moderate) Coadministration of sildenafil with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in sildenafil plasma concentrations. No dose adjustments are required when treating erectile dysfunction. If treating pulmonary arterial hypertension, start at the lowest sildenafil dose and increase as needed while monitoring clinically.
Silodosin: (Moderate) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of silodosin, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of silodosin, such as dizziness and hypotension.
Simvastatin: (Moderate) Coadministration of simvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased simvastatin plasma concentrations. If these drugs are given together, titrate the simvastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Simvastatin; Sitagliptin: (Moderate) Coadministration of simvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased simvastatin plasma concentrations. If these drugs are given together, titrate the simvastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Sirolimus: (Moderate) Caution is advised when administering simeprevir with sirolimus, as concurrent use may result in altered sirolimus plasma concentrations. Although no dose adjustments are recommended, routine monitoring of sirolimus plasma concentrations is advised.
Sofosbuvir: (Major) Avoid coadministration of sofosbuvir with simeprevir, a P-glycoprotein (P-gp) inhibitor. Taking these drugs together may increase sofosbuvir plasma concentrations, potentially resulting in adverse effects.
Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of sofosbuvir with simeprevir, a P-glycoprotein (P-gp) inhibitor. Taking these drugs together may increase sofosbuvir plasma concentrations, potentially resulting in adverse effects. (Moderate) Use caution when administering velpatasvir with simeprevir. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). Simeprevir also inhibits the Breast Cancer Resistance Protein (BCRP); while velpatasvir is a BCRP substrate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of sofosbuvir with simeprevir, a P-glycoprotein (P-gp) inhibitor. Taking these drugs together may increase sofosbuvir plasma concentrations, potentially resulting in adverse effects. (Moderate) Use caution when administering velpatasvir with simeprevir. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). Simeprevir also inhibits the Breast Cancer Resistance Protein (BCRP); while velpatasvir is a BCRP substrate.
Solifenacin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of solifenacin, which is a CYP3A4 substrate. Monitor patients for adverse effects of solifenacin, such as antimuscarinic effects.
Sorafenib: (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.
St. John's Wort, Hypericum perforatum: (Major) Avoid concurrent use of simeprevir and St. John's Wort, Hypericum perforatum. Induction of CYP3A4 by St. John's Wort may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if simeprevir must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of simeprevir is necessary. If simeprevir is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like simeprevir can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If simeprevir is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulfasalazine: (Moderate) Systemic exposure of sulfasalazine, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with simeprevir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of sulfasalazine; monitor patients for potential adverse effects.
Tadalafil: (Moderate) Coadministration of tadalafil with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in tadalafil plasma concentrations. No dose adjustments are required when treating erectile dysfunction. If treating pulmonary arterial hypertension, start at the lowest tadalafil dose and increase as needed while monitoring clinically.
Tamsulosin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tamsulosin, which is a CYP3A4 substrate. Monitor patients for adverse effects of tamsulosin, such as hypotension, dizziness, syncope, and vertigo.
Telithromycin: (Major) Avoid concurrent use of simeprevir and telithromycin. Inhibition of CYP3A4 by telithromycin may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and simeprevir is necessary, as the systemic exposure of simeprevir may be decreased resulting in reduced efficacy and viral resistance; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of simeprevir as well as an increase in adverse reactions related to telotristat ethyl. Simeprevir is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and simeprevir is a weak P-gp inhibitor. Exposure to telotristat ethyl may increase.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus- and simeprevir-related adverse reactions if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of both temsirolimus and simeprevir.
Teniposide: (Moderate) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of teniposide, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of teniposide, such as bone marrow suppression and GI effects.
Tenofovir Alafenamide: (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir alafenamide. Tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Tenofovir, PMPA: (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir, PMPA. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP.
Teriflunomide: (Minor) Use caution with concurrent use of simeprevir and teriflunomide. Teriflunomide is an inhibitor of OAT1B1, which may increase the plasma concentrations of simeprevir, a substrate of OATP1B1/3 in vitro, resulting in adverse effects, such as rash.
Theophylline, Aminophylline: (Moderate) Theophylline, aminophylline is primarily metabolized by CYP1A2 isoenzymes. Since the therapeutic range is narrow for theophylline, it is prudent to monitor theophylline serum concentrations upon initiation, dosage adjustment, or discontinuation of medications that may alter the function of CYP1A2, such as simeprevir, which is a mild CYP1A2 inhibitor.
Thiabendazole: (Moderate) Concomitant use of simeprevir and thiabendazole may result in increased thiabendazole plasma concentrations and side effects. Thiabendazole is primarily metabolized by CYP1A2 and simeprevir is a mild CYP1A2 inhibitor. Monitor patients for adverse events such as anorexia, nausea, vomiting, drowsiness, and dizziness.
Tiagabine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tiagabine, which is a CYP3A4 substrate. Monitor patients for adverse effects of tiagabine, such as CNS effects.
Ticagrelor: (Minor) Coadministration of ticagrelor and simeprevir may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and simeprevir is a mild P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
Tinidazole: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tinidazole, which is a CYP3A4 substrate. Monitor patients for adverse effects of tinidazole, such as GI effects.
Tipranavir: (Major) Avoid concurrent use of simeprevir and tipranavir. Inhibition of CYP3A4 by tipranavir may increase the plasma concentrations of simeprevir, resulting in adverse effects.
Tizanidine: (Moderate) Tizanidine is primarily metabolized by CYP1A2. Tizanidine clearance may be reduced by coadministration of mild inhibitors of CYP1A2, such as simeprevir. Increased tizanidine concentrations may lead to oversedation, significant hypotension, potential liver problems, and other events.
Tolterodine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tolterodine, which is a CYP3A4 substrate.Tolterodine is metabolized primarily by CYP2D6 and, alternatively, CYP3A4 in those patients who are poor CYP2D6 metabolizers; however, it is difficult to assess which patients will be poor CYP2D6 metabolizers. Monitor patients for adverse effects of tolterodine, such as QT prolongation which is dose-dependent, especially in poor CYP2D6 metabolizers.
Topiramate: (Major) Avoid concurrent use of simeprevir and topiramate. Induction of CYP3A4 by topiramate may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
Topotecan: (Major) Avoid coadministration of simeprevir with oral topotecan due to increased topotecan exposure; simeprevir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); simeprevir is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
Tramadol: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tramadol, which is partially metabolized by CYP3A4. Monitor patients for adverse effects of tramadol, such as seizures and serotonin syndrome.
Trandolapril; Verapamil: (Moderate) Coadministration of orally administered verapamil with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased verapamil plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Trazodone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of trazodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of trazodone, such as QT prolongation and drowsiness/sedation.
Triamterene: (Minor) Concomitant use of simeprevir and triamterene may result in increased triamterene plasma concentrations and side effects. Triamterene is metabolized by CYP1A2 and simeprevir is a mild CYP1A2 inhibitor. Monitor patients for adverse events such as hyperkalemia.
Triazolam: (Moderate) Coadministration of orally administered triazolam with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in triazolam plasma concentrations. Caution is advised if these drugs are administered concurrently.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with simeprevir. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4, BCRP, and P-gp substrate; simeprevir is a weak CYP3A4 inhibitor and a BCRP and P-gp inhibitor.
Valsartan: (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
Vemurafenib: (Major) Avoid concurrent use of simeprevir and vemurafenib as the interaction is complex. Induction of CYP3A4 by vemurafenib may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. However, vemurafenib is also a P-glycoprotein (P-gp) inhbitor, while simeprevir is P-gp substrate in vitro. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor and P-gp inhibitor, may increase the side effects of vemurafenib, which is a CYP3A4 and P-gp substrate. Monitor patients for adverse effects of vemurafenib, such as QT 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 simeprevir due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of simeprevir. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; simeprevir is a CYP3A4 (weak) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Verapamil: (Moderate) Coadministration of orally administered verapamil with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased verapamil plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with simeprevir is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like simeprevir may increase the risk of a photosensitivity reaction.
Vinblastine: (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of vinblastine, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of vinblastine, such as myelosupression.
Vincristine Liposomal: (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of vincristine, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of vincristine, such as myelosuppression and neurotoxicity.
Vincristine: (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of vincristine, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of vincristine, such as myelosuppression and neurotoxicity.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with simeprevir is necessary. Vinorelbine is a CYP3A4 substrate and simeprevir is a weak CYP3A4 inhibitor.
Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and simeprevir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with simeprevir, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
Voriconazole: (Major) Coadministration of simeprevir with voriconazole is not recommended due to increased plasma concentrations of simeprevir which increase the risk for treatment-related adverse reactions. Simeprevir is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
Warfarin: (Moderate) Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections, including simeprevir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.
Zafirlukast: (Moderate) Use caution with concurrent use of simeprevir and zafirlukast. Zafirlukast is a minor inhibitor of CYP3A4 which may increase the plasma concentrations of simeprevir, resulting in adverse effects. The FDA-labeling recommends avoiding moderate and strong CYP3A4 inhibitors.
Ziprasidone: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of ziprasidone, which is a CYP3A4 substrate. Monitor patients for adverse effects of ziprasidone, such as QT prolongation, CNS effects, and extrapyramidal symptoms.
Zolpidem: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of zolpidem, which is a CYP3A4 substrate. Monitor patients for adverse effects of zolpidem.
Zonisamide: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of zonisamide, which is a CYP3A4 substrate. Monitor patients for adverse effects of zonisamide.

How Supplied

Olysio Oral Cap: 150mg

Maximum Dosage
Adults

150 mg/day PO.

Geriatric

150 mg/day PO.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Mechanism Of Action

Simeprevir prevents hepatitis C viral (HCV) replication by blocking the proteolytic activity of HCV NS3/4A protease. Hepatitis C virus NS3/4A protease is an enzyme responsible for the conversion of HCV encoded polyproteins to mature and functioning viral proteins. These mature proteins, NS4A, NS4B, NS5A, and NS5B, are essential for viral replication.
Hepatitis C viral resistance to simeprevir has been demonstrated in both cell cultures and during clinical studies. An evaluation of cell cultures found viruses containing amino acid substitutions in the NS3 domain display reduced susceptibility to simeprevir. In HCV genotype 1 infected patients treated with simeprevir, peginterferon, ribavirin who did not achieve sustained viral response during clinical trials, 91% (n = 180 of 197) were found to have emerging amino acid substitutions at NS3 positions (Q80, S122, R155K, D168V). Similarly, NS3 substitutions at Q80, T122, R155, A156, D168 were identified in 88% (n = 30 of 34) of patients with HCV genotype 4 who did not achieve SVR. For those receiving simeprevir in combination with sofosbuvir for treatment of HCV genotype 1, the majority of patients that did not achieve sustained viral response had emerging NS3 amino acid substitutions at position 168 or R155k. Cross-resistance is expected among NS3/4A protease inhibitors (i.e., boceprevir, grazoprevir). No cross-resistance is expected between direct-acting antiviral agents with different mechanisms of action (i.e., NS5A inhibitors, NS5B nucleoside, and non-nucleoside polymerase inhibitors).

Pharmacokinetics

Simeprevir is administered orally. Following administration, more than 99.9% of the systemically absorbed drug is bound to plasma protein, primarily albumin and, to a smaller degree, alpha 1-acid glycoprotein. It distributes into the gut and liver, with hepatic uptake occurring via the OATP1B1/3 transporter. Once in the liver, simeprevir undergoes oxidative metabolism by CYP3A; involvement of CYP2C8 and CYP2C19 has not been fully excluded. Biliary excretion is the primary elimination route, with 91% of the total dose recovered in the feces; 31% as unchanged drug. Renal clearance is negligible with less than 1% of the dose recovered in the urine. The terminal elimination half-life is 10 to 13 hours in HCV-uninfected patients and 41 hours in HCV-infected patients.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP3A4, P-glycoprotein (P-gp)/MDR1, OATP1B1/3, OATP2B1, BCRP, MRP2, NTCP, BSEP
Simeprevir is a primarily metabolized by the CYP3A isoenzyme and is a mild inhibitor of intestinal CYP3A4 and CYP1A2; it does not affect hepatic CYP3A4 activity. According to the FDA labeling, coadministration with moderate and strong CYP3A4 inducers or inhibitors is not recommended as this may lead to significantly lower or higher simeprevir exposure, respectively. Additionally, concurrent administration with drugs that are primarily metabolized by CYP3A4 may cause the plasma concentrations of the coadministered drugs to be increased. In vitro studies show simeprevir to be a substrate for the drug transporters P-gp, MRP2, BCRP, OATP1B1/3, and OATP2B1. In addition, simeprevir inhibits the drug uptake transporters OATP1B1/3 and NTCP, and the drug efflux transporters P-gp/MDR1, MRP2, BRCP, and BSEP. Simeprevir does not induce CYP1A2 or CYP3A4, nor does it affect CYP2C9, CYP2C19, CYP2D6, or cathepsin A enzyme activity. Simeprevir does not inhibit OCT2.

Oral Route

The mean absolute oral bioavailability of a single simeprevir dose under fed conditions is 62%. Following oral administration, the time to reach maximum plasma concentrations is 4 to 6 hour (Tmax) with steady state simeprevir concentrations achieved after 7 daily doses. Accumulation occurs after repeated dosing, and exposure (AUC) in HCV-infected patients are 2- to 3-fold higher than uninfected subjects. Administration with a high-fat, high-caloric meal (928 kcal) and a normal-caloric meal (533 kcal) increases the relative bioavailability by 61% and 69%, respectively, and delays absorption by 1 hour and 1.5 hours, respectively.

Pregnancy And Lactation
Pregnancy

There are no well controlled studies evaluating the use of simeprevir in pregnant women; however, when the drug is administered in combination with peginterferon alfa and ribavirin, use of simeprevir is contraindicated in pregnant women and in the male partners of women who are pregnant. Use of ribavirin may cause birth defects or death of the exposed fetus. Ribavirin therapy also may cause male-mediated teratogenicity and is contraindicated for use during pregnancy, in females who may become pregnant, or in men whose female partners are pregnant. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all of the animal species tested. Use of peginterferon alfa has produced abortifacient effects in animals, and thus, the potential for abortifacient effects in humans must be considered. Health care providers must also consider the potential for decreased efficacy of systemic hormonal contraception as interferon therapy may decrease serum estradiol and progesterone concentrations. Patients and their partners are required use 2 reliable forms of effective contraception (e.g., intrauterine devices, barrier methods) during treatment and for 6 months post-therapy. Patients who are not willing to practice strict contraception should not receive treatment with simeprevir, peginterferon alfa, and ribavirin. Females must also undergo a pregnancy test prior to initiation of therapy, monthly during therapy, and for 6 months post-therapy. To monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214.