Harvoni

NS5A Protein Inhibitor Antivirals in Combination with NS5B RNA Polymerase Inhibitor Antivirals for Hepatitis C

Oral Administration

May be administered with or without food.

Oral Solid Formulations

Oral pellets
Inspect the packaging for damage. Do not use if the carton tamper-evident seal or the pellet packet seal is broken or damaged.
Do not open packets until ready for use; shake the pellets packet gently to settle the pellets.
If pellets are taken with food:
Add 1 or more spoonfuls of non-acidic soft food (i.e., pudding, chocolate syrup, mashed potato, ice cream) to a bowl at or below room temperature.
Sprinkle the entire contents of the prescribed number of pellet packets onto the food in the bowl.
Gently mix with a spoon.
Ingest pellets within 30 minutes of mixing with food and swallow entire contents without chewing to avoid a bitter taste. Do not store any leftover oral pellets mixed with food for use at a later time.
If pellets are taken without food:
Pour the entire contents of the pellet packet directly in the mouth and swallow without chewing to avoid a bitter taste.
If needed, water may be taken after swallowing the pellets.
Repeat the process if more than 1 pellet packet is prescribed.
Discard any unused portion.

Severe

suicidal ideation / Delayed / 0-1.0
angioedema / Rapid / Incidence not known
hepatic failure / Delayed / Incidence not known
hepatitis B exacerbation / Delayed / Incidence not known

Moderate

dyspnea / Early / 3.0-9.0
depression / Delayed / 0-5.0
hyperbilirubinemia / Delayed / 0-3.0

Mild

asthenia / Delayed / 18.0-36.0
headache / Early / 4.0-29.0
fatigue / Early / 4.0-18.0
cough / Delayed / 5.0-11.0
nausea / Early / 6.0-9.0
myalgia / Early / 4.0-9.0
irritability / Delayed / 7.0-8.0
diarrhea / Early / 3.0-7.0
insomnia / Early / 3.0-6.0
dizziness / Early / 1.0-5.0
rash / Early / Incidence not known

Hepatitis B exacerbation

Use of direct-acting antivirals (DAA), such as ledipasvir and sofosbuvir, to treat hepatitis C virus (HCV) infection in patients currently or previously infected with hepatitis B virus (HBV) has been associated with reactivation and hepatitis B exacerbation. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. 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. HBV reactivation is characterized as an abrupt increase in viral replication manifesting as a rapid increase in serum HBV DNA concentration. In patients with resolved HBV infection, the reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis (i.e., increases in aminotransferase concentrations) and, in severe cases, increases in bilirubin concentrations, liver failure, and death can occur. To decrease the risk of reactivating an HBV infection, screen all potential drug recipients for evidence of current or prior HBV infection by measuring the 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 ledipasvir; sofosbuvir. 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 ledipasvir; sofosbuvir recipient develops signs of HBV reactivation, initiate appropriate treatment for HBV infection as clinically indicated.

Harvoni

Rx

Combination antiviral containing a hepatitis C virus (HCV) NS5A protein inhibitor and a nucleotide analog HCV NS5B polymerase inhibitor
Used to treat chronic HCV genotype 1, 4, 5, and 6 infections in adults and pediatric patients 3 years and older
Black Box Warning regarding reactivation of hepatitis B virus (HBV) infection in HCV/HBV coinfected patients; screen all patients for HBV before initiating treatment

For the treatment of chronic hepatitis C infection. For the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. Oral dosage Treatment-naive Adults without cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily. The recommended duration of therapy is 12 weeks; however, an 8-week treatment course can be considered for those patients with a baseline hepatitis C virus RNA less than 6 million International Units/mL.[58167] There are limited data regarding a shortened 8-week course in patients coinfected with HIV; therefore, guidelines recommend these patients receive treatment for the entire 12 weeks.

Treatment-naive Adults with compensated (Child-Pugh A) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.[58167]

Treatment-experienced Adults without cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.[58167]

Treatment-experienced Adults with compensated (Child-Pugh A) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily. The recommended duration of treatment is 24 weeks. Alternatively, treatment duration may be reduced to 12 weeks if ledipasvir; sofosbuvir is administered in combination with ribavirin. Ribavirin must be administered with food in 2 divided doses, and the dose is based on weight as follows: less than 75 kg give 500 mg PO twice daily; 75 kg or more give 600 mg PO twice daily. Recommendation includes patients coinfected with HIV.[58167]

Adults with decompensated (Child-Pugh B or C) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily with ribavirin (600 mg PO once daily) for 12 weeks. Ribavirin must be administered with food, and if tolerated, the dose may be increased as follows: if less than 75 kg give 500 mg PO twice daily; if 75 kg or more give 600 mg PO twice daily. Consider decreasing ribavirin dose for abnormal hemoglobin. Recommendation includes patients coinfected with HIV. For patients unable to take ribavirin, guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily for 24 weeks. Recommendation includes patients who may or may not be candidates for liver transplant, including those with hepatocellular carcinoma.

Adults with decompensated (Child-Pugh B or C) cirrhosis in whom prior sofosbuvir-based treatment failed†

Guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily with ribavirin (600 mg PO once daily) for 24 weeks. If tolerated, the ribavirin dose may be increased based on weight. Recommendation includes patients who may or may not be candidates for liver transplant, including those with hepatocellular carcinoma.

Adults who have undergone liver transplantation and are without cirrhosis or have compensated (Child-Pugh A) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily with ribavirin for 12 weeks. Ribavirin must be administered with food in 2 divided doses, and the dose is based on weight as follows: less than 75 kg give 500 mg PO twice daily; 75 kg or more give 600 mg PO twice daily. Recommendation includes patients coinfected with HIV. Guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily for 12 weeks WITHOUT the addition of ribavirin.

Adults who have undergone liver transplantation and have decompensated (Child-Pugh B or C) cirrhosis†

Guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily with ribavirin for 12 weeks (for treatment-naive) or 24 weeks (for treatment experienced). Starting dose of ribavirin is 600 mg daily and increased or decreased as tolerated. Maximum ribavirin dose is 500 mg PO twice daily if less than 75 kg or 600 mg PO twice daily if 75 kg or more.

Treatment-naive Children and Adolescents 3 to 17 years weighing 35 kg or more without cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir once daily. The recommended duration of therapy is 12 weeks; however, an 8-week treatment course can be considered for those patients with a baseline hepatitis C virus RNA less than 6 million International Units/mL.[58167] There are limited data regarding a shortened 8-week course in patients coinfected with HIV; therefore, guidelines recommend these patients receive treatment for the entire 12 weeks.

Treatment-naive Children and Adolescents 3 to 17 years weighing 35 kg or more with compensated (Child-Pugh A) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

Treatment-experienced Children and Adolescents 3 to 17 years weighing 35 kg or more without cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir once daily. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

Treatment-experienced Children and Adolescents 3 to 17 years weighing 35 kg or more with compensated (Child-Pugh A) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily. The recommended duration of treatment is 24 weeks. Alternatively, treatment duration may be reduced to 12 weeks if ledipasvir; sofosbuvir is administered in combination with ribavirin. Recommendation includes patients coinfected with HIV.

Children and Adolescents 3 to 17 years weighing 35 kg or more with decompensated (Child-Pugh B or C) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily with ribavirin for 12 weeks. Recommendation includes patients coinfected with HIV.

Children and Adolescents 3 to 17 years weighing 35 kg or more who have undergone liver transplantation and are without cirrhosis or have compensated (Child-Pugh A) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily with ribavirin for 12 weeks. Recommendation includes patients coinfected with HIV.

Treatment-naive Children and Adolescents 3 to 17 years weighing 17 to 34 kg without cirrhosis

45 mg ledipasvir; 200 mg sofosbuvir PO once daily. The recommended duration of therapy is 12 weeks; however, an 8-week treatment course can be considered for those patients with a baseline hepatitis C virus RNA less than 6 million International Units/mL.[58167] There are limited data regarding a shortened 8-week course in patients coinfected with HIV; therefore, guidelines recommend these patients receive treatment for the entire 12 weeks.

Treatment-naive Children and Adolescents 3 to 17 years weighing 17 to 34 kg with compensated (Child-Pugh A) cirrhosis

45 mg ledipasvir; 200 mg sofosbuvir PO once daily. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

Treatment-experienced Children and Adolescents 3 to 17 years weighing 17 to 34 kg without cirrhosis

45 mg ledipasvir; 200 mg sofosbuvir PO once daily. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.[58167]

Treatment-experienced Children and Adolescents 3 to 17 years weighing 17 to 34 kg with compensated (Child-Pugh A) cirrhosis

45 mg ledipasvir; 200 mg sofosbuvir PO once daily. The recommended duration of treatment is 24 weeks. Alternatively, treatment duration may be reduced to 12 weeks if ledipasvir; sofosbuvir is administered in combination with ribavirin. Recommendation includes patients coinfected with HIV.[58167]

Children and Adolescents 3 to 17 years weighing 17 to 34 kg with decompensated (Child-Pugh B or C) cirrhosis

45 mg ledipasvir; 200 mg sofosbuvir PO once daily with ribavirin for 12 weeks. Recommendation includes patients coinfected with HIV.

Children and Adolescents 3 to 17 years weighing 17 to 34 kg who have undergone liver transplantation and are without cirrhosis or have compensated (Child-Pugh A) cirrhosis

45 mg ledipasvir; 200 mg sofosbuvir PO once daily with ribavirin for 12 weeks. Recommendation includes patients coinfected with HIV.

Treatment-naive Children 3 to 12 years weighing less than 17 kg without cirrhosis

33.75 mg ledipasvir; 150 mg sofosbuvir PO once daily (oral pellets). The recommended duration of therapy is 12 weeks; however, an 8-week treatment course can be considered for those patients with a baseline hepatitis C virus RNA less than 6 million International Units/mL.[58167] There are limited data regarding a shortened 8-week course in patients coinfected with HIV; therefore, guidelines recommend these patients receive treatment for the entire 12 weeks.

Treatment-naive Children 3 to 12 years weighing less than 17 kg with compensated (Child-Pugh A) cirrhosis

33.75 mg ledipasvir; 150 mg sofosbuvir PO once daily (oral pellets). The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.[58167]

Treatment-experienced Children 3 to 12 years weighing less than 17 kg without cirrhosis

33.75 mg ledipasvir; 150 mg sofosbuvir PO once daily (oral pellets). The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.[58167]

Treatment-experienced Children 3 to 12 years weighing less than 17 kg with compensated (Child-Pugh A) cirrhosis

33.75 mg ledipasvir; 150 mg sofosbuvir PO once daily (oral pellets). The recommended duration of treatment is 24 weeks. Alternatively, treatment duration may be reduced to 12 weeks if ledipasvir; sofosbuvir is administered in combination with ribavirin. Recommendation includes patients coinfected with HIV.

Children 3 to 12 years weighing less than 17 kg with decompensated (Child-Pugh B or C) cirrhosis

33.75 mg ledipasvir; 150 mg sofosbuvir PO once daily (oral pellets) with ribavirin for 12 weeks. Recommendation includes patients coinfected with HIV.

Children 3 to 12 years weighing less than 17 kg who have undergone liver transplantation and are without cirrhosis or have compensated (Child-Pugh A) cirrhosis

33.75 mg ledipasvir; 150 mg sofosbuvir PO once daily (oral pellets) with ribavirin for 12 weeks. Recommendation includes patients coinfected with HIV.

For the treatment of chronic hepatitis C virus (HCV) genotypes 5 or 6 infection. Oral dosage Adults without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.[58167] According to guidelines, the drug is not recommended for genotype 6e if subtype is known.

Adults with decompensated (Child-Pugh B or C) cirrhosis†

Guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily with low initial dose of ribavirin (600 mg once daily) for 12 weeks. Increase ribavirin dose as tolerated. For patients unable to take ribavirin, guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily for 24 weeks. Recommendation includes patients who may or may not be candidates for liver transplant, including those with hepatocellular carcinoma.

Adults with decompensated (Child-Pugh B or C) cirrhosis in whom prior sofosbuvir-based treatment failed†

Guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily with ribavirin (600 mg PO once daily) for 24 weeks. If tolerated, the ribavirin dose may be increased based on weight. Recommendation includes patients who may or may not be candidates for liver transplant, including those with hepatocellular carcinoma.

Adults who have undergone liver transplantation and are without cirrhosis or have compensated (Child-Pugh A) cirrhosis†

Guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily for 12 weeks.

Adults who have undergone liver transplantation and have decompensated (Child-Pugh B or C) cirrhosis†

Guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily with ribavirin for 12 weeks (for treatment-naive) or 24 weeks (for treatment experienced). Starting dose of ribavirin is 600 mg daily and increased or decreased as tolerated. Maximum ribavirin dose is 500 mg PO twice daily if less than 75 kg or 600 mg PO twice daily if 75 kg or more.

Children and Adolescents 3 to 17 years weighing 35 kg or more without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.[58167]

Children and Adolescents 3 to 17 years weighing 17 to 34 kg without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

45 mg ledipasvir; 200 mg sofosbuvir PO once daily. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.[58167]

Children 3 to 12 years weighing less than 17 kg without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

33.75 mg ledipasvir; 150 mg sofosbuvir PO once daily (oral pellets). The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.[58167]

For the treatment of chronic hepatitis C virus (HCV) genotype 4 infection. Oral dosage Adults without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.[58167] According to guidelines, an 8-week regimen can be considered in patients with favorable baseline characteristics (i.e., no cirrhosis, HCV RNA less than 6 million International units/mL, and absence of genotype 4r).

Adults with decompensated (Child-Pugh B or C) cirrhosis†

Guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily with low initial dose of ribavirin (600 mg once daily) for 12 weeks. Increase ribavirin dose as tolerated. For patients unable to take ribavirin, guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily for 24 weeks. Recommendation includes patients who may or may not be candidates for liver transplant, including those with hepatocellular carcinoma.

Adults with decompensated (Child-Pugh B or C) cirrhosis in whom prior sofosbuvir-based treatment failed†

Guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily with ribavirin (600 mg PO once daily) for 24 weeks. If tolerated, the ribavirin dose may be increased based on weight. Recommendation includes patients who may or may not be candidates for liver transplant, including those with hepatocellular carcinoma.

Adults who have undergone liver transplantation and are without cirrhosis or have compensated (Child-Pugh A) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily with ribavirin for 12 weeks. Ribavirin must be administered with food in 2 divided doses, and the dose is based on weight as follows: less than 75 kg give 500 mg PO twice daily; 75 kg or more give 600 mg PO twice daily. Recommendation includes patients coinfected with HIV. Guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily for 12 weeks WITHOUT the addition of ribavirin.

Adults who have undergone liver transplantation and have decompensated (Child-Pugh B or C) cirrhosis†

Guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily with ribavirin for 12 weeks (for treatment-naive) or 24 weeks (for treatment experienced). Starting dose of ribavirin is 600 mg daily and increased or decreased as tolerated. Maximum ribavirin dose is 500 mg PO twice daily if less than 75 kg or 600 mg PO twice daily if 75 kg or more.

Children and Adolescents 3 to 17 years weighing 35 kg or more without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.[58167] [63286]

Children and Adolescents 3 to 17 years weighing 35 kg or more who have undergone liver transplantation and are without cirrhosis or have compensated (Child-Pugh A) cirrhosis

90 mg ledipasvir; 400 mg sofosbuvir PO once daily with ribavirin for 12 weeks. Recommendation includes patients coinfected with HIV.[58167]

Children and Adolescents 3 to 17 years weighing 17 to 34 kg without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

45 mg ledipasvir; 200 mg sofosbuvir PO once daily. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.[58167]

Children and Adolescents 3 to 17 years weighing 17 to 34 kg who have undergone liver transplantation and are without cirrhosis or have compensated (Child-Pugh A) cirrhosis

45 mg ledipasvir; 200 mg sofosbuvir PO once daily with ribavirin for 12 weeks. Recommendation includes patients coinfected with HIV.[58167]

Children 3 to 12 years weighing less than 17 kg without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

33.75 mg ledipasvir; 150 mg sofosbuvir PO once daily (oral pellets). The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.[58167]

Children 3 to 12 years weighing less than 17 kg who have undergone liver transplantation and are without cirrhosis or have compensated (Child-Pugh A) cirrhosis

33.75 mg ledipasvir; 150 mg sofosbuvir PO once daily (oral pellets) with ribavirin for 12 weeks. Recommendation includes patients coinfected with HIV.[58167]

For the treatment of chronic hepatitis C genotypes 1, 4, 5, and 6 infection in treatment-naive and non-DAA-experienced patients with and without compensated cirrhosis (Child-Pugh A) who have undergone a kidney transplant†. Oral dosage Adults

Guidelines recommend 90 mg ledipasvir; 400 mg sofosbuvir PO once daily for 12 weeks.

Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Renal Impairment

No dosage adjustments are needed for any degree of renal impairment, including end stage renal disease requiring hemodialysis.

Acalabrutinib: (Moderate) Coadministration of acalabrutinib and sofosbuvir may increase the exposure and the risk of toxicity of sofosbuvir. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Sofosbuvir is a BCRP transporter substrate.
Acarbose: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Afatinib: (Moderate) If the concomitant use of ledipasvir; sofosbuvir 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 ledipasvir; sofosbuvir. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and ledipasvir is a weak P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. 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.
Albuterol; Budesonide: (Minor) Caution and close monitoring of budesonide-associated adverse reactions is advised with concomitant administration of ledipasvir. Budesonide is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase budesonide plasma concentrations.
Alogliptin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Alogliptin; Metformin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Alogliptin; Pioglitazone: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Alpelisib: (Major) Avoid coadministration of alpelisib with ledipasvir 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 ledipasvir is a BCRP inhibitor.
Aluminum Hydroxide: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Amiodarone: (Major) Coadministration of amiodarone with sofosbuvir is not recommended due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, including cases requiring pacemaker intervention, have been reported with the concurrent use of amiodarone with sofosbuvir-containing regimens; 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 is required, cardiac monitoring in an inpatient setting for the first 48 hours of coadministration 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 sofosbuvir should also undergo similar cardiac monitoring as outlined above.
Amlodipine; Atorvastatin: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of atorvastatin and ledipasvir; sofosbuvir. Concurrent use may result in increased atorvastatin exposure. Atorvastatin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Antacids: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Antidiabetic Agents: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Apalutamide: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp) and BCRP, such as apalutamide. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Coadministration of ledipasvir with apalutamide is not recommended. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Ledipasvir is a P-glycoprotein (P-gp) substrate and apalutamide is a weak P-gp inducer.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Aspirin, ASA; Omeprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Both ledipasvir and sofosbuvir are substrates of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp or BCRP inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect. (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
Atorvastatin: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of atorvastatin and ledipasvir; sofosbuvir. Concurrent use may result in increased atorvastatin exposure. Atorvastatin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor.
Atorvastatin; Ezetimibe: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of atorvastatin and ledipasvir; sofosbuvir. Concurrent use may result in increased atorvastatin exposure. Atorvastatin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking ledipasvir. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a P-gp and BCRP substrate and ledipasvir is a P-gp and BCRP inhibitor. Coadministration with another P-gp and BCRP inhibitor increased berotralstat exposure by 69%.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving ledipasvir. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving ledipasvir. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; ledipasvir inhibits P-gp.
Budesonide: (Minor) Caution and close monitoring of budesonide-associated adverse reactions is advised with concomitant administration of ledipasvir. Budesonide is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase budesonide plasma concentrations.
Budesonide; Formoterol: (Minor) Caution and close monitoring of budesonide-associated adverse reactions is advised with concomitant administration of ledipasvir. Budesonide is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase budesonide plasma concentrations.
Budesonide; Glycopyrrolate; Formoterol: (Minor) Caution and close monitoring of budesonide-associated adverse reactions is advised with concomitant administration of ledipasvir. Budesonide is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase budesonide plasma concentrations.
Calcium Carbonate: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily. (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Calcium Carbonate; Simethicone: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Calcium; Vitamin D: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Canagliflozin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Canagliflozin; Metformin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Carbamazepine: (Major) Avoid coadministration of ledipasvir with carbamazepine. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as carbamazepine. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
Carvedilol: (Moderate) Concurrent administration of ledipasvir; sofosbuvir and carvedilol may result in elevated plasma concentrations of ledipasvir, sofosbuvir, and carvedilol. All three are substrates for the drug transporter, P-glycoprotein (P-gp), while both ledipasvir and carvedilol are also P-gp inhibitors. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. For carvedilol, monitor heart rate and blood pressure as per standards of care. (Minor) Coadministration of sofosbuvir and carvedilol may result in elevated sofosbuvir plasma concentrations. Sofosbuvir is a substrate for the drug transporter P-glycoprotein (P-gp); carvedilol is a P-gp inhibitor. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect.
Chlorpropamide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Cimetidine: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily.
Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Both ledipasvir and sofosbuvir are substrates of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp or BCRP inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect. (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
Cobimetinib: (Minor) If concurrent use of cobimetinib and ledipasvir; sofosbuvir is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and ledipasvir is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Colchicine: (Major) Avoid concomitant use of colchicine and ledipasvir due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and ledipasvir is a P-gp inhibitor.
Conivaptan: (Moderate) Caution is warranted when conivaptan is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Caution is warranted when conivaptan is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects.
Cyclosporine: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of cyclosporine and ledipasvir. Both ledipasvir and cyclosporine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). In addition, cyclosporine is a breast cancer resistance protein (BCRP) inhibitor; ledipasivr is a BCRP substrate. Taking these drugs together may increase plasma concentrations of both drugs. According to the manufacturer, no significant interactions were observed when these medications were administered concurrently during drug interaction studies.
Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ledipasvir; sofosbuvir. Ledipasvir is a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like ledipasvir; sofosbuvir in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with ledipasvir; sofosbuvir, 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.
Dapagliflozin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Dapagliflozin; Metformin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Dapagliflozin; Saxagliptin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Both ledipasvir and sofosbuvir are substrates of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp or BCRP inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect. (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Both ledipasvir and sofosbuvir are substrates of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp or BCRP inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect. (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
Dexlansoprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Dextromethorphan; Quinidine: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of quinidine and ledipasvir; sofosbuvir. Both ledipasvir and quinidine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
Digoxin: (Moderate) Caution and close monitoing of digoxin therapeutic concentrations is advised when administering digoxin with ledipasvir. Digoxin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase digoxin plasma concentrations.
Docetaxel: (Minor) Caution and close monitoring of docetaxel-associated adverse reactions is advised with concomitant administration of ledipasvir. Docetaxel is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase docetaxel plasma concentrations.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP.
Doxorubicin Liposomal: (Moderate) Ledipsavir is a P-glycoprotein (P-gp) inhibitor and doxorubicin is a major P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ledipsavir and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
Doxorubicin: (Moderate) Ledipsavir is a P-glycoprotein (P-gp) inhibitor and doxorubicin is a major P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ledipsavir and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
Dulaglutide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP.
Elbasvir; Grazoprevir: (Major) Administering ledipasvir with elbasvir may result in elevated ledipasvir plasma concentrations. Ledipasvir is a substrate for the breast cancer resistance protein (BCRP); elbasvir is a BCRP inhibitor. (Major) Administering ledipasvir with grazoprevir may result in elevated ledipasvir plasma concentrations. Ledipasvir is a substrate for the breast cancer resistance protein (BCRP);grazoprevir is a BCRP inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Both ledipasvir and sofosbuvir are substrates of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp or BCRP inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect. (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Both ledipasvir and sofosbuvir are substrates of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp or BCRP inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect. (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP. (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
Empagliflozin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Empagliflozin; Linagliptin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Empagliflozin; Linagliptin; Metformin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Empagliflozin; Metformin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP.
Ertugliflozin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Ertugliflozin; Metformin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Ertugliflozin; Sitagliptin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Erythromycin: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of erythromycin and ledipasvir; sofosbuvir. Both ledipasvir and erythromycin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
Esomeprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ledipasvir is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and ledipasvir is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
Exenatide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Famotidine: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily.
Fentanyl: (Moderate) Caution and close monitoring of fentanyl-associated adverse reactions is advised with concomitant administration of ledipasvir. Fentanyl is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase fentanyl plasma concentrations.
Fosamprenavir: (Moderate) Caution is advised when administering sofosbuvir with fosamprenavir, as concurrent use may result in reduced sofosbuvir plasma concentrations. Sofosbuvir is a substrate for the drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is a P-gp inducer.
Fosphenytoin: (Major) Avoid coadministration of ledipasvir with fosphenytoin. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with fosphenytoin. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
Fostamatinib: (Moderate) Monitor for ledipasvir toxicities that may require ledipasvir dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP or P-gp substrate may increase the concentration of the BCRP or P-gp substrate. Fostamatinib is a P-gp inhibitor, and the active metabolite of fostamatinib, R406, is a BCRP inhibitor; ledipasvir is a substrate for BCRP and P-gp. Coadministration of fostamatinib with another BCRP substrate increased the substrate AUC by 95% and Cmax by 88%. Coadministration of fostamatinib with another P-gp substrate increased the substrate AUC by 37% and Cmax by 70%.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and ledipasvir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and ledipasvir are both substrates and inhibitors of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). (Moderate) Caution is advised with the coadministration of pibrentasvir and ledipasvir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Pibrentasvir and ledipasvir are both substrates and inhibitors of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
Glimepiride: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Glipizide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Glipizide; Metformin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Glyburide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Glyburide; Metformin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
H2-blockers: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily.
Ibuprofen; Famotidine: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily.
Insulin Aspart: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Insulin Aspart; Insulin Aspart Protamine: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Insulin Degludec; Liraglutide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Insulin Detemir: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Insulin Glargine: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Insulin Glargine; Lixisenatide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Insulin Glulisine: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Insulin Lispro: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Insulin Lispro; Insulin Lispro Protamine: (Moderate) Closely monitor blood glucose levels if led

ipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Insulin, Inhaled: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of ledipasvir with potent inducers of intestinal P-glycoprotein (P-gp), such as rifampin. Taking these drugs together may significantly decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate, with inducers of P-gp, such as rifampin. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. In a single-dose study, coadministration reduced the sofosbuvir Cmax and AUC to 23% and 28% of normal concentrations, respectively.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of ledipasvir with potent inducers of intestinal P-glycoprotein (P-gp), such as rifampin. Taking these drugs together may significantly decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate, with inducers of P-gp, such as rifampin. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. In a single-dose study, coadministration reduced the sofosbuvir Cmax and AUC to 23% and 28% of normal concentrations, respectively.
Isophane Insulin (NPH): (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Itraconazole: (Minor) Itraconazole and ledipasvir may be given together with caution and close monitoring. Taking these drugs together may increase plasma concentrations of ledipasvir. Ledipasvir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor; itraconazole is a P-gp and BCRP inhibitor. (Minor) Itraconazole and sofosbuvir may be given together with caution. Taking these drugs together may increase plasma concentrations of sofosbuvir, without increasing GS-331007 plasma concentrations. Sofosbuvir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor; itraconazole is a P-gp and BCRP inhibitor.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP.
Lansoprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with ledipasvir is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and ledipasvir is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
Lefamulin: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with ledipasvir 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 ledipasvir is a P-gp inhibitor.
Linagliptin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Linagliptin; Metformin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Liraglutide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Lixisenatide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Loperamide: (Moderate) 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), if coadministered with ledipasvir. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and ledipasvir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) 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), if coadministered with ledipasvir. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and ledipasvir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Moderate) Caution is warranted when ritonavir is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Ritonavir is an inhibitor of the transporter P-glycoprotein (P-gp). Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects.
Lorlatinib: (Major) Coadministration of ledipasvir with lorlatinib is not recommended. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Ledipasvir is a P-glycoprotein (P-gp) substrate and lorlatinib is a P-gp inducer.
Lumacaftor; Ivacaftor: (Minor) Although the clinical significance of this interaction is unknown, concurrent use of ledipasvir; sofosbuvir and lumacaftor; ivacaftor may alter ledipasvir; sofosbuvir exposure; avoid concurrent use. Both ledipasvir and sofosbuvir are substrates of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected. FDA-approved labeling for ledipasvir; sofosbuvir recommends to avoid coadministration with P-gp inducers. (Minor) Although the clinical significance of this interaction is unknown, concurrent use of sofosbuvir and lumacaftor; ivacaftor may alter sofosbuvir exposure; caution and close monitoring are advised if these drugs are used together. Sofosbuvir is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events. FDA-approved labeling for sofosbuvir recommends to avoid coadministration with potent P-gp inducers.
Magnesium Hydroxide: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Maraviroc: (Minor) Use caution and closely monitor for increased adverse effects with the coadministration of maraviroc and ledipasvir as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp); ledipasvir is a weak inhibitor of P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
Mefloquine: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of mefloquine and ledipasvir; sofosbuvir. Both ledipasvir and mefloquine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
Metformin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Metformin; Repaglinide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Metformin; Rosiglitazone: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Metformin; Saxagliptin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Metformin; Sitagliptin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Methadone: (Moderate) Caution and close monitoring of methadone-associated adverse reactions is advised with concomitant administration of ledipasvir. Methadone is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase methadone plasma concentrations.
Miglitol: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Morphine: (Moderate) Caution and close monitoring of morphine-associated adverse reactions is advised with concomitant administration of ledipasvir. Morphine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase morphine plasma concentrations.
Morphine; Naltrexone: (Moderate) Caution and close monitoring of morphine-associated adverse reactions is advised with concomitant administration of ledipasvir. Morphine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase morphine plasma concentrations.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and ledipasvir. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and ledipasvir is a P-gp inhibitor.
Naproxen; Esomeprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Nateglinide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Nirmatrelvir; Ritonavir: (Moderate) Caution is warranted when ritonavir is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Ritonavir is an inhibitor of the transporter P-glycoprotein (P-gp). Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects.
Nizatidine: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily.
Omeprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of ledipasvir with rifabutin. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with rifabutin. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy. (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Omeprazole; Sodium Bicarbonate: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day. (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Ondansetron: (Moderate) Caution and close monitoring of ondansetron-associated adverse reactions is advised with concomitant administration of ledipasvir. Ondansetron is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase ondansetron plasma concentrations.
Osimertinib: (Moderate) Monitor for an increase in sofosbuvir-related adverse reactions if coadministration with osimertinib is necessary. Sofosbuvir is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
Oxcarbazepine: (Major) Avoid coadministration of sofosbuvir with oxcarbazepine. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
Paclitaxel: (Minor) Caution and close monitoring of paclitaxel-associated adverse reactions is advised with concomitant administration of ledipasvir. Paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase paclitaxel plasma concentrations.
Pantoprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Pazopanib: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of pazopanib and ledipasvir; sofosbuvir. Both ledipasvir and pazopanib are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp) ; sofosbuvir is a P-gp substrate. In addition pazopanib and sofosbuvir are substrates of and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor and substrate of BCRP. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
Phenobarbital: (Major) Avoid coadministration of ledipasvir with phenobarbital. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenobarbital. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of ledipasvir with phenobarbital. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenobarbital. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
Phenytoin: (Major) Avoid coadministration of ledipasvir with phenytoin. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenytoin. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
Pioglitazone: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Pioglitazone; Glimepiride: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Pioglitazone; Metformin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Posaconazole: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of posaconazole and ledipasvir; sofosbuvir. Both ledipasvir and posaconazole are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
Pralsetinib: (Major) Avoid concomitant use of ledipasvir with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a P-gp substrate and ledipasvir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
Pramlintide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Prednisone: (Moderate) Caution and close monitoring of prednisone-associated adverse reactions is advised with concomitant administration of ledipasvir. Prednisone is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase prednisone plasma concentrations.
Primidone: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein, such as primidone. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and ledipasvir due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and ledipasvir is a P-gp inhibitor.
Proton pump inhibitors: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Quinidine: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of quinidine and ledipasvir; sofosbuvir. Both ledipasvir and quinidine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
Quinine: (Moderate) Caution and close monitoring of quinine-associated adverse reactions is advised with concomitant administration of ledipasvir. Quinine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase quinine plasma concentrations.
Rabeprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Ranitidine: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily.
Ranolazine: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of ranolazine and ledipasvir; sofosbuvir. Both ledipasvir and ranolazine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
Regular Insulin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Regular Insulin; Isophane Insulin (NPH): (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Relugolix: (Major) Avoid concomitant use of relugolix and oral ledipasvir. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer ledipasvir at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and ledipasvir is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral ledipasvir. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer ledipasvir at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and ledipasvir is a P-gp inhibitor.
Repaglinide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Rifabutin: (Major) Avoid coadministration of ledipasvir with rifabutin. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with rifabutin. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
Rifampin: (Major) Avoid coadministration of ledipasvir with potent inducers of intestinal P-glycoprotein (P-gp), such as rifampin. Taking these drugs together may significantly decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate, with inducers of P-gp, such as rifampin. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. In a single-dose study, coadministration reduced the sofosbuvir Cmax and AUC to 23% and 28% of normal concentrations, respectively.
Rifapentine: (Major) Avoid coadministration of sofosbuvir with rifapentine. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ledipasvir is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ledipasvir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with ledipasvir; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and ledipasvir is a P-gp inhibitor.
Ritonavir: (Moderate) Caution is warranted when ritonavir is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Ritonavir is an inhibitor of the transporter P-glycoprotein (P-gp). Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects.
Rivaroxaban: (Moderate) Coadministration of rivaroxaban and ledipasvir may result in increases in rivaroxaban exposure and may increase bleeding risk. Ledipasviris an 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.
Rolapitant: (Moderate) Use caution if ledipasvir; sofosbuvir and rolapitant are used concurrently, and monitor for ledipasvir- or sofosbuvir-related adverse effects. Ledipasvir and sofosbuvir are both substrates of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. (Moderate) Use caution if sofosbuvir and rolapitant are used concurrently, and monitor for sofosbuvir-related adverse effects. Sofosbuvir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
Rosiglitazone: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Rosuvastatin: (Major) Avoid coadministration of ledipasvir with rosuvastatin. Taking these drugs together may significantly increase rosuvastatin plasma concentrations, potentially resulting in myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the breast cancer resistance protein (BCRP); ledipasvir is a BCRP inhibitor.
Rosuvastatin; Ezetimibe: (Major) Avoid coadministration of ledipasvir with rosuvastatin. Taking these drugs together may significantly increase rosuvastatin plasma concentrations, potentially resulting in myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the breast cancer resistance protein (BCRP); ledipasvir is a BCRP inhibitor.
Saxagliptin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Semaglutide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Silodosin: (Moderate) Caution and close monitoring of silodosin-associated adverse reactions is advised with concomitant administration of ledipasvir. Silodosin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase silodosin plasma concentrations.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ledipasvir. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and ledipasvir is a P-gp inhibitor.
Sitagliptin: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Sodium Bicarbonate: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
Sofosbuvir; Velpatasvir: (Contraindicated) Taking these drugs together is a duplication of therapy, and may result in adverse effects.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Contraindicated) Taking these drugs together is a duplication of therapy, and may result in adverse effects. (Major) Avoid concurrent administration of voxilaprevir with ledipasvir. Taking these medications together may increase ledipasvir plasma concentrations, potentially increasing the risk for adverse events. Ledipasvir is a substrate for the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Voxilaprevir is a P-gp and BCRP inhibitor.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of ledipasvir with potent inducers of intestinal P-glycoprotein (P-gp), such as St. John's Wort, Hypericum perforatum. Taking these drugs together may significantly decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate with inducers of P-gp, such as St. John's Wort, Hypericum perforatum. Taking these drugs together may significantly decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
Tacrolimus: (Moderate) Closely monitor tacrolimus serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as ledipasvir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations. (Moderate) Closely monitor tacrolimus serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as sofosbuvir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations.
Tafamidis: (Moderate) Caution is advised with the coadministration of tafamidis and ledipasvir due to the potential for increased plasma concentrations of ledipasvir increasing the risk of adverse effects. Ledipasvir dose adjustment may be needed with coadministration. Ledipasvir is a substrate of breast cancer resistance protein (BCRP) and tafamidis is a BCRP inhibitor. (Minor) Caution is advised with the coadministration of tafamidis and sofosbuvir as coadminstration may increase the plasma concentrations of sofosbuvir and increase the risk of adverse effects. Sofosbuvir is a substrate of the breast cancer resistance protein (BCRP) and tafamidis is a BCRP inhibitor.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of ledipasvir is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a P-gp and BCRP substrate; ledipasvir is a P-gp and BCRP inhibitor.
Tedizolid: (Moderate) If possible, stop use of ledipasvir temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for ledipasvir--associated adverse events. Ledipasvir plasma concentrations may be increased when ledipasvir is administered concurrently with oral tedizolid. Ledipasvir is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine. (Moderate) If possible, stop use of sofosbuvir temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for sofosbuvir-associated adverse events. Sofosbuvir plasma concentrations may be increased when administered concurrently with oral tedizolid. Sofosbuvir is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus- and ledipasvir-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 ledipasvir.
Teniposide: (Major) Caution and close monitoring of teniposide-associated adverse reactions is advised with concomitant administration of ledipasvir. Teniposide is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase teniposide plasma concentrations.
Tenofovir Alafenamide: (Minor) According to the manufacturer, interactions are not expected during coadministration of ledipasvir; sofosbuvir and tenofovir alafenamide; however based on the metabolic pathways of these medications, monitoring for tenofovir-associated adverse reactions should be considered if these drugs are given together. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP. Use of these drugs together may increase tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP.
Ticagrelor: (Moderate) Coadministration of ticagrelor and ledipasvir; sofosbuvir may result in increased exposure to all three drugs, which may increase the bleeding risk. Both ledipasvir and ticagrelor are P-glycoprotein (P-gp) substrates and inhibitors; sofosbuvir is a P-gp substrate. No dose adjustment is recommended by the manufacturer. Use combination with caution and monitor for evidence of bleeding.
Tipranavir: (Major) Avoid coadministration of ledipasvir with tipranavir boosted with ritonavir. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as tipranavir. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Sofosbuvir is a P-gp substrate. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer. The administration with ritonavir appears to result in a net P-gp induction at steady state, even though, when given alone, ritonavir is a P-gp inhibitor.
Tolazamide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Tolbutamide: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Topotecan: (Major) Avoid coadministration of ledipasvir with oral topotecan due to increased topotecan exposure; ledipasvir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); ledipasvir 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.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with ledipasvir. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP and P-gp drug transporters; ledipasvir is a BCRP and P-gp inhibitor.
Vemurafenib: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of vemurafenib and ledipasvir; sofosbuvir. Both ledipasvir and vemurafenib are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
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 ledipasvir due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of ledipasvir. Venetoclax is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); ledipasvir is an inhibitor of P-gp and BCRP. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Vincristine Liposomal: (Moderate) Caution and close monitoring of vincristine-associated adverse reactions is advised with concomitant administration of ledipasvir. Vincristine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase vincristine plasma concentrations.
Vincristine: (Moderate) Caution and close monitoring of vincristine-associated adverse reactions is advised with concomitant administration of ledipasvir. Vincristine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase vincristine plasma concentrations.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of ledipasvir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ledipasvir reducing its efficacy.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of ledipasvir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ledipasvir reducing its efficacy.
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 ledipasvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen. (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 sofosbuvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.
Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ledipasvir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates. (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and sofosbuvir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Vincristine Liposomal: (Moderate) Caution and close monitoring of vincristine-associated adverse reactions is advised with concomitant administration of ledipasvir. Vincristine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase vincristine plasma concentrations.
Vincristine: (Moderate) Caution and close monitoring of vincristine-associated adverse reactions is advised with concomitant administration of ledipasvir. Vincristine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase vincristine plasma concentrations.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of ledipasvir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ledipasvir reducing its efficacy.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of ledipasvir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ledipasvir reducing its efficacy.
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 ledipasvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen. (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 sofosbuvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.
Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ledipasvir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates. (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and sofosbuvir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

Harvoni Oral Gran: 33.75-150mg, 45-200mg
Harvoni/Ledipasvir, Sofosbuvir Oral Tab: 45-200mg, 90-400mg

Adults

90 mg/day PO for ledipasvir; 400 mg/day PO for sofosbuvir.

Geriatric

90 mg/day PO for ledipasvir; 400 mg/day PO for sofosbuvir.

Adolescents

weighing 35 kg or more: 90 mg/day PO for ledipasvir; 400 mg/day PO for sofosbuvir.
weighing 17 to 34 kg: 45 mg/day PO for ledipasvir; 200 mg/day PO for sofosbuvir.

Children

3 to 12 years weighing 35 kg or more: 90 mg/day PO for ledipasvir; 400 mg/day PO for sofosbuvir.
3 to 12 years weighing 17 to 34 kg: 45 mg/day PO for ledipasvir; 200 mg/day PO for sofosbuvir.
3 to 12 years weighing less than 17 kg: 33.75 mg/day PO for ledipasvir; 150 mg/day PO for sofosbuvir.
1 to 2 years: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Ledipasvir; sofosbuvir is active against chronic infections caused by genotypes 1, 4, 5, and 6 hepatitis C virus (HCV). Ledipasvir is an inhibitor of HCV NS5A protein. Sofosbuvir is a HCV nucleotide analog NS5B polymerase inhibitor.
•Ledipasvir: Ledipasvir prevents hepatitis C viral replication by inhibiting the HCV NS5A protein. Although the exact mechanism is unknown, data suggest NS5A inhibitors may prevent replication by blocking viral hyperphosphorylation. It has been proposed that tight control of phosphorylation versus hyperphosphorylation is needed for efficient viral function.
In cell cultures, HCV replicons with NS5A amino acid substitutions Y93H (genotype 1a and 1b) and Q30E (genotype 1a) displayed significant reductions in the susceptibility of the virus to ledipasvir (more than 1,000-fold change in EC50). In clinical trials, 37 patients were deemed virologic failures following treatment with ledipasvir; sofosbuvir. An analysis of these 37 patients found 55% (n = 16/29) of the genotype 1a failures and 88% (n = 7/8) of the genotype 1b failures had viruses with emergent NS5A resistance-associated substitutions. The most common substitutions for genotype 1a failures were Q30R, Y93H/N, and L31M; Y93H was the most common substitution detected in genotype 1b failures. A phenotypic analysis showed these substitutions resulted in a 20- to more than 243-fold reduction in susceptibility to ledipasvir; however, viruses with these substitutions remain susceptible to sofosbuvir. For genotypes 4, 5, and 6, resistance analyses were performed on 6 relapse patients. Of the 6 patients, 5 had pretreatment NS5A sequencing data that showed resistance-associated polymorphisms. For genotype 4, NS5A substitutions Y93C and L28V emerged in 2 patients. Cross resistance is not expected between ledipasvir and sofosbuvir, NS5B non-nucleoside inhibitors, nor NS3 protease inhibitors.
 
•Sofosbuvir: Sofosbuvir is a nucleotide prodrug that prevents hepatitis C viral replication by inhibiting the activity of HCV NS5B RNA polymerase. It undergoes intracellular metabolism to form GS-461203, a pharmacologically active uridine analog triphosphate. Hepatitis C virus NS5B RNA polymerase incorporates this metabolite into the viral RNA, where it acts as a chain terminator. GS-461203 does not inhibit human DNA or RNA polymerase, nor does it block mitochondrial RNA polymerase.
 
In cell cultures, recombinant NS5B polymerase expressing a S282T substitution displayed a 2- to 18-fold decrease in susceptibility to sofosbuvir in all genotypes tested. This substitution was detected in one patient with HCV genotype 1 who received ledipasvir; sofosbuvir for 8 weeks, and in 3 patients with genotypes 4, 5, and 6 (one in each genotype) who received treatment for 12 weeks. In addition, the genotype 5 patient also had the emergent nucleotide inhibitor substitution M289I. While sofosbuvir susceptibility is reduced with the S282T substitution, these viruses remain susceptible to ledipasvir. Cross resistance is not expected between sofosbuvir and ribavirin, NS3/4A protease inhibitors, NS5B non-nucleoside inhibitors, or NS5A inhibitors.

Ledipasvir; sofosbuvir is administered orally.
Ledipasvir: Once in systemic circulation, more than 99.8% of the drug is bound to plasma protein. The mechanism by which ledipasvir is metabolized is unknown; however, evidence suggests it undergoes slow oxidative metabolism to form the metabolite M19. Elimination occurs primarily by biliary excretion, with approximately 70% of the administered dose excreted in the feces as the unchanged parent drug and 2.2% excreted as M19. Only 1% of the dose is eliminated via the kidneys. The mean terminal half-life is 47 hours.[58167]
Sofosbuvir: After administration, approximately 61% to 65% is bound to plasma protein. In the liver, sofosbuvir is converted from the nucleotide prodrug to the pharmacologically active nucleoside analog triphosphate, GS-461203. This conversion occurs via hydrolysis of the carboxy ester moiety by human cathepsin A (CatA) or carboxylesterase 1 (CES1), phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT 1), and phosphorylation by pyrimidine nucleotide biosynthesis pathway. GS-461203 is then further metabolized by dephosphorylation to form GS-331007, a metabolite that lacks anti-HCV activity and cannot be rephosphorylated. GS-331007 is the predominant circulating metabolite and represents more than 90% of drug related material, while the parent drug accounts for approximately 4%. Elimination occurs primarily through the kidneys with approximately 80% of the dose recovered in the urine (78% as GS-331007, 3.5% as sofosbuvir). Other routes of elimination include the feces (14%) and expired air (2.5%). The median terminal elimination half-lives of sofosbuvir and GS-331007 are 0.5 and 27 hours, respectively.[56528] [58167]
 
Affected drug transporters: P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)
Both ledipasvir and sofosbuvir are substrates of the drug transporters P-gp and BCRP. Ledipasvir is also an inhibitor of P-gp and BCRP. The major inactive metabolite of sofosbuvir, GS-331007, is neither a substrate nor inhibitor of P-gp or BCRP. FDA-labeling suggests that inhibitors of P-gp and BCRP may be coadministered with ledipasvir; sofosbuvir. In clinical trials, no clinically significant interaction was noted when ledipasvir; sofosbuvir was administered with darunavir/ritonavir (P-gp inhibitors) or cyclosporine (a P-gp and BCRP inhibitor).[58167]

Oral Route

Ledipasvir: Peak plasma concentrations are achieved within 4 to 4.5 hours after oral administration. Compared to healthy subjects, the geometric mean steady state concentrations (AUC) and the maximum plasma concentrations (Cmax) for ledipasvir are 24% and 32% lower, respectively, in patients infected with hepatitis C. Food does not alter the pharmacokinetic parameters of ledipasvir.[58167]
Sofosbuvir: After oral administration, the time to reach maximum plasma concentrations (Tmax) is approximately 0.8 to 1 hours for the parent drug sofosbuvir and 3.5 to 4 hours for the major metabolite GS-331007. The geometric mean steady state concentrations (AUC) and the maximum plasma concentrations (Cmax) for sofosbuvir and GS-331007 in patients infected with hepatitis C are similar to those observed in healthy subjects. Administration of a single dose with a moderate fat (600 kcal, 25% to 30% fat) or high fat (1,000 kcal, 50% fat) meal resulted in a 2-fold increase in the AUC of sofosbuvir; the Cmax remained unaffected. Food does not alter the pharmacokinetic parameters of GS-331007.[58167]

Pregnancy

There are no well controlled studies evaluating the use of ledipasvir; sofosbuvir during human pregnancy. In animal studies involving rats and rabbits, no adverse effects on fetal development were observed with either ledipasvir or sofosbuvir. In certain patient populations, ledipasvir; sofosbuvir must be administered with ribavirin, which is contraindicated for use during pregnancy (FDA pregnancy risk category X) and in females who may become pregnant. Ribavirin may cause birth defects and death of the exposed fetus. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all the animal species tested. To monitor maternal-fetal outcomes of pregnancies in female 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. For patients who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

It is unknown whether ledipasvir or sofosbuvir or their metabolites are excreted in human milk, affect milk production, or have an adverse effect on nursing infants. Simeprevir may be considered as an alternative; however, its excretion into human breast milk is also unknown. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.