Side Effects of Harvoni (sofosbuvir and ledipasvir)

Harvoni (sofosbuvir and ledipasvir) is a combination of direct-acting antiviral agents used to treat chronic infection with the hepatitis C virus (HCV), genotype 1 in adults. 

Sofosbuvir is converted to an active form in the body before it is effective. The active form of sofosbuvir directly blocks replication of the HVC by interfering with a hepatitis C virus enzyme called NS5B. Ledipasvir is an inhibitor of another hepatitis C virus enzyme called NS5A, which also is needed for viral replication. 

Both drugs in Harvoni interfere with enzymes needed by hepatitis C virus to multiply and make new viruses, thus reducing the overall viral load. The efficacy of sofosbuvir has been established in subjects with hepatitis C virus genotype 1, 2, 3 and 4.

Common side effects of Harvoni include

• headache,
• fatigue,
• nausea,
• insomnia,
• diarrhea, and
• weakness.

Serious side effects of Harvoni include

• serious symptomatic low heart rate (bradycardia) when coadministered with amiodarone. 

Drug interactions of Harvoni include amiodarone because there is an increased risk of serious heart-related side effects including low heart rate (bradycardia) when the drugs are combined.

• Harvoni should not be combined with Sovaldi or other drugs containing sofosbuvir.
• Acid reducing agents such as antacids, histamine 2 receptor antagonists, and proton pump inhibitors (PPIs) may decrease the effectiveness of Harvoni treatment by decreasing blood levels of ledipasvir. 
• Anti-seizure medications including carbamazepine, phenytoin, phenobarbital, and oxcarbazepine may increase the breakdown of Harvoni, leading to reduced therapeutic effectiveness.
• Taking St. John's wort or rifampin with Harvoni may also reduce the effectiveness of treatment and is not recommended.
• Certain medications used to treat tuberculosis (TB) infection may decrease the effectiveness of Harvoni treatment.
• Patients taking rifampin, rifabutin, or rifapentine should consult with their doctor or pharmacist before starting Harvoni.
• Co-administration of Harvoni with rosuvastatin may significantly increase the blood concentration of rosuvastatin and increase the risk of side effects such as serious muscle injury. 
• Drug interactions with certain HIV antiretroviral therapies and Harvoni have been reported. 

If Harvoni is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. No adequate human data are available to establish whether or not Harvoni alone poses a risk to pregnancy outcomes. 

It is unknown if ledipasvir or sofosbuvir, the components of Harvoni, or their metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant. If Harvoni is administered with ribavirin, the nursing mother’s information for ribavirin also applies to this combination regimen. Consult your doctor before breastfeeding.

WARNING

• There is an increased risk of low heart rate (bradycardia) when Harvoni is combined with amiodarone (Cordarone).
• Harvoni should not be combined with Sovaldi (sofosbuvir) or other drugs containing sofosbuvir.

The following serious adverse reactions are described below and elsewhere in labeling:

• Serious Symptomatic Bradycardia When Coadministered with Amiodarone.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

If Harvoni is administered with ribavirin to adults, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions.

Clinical Trials In Adult Subjects

The safety assessment of Harvoni was based on pooled data from three randomized, open-label Phase 3 clinical trials (ION-3, ION-1, and ION-2) of subjects with genotype 1 HCV with compensated liver disease (with and without cirrhosis) including 215, 539, and 326 subjects who received Harvoni once daily by mouth for 8, 12, and 24 weeks, respectively.

The proportion of subjects who permanently discontinued treatment due to adverse events was 0%, less than 1%, and 1% for subjects receiving Harvoni for 8, 12, and 24 weeks, respectively.

The most common adverse reactions (at least 10%) were fatigue and headache in subjects treated with 8, 12, or 24 weeks of Harvoni.

Table 4 lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in at least 5% of subjects receiving 8, 12, or 24 weeks of treatment with Harvoni in clinical trials. The majority of adverse reactions presented in Table 4 occurred at severity of grade 1. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.

Table 4 : Adverse Reactions (All Grades) Reported in =5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with Harvoni

• The safety assessment of Harvoni was also based on pooled data from three openlabel trials (Study 1119, ION-4, and ELECTRON-2) in 118 subjects with chronic HCV genotype 4, 5, or 6 infection with compensated liver disease (with or without cirrhosis).
• The subjects received Harvoni once daily by mouth for 12 weeks.
• The safety profile in subjects with chronic HCV genotype 4, 5, or 6 infection with compensated liver disease was similar to that observed in subjects with chronic HCV genotype 1 infection with compensated liver disease.
• The most common adverse reactions occurring in at least 10% of subjects were asthenia (18%), headache (14%), and fatigue (10%).

Adverse Reactions In Subjects With Cirrhosis

• The safety assessment of Harvoni with or without ribavirin was based on a randomized, double-blind and placebo-controlled trial in treatment-experienced genotype 1 subjects with compensated cirrhosis and was compared to placebo in the SIRIUS trial.
• Subjects were randomized to receive 24 weeks of Harvoni once daily by mouth without ribavirin or 12 weeks of placebo followed by 12 weeks of Harvoni once daily by mouth + ribavirin.
• Table 5 presents the adverse reactions, as defined above, that occurred with at least 5% greater frequency in subjects treated with 24 weeks of Harvoni or 12 weeks of Harvoni + ribavirin, compared to those reported for 12 weeks of placebo.
• The majority of the adverse reactions presented in Table 5 were Grade 1 or 2 in severity.

Table 5 : Adverse Reactions with ≥5% Greater Frequency Reported in Treatment-Experienced Subjects with Cirrhosis Receiving Harvoni for 24 Weeks or Harvoni + Ribavirin for 12 Weeks Compared to Placebo for 12 weeks

Adverse Reactions In Subjects Coinfected With HIV-1

• The safety assessment of Harvoni was based on an open-label clinical trial in 335 genotype 1 or 4 subjects with HCV/HIV-1 coinfection who were on stable antiretroviral therapy in Study ION-4.
• The safety profile in HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected subjects. The most common adverse reactions occurring in at least 10% of subjects were
  • headache (20%) and
  • fatigue (17%).

Adverse Reactions In Liver Transplant Recipients And/Or Subjects With Decompensated Cirrhosis

• The safety assessment of Harvoni with ribavirin in liver transplant recipients and/or those who had decompensated liver disease was based on pooled data from two Phase 2 open-label clinical trials including 336 subjects who received Harvoni plus ribavirin for 12 weeks.
• Subjects with Child-Pugh-Turcotte (CPT) scores greater than 12 were excluded from the trials.
• The adverse events observed were consistent with the expected clinical sequelae of liver transplantation and/or decompensated liver disease, or the known safety profile of Harvoni and/or ribavirin.
• Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were observed in 38% and 13% of subjects treated with Harvoni plus ribavirin for 12 weeks, respectively.
• Ribavirin was permanently discontinued in 11% of subjects treated with Harvoni plus ribavirin for 12 weeks.

Liver Transplant Recipients With Compensated Liver Disease

• Among the 174 liver transplant recipients with compensated liver disease who received Harvoni with ribavirin for 12 weeks, 2 (1%) subjects permanently discontinued Harvoni due to an adverse event.

Subjects With Decompensated Liver Disease

• Among the 162 subjects with decompensated liver disease (pre- or post-transplant) who received Harvoni with ribavirin for 12 weeks, 7 (4%) subjects died, 4 (2%) subjects underwent liver transplantation, and 1 subject (<1%) underwent liver transplantation and died during treatment or within 30 days after discontinuation of treatment.
• Because these events occurred in patients with advanced liver disease who are at risk of progression of liver disease including liver failure and death, it is not possible to reliably assess the contribution of drug effect to outcomes. A total of 4 (2%) subjects permanently discontinued Harvoni due to an adverse event.

Less Common Adverse Reactions Reported In Clinical Trials (Less Than 5%)

• The following adverse reactions occurred in less than 5% of subjects receiving Harvoni in any one trial.
• These events have been included because of their seriousness or assessment of potential causal relationship.

Psychiatric disorders: depression (including in subjects with pre-existing history of psychiatric illness).

• Depression (particularly in subjects with pre-existing history of psychiatric illness) occurred in subjects receiving sofosbuvir containing regimens.
• Suicidal ideation and suicide have occurred in less than 1% of subjects treated with sofosbuvir in combination with ribavirin or pegylated interferon/ribavirin in other clinical trials.

Laboratory Abnormalities

Bilirubin Elevations

• Bilirubin elevations of greater than 1.5xULN were observed in 3%, less than 1%, and 2% of subjects treated with Harvoni for 8, 12, and 24 weeks, respectively.
• Bilirubin elevations of greater than 1.5xULN were observed in 3%, 11%, and 3% of subjects with compensated cirrhosis treated with placebo, Harvoni + ribavirin for 12 weeks, and Harvoni for 24 weeks, respectively, in the SIRIUS trial.

Lipase Elevations

• Transient, asymptomatic lipase elevations of greater than 3xULN were observed in less than 1%, 2%, and 3% of subjects treated with Harvoni for 8, 12, and 24 weeks, respectively.
• Transient, asymptomatic lipase elevations of greater than 3x ULN were observed in 1%, 3%, and 9% of subjects with compensated cirrhosis treated with placebo, Harvoni + ribavirin for 12 weeks, and Harvoni for 24 weeks, respectively, in the SIRIUS trial.

Creatine Kinase

• Creatine kinase was not assessed in Phase 3 trials ION-3, ION-1, or ION-2 of Harvoni. Creatine kinase was assessed in the ION-4 trial.
• Isolated, asymptomatic creatine kinase elevations of greater than or equal to 10xULN was observed in 1% of subjects treated with Harvoni for 12 weeks in the ION-4 trial and has also been previously reported in subjects treated with sofosbuvir in combination with ribavirin or peginterferon/ribavirin in other clinical trials.

Adverse Reactions In Adults With Severe Renal Impairment, Including those On Dialysis

• In an open-label trial (Trial 0154) in which adults with HCV with compensated liver disease (with or without cirrhosis) and severe renal impairment received Harvoni for 12 weeks (N=18), the most common adverse reaction was fatigue (17%).
• In an open-label clinical trial, Trial 4063, a total of 95 adults with HCV with compensated liver disease (with or without cirrhosis) and ESRD requiring dialysis received Harvoni for 8 (n=45), 12 (n=31), or 24 (n=19) weeks.
• The most common adverse reactions were insomnia and headache (each reported in 4% of subjects overall).

Adverse Reactions In Pediatric Subjects 3 Years Of Age And Older

• The safety assessment of Harvoni in pediatric subjects 3 years of age and older is based on data from a Phase 2, open-label clinical trial (Study 1116).
• In total, 226 subjects were enrolled, which included 223 subjects without cirrhosis or with compensated cirrhosis who were treated with Harvoni for 12 weeks; one genotype 1 treatment-experienced subject with cirrhosis who was treated with Harvoni for 24 weeks; and two genotype 3 subjects who were treated with Harvoni + ribavirin for 24 weeks.
• The adverse reactions observed were consistent with those observed in clinical studies of Harvoni in adults.
• Limited safety data are available in pediatric subjects receiving Harvoni for 24 weeks.
• No Grade 3 or 4 adverse reactions or discontinuation due to an adverse reaction was observed in those pediatric subjects receiving Harvoni for 24 weeks.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Harvoni. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders

• Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with Harvoni.

Skin And Subcutaneous Tissue Disorders

• Skin rashes, sometimes with blisters or angioedema-like swelling
• Angioedema

Potential For Drug Interaction

• As Harvoni contains ledipasvir and sofosbuvir, any interactions that have been identified with these agents individually may occur with Harvoni.
• After oral administration of Harvoni, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction. In clinical pharmacology studies, both sofosbuvir and the inactive metabolite GS-331007 were monitored for purposes of pharmacokinetic analyses.
• Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters.
• Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin, St. John's wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of Harvoni, and the use with P-gp inducers is not recommended with Harvoni.

Established And Potentially Significant Drug Interactions

• Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications.
• For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies.
• Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment.
• Frequent monitoring of relevant laboratory parameters (e.g., International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.
• Table 6 provides a listing of established or potentially clinically significant drug interactions.
• The drug interactions described are based on studies conducted with either Harvoni, the components of Harvoni (ledipasvir and sofosbuvir) as individual agents, or are predicted drug interactions that may occur with Harvoni.

Table 6 : Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction^a

Drugs Without Clinically Significant Interactions With Harvoni

• Based on drug interaction studies conducted with the components of Harvoni (ledipasvir or sofosbuvir) or Harvoni, no clinically significant drug interactions have been either observed or are expected when Harvoni is used with the following drugs:
  • abacavir,
  • atazanavir/ritonavir,
  • cyclosporine,
  • darunavir/ritonavir,
  • dolutegravir,
  • efavirenz,
  • elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide,
  • emtricitabine,
  • lamivudine,
  • methadone,
  • midazolam,
  • oral contraceptives,
  • pravastatin,
  • raltegravir,
  • rilpivirine,
  • tacrolimus, or
  • verapamil.
• See Table 6 for use of Harvoni with certain HIV antiretroviral regimens.