Medical Editor: John P. Cunha, DO, FACOEP
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Harvoni is a two-drug fixed-dose combination product that contains 90 mg of ledipasvir and 400 mg of sofosbuvir in a single tablet. The recommended dosage of Harvoni is one tablet taken orally once daily with or without food. Harvoni may interact with rifampin, and St. John's wort. Tell your doctor all medications and supplements you use. Tell your doctor if you are pregnant or plant to become pregnant before using Harvoni. It is unknown if this drug passes into breast milk. Consult your doctor before breastfeeding.
Our Harvoni (ledipasvir and sofosbuvir) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
The following serious adverse reactions are described below and elsewhere in labeling:
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 [see Clinical Studies].
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 3 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 treatment with HARVONI in clinical trials. The majority of adverse reactions presented in Table 3 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 3 : 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 open-label 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) [see Clinical Studies]. 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 [see Clinical Studies]. Table 4 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 4 were Grade 1 or 2 in severity.
Table 4 : Adverse Reactions with ≥ 5% Greater
Frequency Reported in Treatment-Experienced Subjects with Cirrhosis Receiving
HARVONI for 24 Weeks or HARVONI + RBV for 12 Weeks Compared to Placebo for 12
|HARVONI + RBV
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 [see Clinical Studies]. 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 (RBV) 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 RBV for 12 weeks. Subjects with Child-Pugh-Turcotte (CPT) scores greater than 12 were excluded from the trials [see Clinical Studies].
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 RBV for 12 weeks, respectively. Ribavirin was permanently discontinued in 11% of subjects treated with HARVONI plus RBV for 12 weeks.
Liver Transplant Recipients with Compensated Liver Disease
Among the 174 liver transplant recipients with compensated liver disease who received HARVONI with RBV 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 RBV 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.
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 Pediatric Subjects 12 Years Of Age And Older
The safety assessment of HARVONI in pediatric subjects 12 years of age and older is based on data from a Phase 2, open-label clinical trial (Study 1116) that enrolled 100 subjects without cirrhosis or with compensated cirrhosis who were treated with HARVONI for 12 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 [see Clinical Studies].
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.
Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with HARVONI [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
Skin And Subcutaneous Tissue Disorders
Skin rashes, sometimes with blisters or angioedema-like swelling Angioedema
Read the entire FDA prescribing information for Harvoni (Ledipasvir and Sofosbuvir Tablets)