Harvoni

Last updated on RxList: 6/1/2021
Harvoni Side Effects Center

What Is Harvoni?

Harvoni (ledipasvir and sofosbuvir) is a direct-acting antiviral agent used to treat chronic hepatitis C (CHC) genotype 1 infection in adults.

What Are Side Effects of Harvoni?

Common side effects of Harvoni include:

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

Dosage for Harvoni

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.

What Drugs, Substances, or Supplements Interact with Harvoni?

Harvoni may interact with rifampin, and St. John's wort. Tell your doctor all medications and supplements you use.

Harvoni During Pregnancy and Breastfeeding

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.

Additional Information

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.

QUESTION

Hepatitis C virus causes an infection of the ______________. See Answer
Harvoni Consumer Information

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Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have new or worsening symptoms such as:

  • right-sided upper stomach pain;
  • vomiting, loss of appetite; or
  • jaundice (yellowing of the skin or eyes), and not feeling well.

If you take ledipasvir and sofosbuvir and you also take a heart rhythm medicine called amiodarone: This combination of medicines can cause dangerous side effects on your heart. Get medical help right away if you take these medicines and you have:

  • very slow heartbeats, chest pain, shortness of breath;
  • confusion, memory problems; or
  • weakness, extreme tiredness, light-headed feeling (like you might pass out).

Common side effects may include:

  • weakness;
  • headache; or
  • tired feeling.

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.

Read the entire detailed patient monograph for Harvoni (Ledipasvir and Sofosbuvir Tablets)

SLIDESHOW

Hepatitis: How Do You Get Hepatitis A, B, and C? See Slideshow
Harvoni Professional Information

SIDE EFFECTS

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

  • Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see WARNINGS AND PRECAUTIONS].

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 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

HARVONI
8 weeks
(N=215)
HARVONI
12 weeks
(N=539)
HARVONI
24 weeks
(N=326)
Fatigue 16% 13% 18%
Headache 11% 14% 17%
Nausea 6% 7% 9%
Diarrhea 4% 3% 7%
Insomnia 3% 5% 6%

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 treatmentexperienced 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 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

HARVONI
24 weeks
(N=78)
HARVONI + RBV
12 weeks
(N=76)
Placebo
12 weeks
(N=77)
Asthenia 31% 36% 23%
Headache 29% 13% 16%
Fatigue 18% 4% 1%
Cough 5% 11% 1%
Myalgia 9% 4% 0
Dyspnea 3% 9% 1%
Irritability 8% 7% 1%
Dizziness 5% 1% 0
RBV=ribavirin

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 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 [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 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 1.5×ULN 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 1.5×ULN 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 3×ULN 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 3× 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 10×ULN 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%) [see Clinical Studies].

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) [see Clinical Studies].

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 [see Clinical Studies].

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 [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].

Skin And Subcutaneous Tissue Disorders

Skin rashes, sometimes with blisters or angioedema-like swelling

Angioedema

DRUG INTERACTIONS

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 [see WARNINGS AND PRECAUTIONS].

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 [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

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

Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment
Acid Reducing Agents: ↓ ledipasvir Ledipasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of ledipasvir.
Antacids (e.g., aluminum and magnesium hydroxide) It is recommended to separate antacid and HARVONI administration by 4 hours.
H2 -receptor antagonists (e.g., famotidine) H2 -receptor antagonists may be administered simultaneously with or 12 hours apart from HARVONI at a dose that does not exceed doses comparable to famotidine 40 mg twice daily.
Proton-pump inhibitors (e.g., omeprazole) Proton-pump inhibitor doses comparable to omeprazole 20 mg or lower can be administered simultaneously with HARVONI under fasted conditions.
Antiarrhythmics:
amiodarone
Effect on amiodarone, ledipasvir, and sofosbuvir concentrations unknown Coadministration of amiodarone with HARVONI may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with HARVONI is not recommended; if coadministration is required, cardiac monitoring is recommended [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].
digoxin ↑ digoxin Coadministration of HARVONI with digoxin may increase the concentration of digoxin. Therapeutic concentration monitoring of digoxin is recommended when coadministered with HARVONI.
Anticonvulsants:
carbamazepine
phenytoin
phenobarbital
↓ ledipasvir
↓ sofosbuvir
Coadministration of HARVONI with carbamazepine, phenytoin, or phenobarbital is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of HARVONI.
Coadministration is not recommended.
Antimycobacterials:
rifabutin
rifampin
rifapentine
↓ ledipasvir
↓ sofosbuvir
Coadministration of HARVONI with rifampin, rifabutin, or rifapentine is not recommended [see WARNINGS AND PRECAUTIONS].
HIV Antiretrovirals:
Regimens containing tenofovir DF without an HIV protease inhibitor/ ritonavir or cobicistat ↑ tenofovir Monitor for tenofovir-associated adverse reactions in patients receiving HARVONI concomitantly with a regimen containing tenofovir DF without an HIV protease inhibitor/ritonavir or cobicistat. Refer to VIREAD or TRUVADA prescribing information for recommendations on renal monitoring.
Regimens containing tenofovir DF and an HIV protease inhibitor/ ritonavir or cobicistat
  • atazanavir/ritonavir or cobicistat + emtricitabine/tenofovir DF
  • darunavir/ritonavir or cobicistat + emtricitabine/tenofovir DF
  • lopinavir/ritonavir + emtricitabine/tenofovir DF
↑ tenofovir The safety of increased tenofovir concentrations in the setting of HARVONI and an HIV protease inhibitor/ritonavir or cobicistat has not been established.

Consider alternative HCV or antiretroviral therapy to avoid increases in tenofovir exposures. If coadministration is necessary, monitor for tenofovir-associated adverse reactions. Refer to VIREAD or TRUVADA prescribing information for recommendations on renal monitoring.

elvitegravir, cobicistat, emtricitabine, tenofovir DF ↑ tenofovir The safety of increased tenofovir concentrations in the setting of HARVONI and the combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF has not been established. Coadministration is not recommended.
tipranavir/ritonavir ↓ ledipasvir
↓ sofosbuvir
Coadministration of HARVONI with tipranavir/ritonavir is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of HARVONI. Coadministration is not recommended.
HCV Products:
simeprevir
↑ ledipasvir
↑ simeprevir
Concentrations of ledipasvir and simeprevir are increased when simeprevir is coadministered with ledipasvir. Coadministration of HARVONI with simeprevir is not recommended.
Herbal Supplements:
St. John's wort (Hypericum perforatum)
↓ ledipasvir
↓ sofosbuvir
Coadministration of HARVONI with St. John's wort, a P-gp inducer, is not recommended [see WARNINGS AND PRECAUTIONS].
HMG-CoA Reductase Inhibitors:
rosuvastatin
↑ rosuvastatin Coadministration of HARVONI with rosuvastatin may significantly increase the concentration of rosuvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Coadministration of HARVONI with rosuvastatin is not recommended.
atorvastatin ↑ atorvastatin Coadministration of HARVONI with atorvastatin may be associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse reactions, such as myopathy and rhabdomyolysis.
tenofovir DF = tenofovir disoproxil fumarate
* This table is not all inclusive.
↓ = decrease, ↑ = increase
These interactions have been studied in healthy adults.

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 [see CLINICAL PHARMACOLOGY]:

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 [see Established And Potentially Significant Drug Interactions].

Read the entire FDA prescribing information for Harvoni (Ledipasvir and Sofosbuvir Tablets)

© Harvoni Patient Information is supplied by Cerner Multum, Inc. and Harvoni Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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