- ACRONYMS AND DEFINITIONS
- AASLD - American Association for the Study of Liver Diseases
- CP - Child-Pugh liver failure classification
- GT - Genotype
- HCV - Hepatitis C virus
- IDSA - Infectious Diseases Society of America
- PegIFN - Pegylated interferon
- RBV - Ribavirin
- ULN - Upper limit of normal
- DRUGS IN CLASS
- Hepatitis C treatment
- Harvoni is part of a new generation of antiviral medications that are highly effective against hepatitis C
- Harvoni is a combination pill that contains 2 medications - ledipasvir and sofosbuvir
- See Hepatitis C treatment for a list of other HCV drugs
- MECHANISM OF ACTION
- Sofosbuvir
- Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication
- Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator
- Ledipasvir
- Ledipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication and virion assembly
- FDA-APPROVED INDICATIONS
- Treatment of HCV genotype 1
- No cirrhosis or Child-Pugh A: Harvoni alone
- Child-Pugh B/C and post-liver transplant: Harvoni + ribavirin
- Treatment of HCV genotype 4
- No cirrhosis and Child-Pugh A: Harvoni alone
- Post-liver transplant without cirrhosis or with Child-Pugh A: Harvoni + ribavirin
- Treatment of HCV genotype 5
- No cirrhosis or Child-Pugh A: Harvoni alone
- Treatment of HCV genotype 6
- No cirrhosis or Child-Pugh A: Harvoni alone
- EFFECTIVENESS
| HCV cure rates for Harvoni ± ribavirin | ||
|---|---|---|
| GT | No cirrhosis or CP A | CP B/C |
| 1 | > 90% | > 85% |
| 4 | > 90% | N/A |
| 5 | > 90% | N/A |
| 6 | > 90% | N/A |
- SIDE EFFECTS
- Overview
- The pooled incidence of side effects from Harvoni™ trials is presented below
- Placebo-control was not used in these trials, so the strength of association is not known
- Harvoni™ is generally well-tolerated with only 0 - 1% of patients in clinical trials discontinuing therapy because of side effects
| Side effect | Harvoni™ 12 weeks N=539 |
Harvoni™ 24 weeks N=326 |
|---|---|---|
| Fatigue | 13% | 18% |
| Headache | 14% | 17% |
| Nausea | 7% | 9% |
| Diarrhea | 3% | 7% |
| Insomnia | 5% | 6% |
| Bilirubin elevations (> 1.5 X ULN) |
< 1% | 2% |
| Lipase elevations (> 3 X ULN) |
2% | 3% |
- CONTRAINDICATIONS
- None known
- PRECAUTIONS
- Kidney disease
- CrCl ≥ 30 ml/min: no dose adjustment necessary
- CrCl < 30 ml/min: safety has not been established. No recommendation made.
- Liver disease
- No dose adjustment of Harvoni is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B or C)
- Hepatitis B coinfection
- In October 2016, the FDA placed a boxed warning on all new hepatitis C drugs about the possible reactivation of hepatitis B infection in coinfected patients who are taking direct-acting antiviral hepatitis C drugs
- At the time of the warning, the FDA had identified 24 cases of hepatitis B reactivation in patients taking these drugs. Reactivation occurred in patients who were HBsAg positive and in those who were HBsAg negative and anti-HBc positive (see hepatitis B serology for more).
- The FDA recommends that providers check all patients for hepatitis B coinfection (HBsAg and anti-HBc) before starting therapy and that they monitor patients for reactivation during and after therapy
- See AASLD guidelines for HBV coinfected patients for more
- MONITORING THERAPY
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT A COMPREHENSIVE LIST of all known interactions. Other interactions exist. The interactions below are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- HIGH ALERT INTERACTIONS
Ledipasvir and sofosbuvir
- See the Harvoni PI for a complete list of potential drug interactions
- Amiodarone (Cordarone®)
- Serious cases of bradycardia (slow heart rate) have been reported in patients taking amiodarone in combination with Harvoni™. Bradycardia typically occurs within hours to days but has been observed as late as 2 weeks after initiating therapy.
- Concomitant therapy with amiodarone and Harvoni™ is not recommended
- In cases where no other options are available, inpatient cardiac monitoring should be performed for the first 48 hours of concomitant therapy, 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
- Atorvastatin (Lipitor®)
- Harvoni™ can increase blood levels of atorvastatin. Monitor patients closely for statin-related adverse events such as myopathy and rhabdomyolysis when taken together.
- P-glycoprotein inducers
- Ledipasvir and sofosbuvir are P-glycoprotein substrates
- Drugs that induce P-glycoprotein may decrease the effectiveness of ledipasvir and sofosbuvir
- Harvoni should not be given with P-glycoprotein inducers (ex. rifampin and St. John's Wort)
- NOTE: Harvoni™ may be given with P-glycoprotein inhibitors
- Examples of common P-glycoprotein inducers include:
- Carbamazepine (Tegretol®)
- Oxcarbazepine (Trileptal®) (decreases sofosbuvir levels probably through P-glycoprotein induction)
- Phenobarbital
- Phenytoin (Dilantin®)
- Rifabutin
- Rifampin
- Rifapentine (Priftin®)
- St John's Wort
- Tipranavir (Aptivus®)
- Ritonavir (Norvir®)
- Rosuvastatin (Crestor®)
- Harvoni™ can increase blood levels of rosuvastatin. Harvoni™ and rosuvastatin should not be taken together.
Ledipasvir
- Drugs that raise stomach pH
- The solubility of ledipasvir decreases as stomach pH increases
- Medications that raise stomach pH can lead to decreased absorption and effectiveness of ledipasvir
- Common acid-reducing agents include:
- Antacids (aluminum and magnesium hydroxide) - separate antacid and Harvoni™ administration by 4 hours
- H₂-receptor blockers (Pepcid®, Tagamet®, famotidine, etc.) - 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 (Nexium®, Prilosec®, Prevacid®) - Proton pump inhibitor doses comparable to omeprazole 20 mg or lower can be administered simultaneously with Harvoni™ under fasted conditions.
- METABOLISM AND ELIMINATION
- NOTE: Drugs can be metabolized by more than one enzyme. Drugs may be metabolized by an enzyme and inhibit/induce the enzyme at the same time. Drug transporters (ex. p-glycoprotein) can play a role in drug metabolism. Not all drug interactions are clinically significant. Consult your physician or pharmacist if you are taking medications together and are concerned about a possible interaction.
- Ledipasvir
- Ledipasvir is subject to slow oxidative metabolism via an unknown mechanism
- In vitro, no detectable metabolism of ledipasvir by CYP enzymes has been observed
- P-glycoprotein - substrate and inhibitor
- BCRP - substrate and inhibitor
- Sofosbuvir
- Sofosbuvir does not undergo CYP450 metabolism
- The metabolic activation pathway of sofosbuvir involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway.
- P-glycoprotein - substrate
- BCRP - substrate
- OTHER
- Digoxin - Harvoni™ may increase digoxin levels.
- Tenofovir (Viread®, etc.) - Harvoni™ may increase levels of tenofovir. Monitor for tenofovir-associated adverse reactions when taken with Harvoni™.
- Simeprevir (Olysio®) - simeprevir increases blood levels of ledipasvir and sofosbuvir. They should not be taken together.
- Warfarin (Coumadin®) - Fluctuations in INR levels may occur when Harvonia is taken with warfarin. Monitor INR levels closely.
- DOSING
- Dosage form
- Each tablet contains ledipasvir 90 mg and sofosbuvir 400 mg
- Harvoni comes in bottles that contain 28 tablets. Harvoni should be dispensed in original container.
- Dosing
- One tablet once daily
- Food
- May take without regard to food
- Treatment regimens
- HCV Genotype 1 (adult dosing)
- Treatment-naïve without cirrhosis, baseline viral load < 6 million IU/ml: May consider Harvoni once daily for 8 weeks
- Treatment-naïve without cirrhosis or with Child-Pugh A: Harvoni once daily for 12 weeks
- Treatment-experienced✝ without cirrhosis: Harvoni once daily for 12 weeks
- Treatment-experienced✝ with Child-Pugh A: Harvoni once daily for 24 weeks
- Treatment-naïve and treatment-experienced✝ with Child-Pugh B or C: Harvoni once daily + ribavirin for 12 weeks. Ribavirin dosing should be weight-based with a starting dose of 600 mg and titration as tolerated.
- Treatment-naïve and treatment-experienced✝ post-liver transplant without cirrhosis or with Child-Pugh A: Harvoni once daily + ribavirin for 12 weeks. Ribavirin dosing should be weight-based.
- ✝Previous treatment with regimens containing PegIFN/RBV with or without an HCV NS3/4A protease inhibitor
- HCV Genotype 4 (adult dosing)
- Treatment-naïve and treatment-experienced✝ without cirrhosis or with Child-Pugh A: Harvoni once daily for 12 weeks.
- Treatment-naïve and treatment-experienced✝ post-liver transplant without cirrhosis or with Child-Pugh A: Harvoni once daily + ribavirin for 12 weeks. Ribavirin dosing should be weight-based.
- ✝Previous treatment with regimens containing PegIFN/RBV with or without an HCV NS3/4A protease inhibitor
- HCV Genotype 5 (adult dosing)
- Treatment-naïve and treatment-experienced✝ without cirrhosis or with Child-Pugh A: Harvoni once daily for 12 weeks
- ✝Previous treatment with regimens containing PegIFN/RBV with or without an HCV NS3/4A protease inhibitor
- HCV Genotype 6 (adult dosing)
- Treatment-naïve and treatment-experienced✝ without cirrhosis or with Child-Pugh A: Harvoni once daily for 12 weeks
- ✝Previous treatment with regimens containing PegIFN/RBV with or without an HCV NS3/4A protease inhibitor
- LONG TERM SAFETY
- Harvoni™ was FDA-approved in 2014
- There is no long-term safety data for the medication
- GENERIC AVAILABILITY
- Generic:
- None
- Possible generic:
- NOTE: Drug companies typically file multiple patents on their drugs in order to protect them from competition. The patent expiration listed here is the date that the earliest patent on the drug expires (accounting for pediatric exclusivity). Because drug companies use numerous techniques to extend the life of their patents, it does not necessarily mean a generic will become available around this date.
| DRUG | PATENT EXPIRES |
|---|---|
| Harvoni™ | MAR 2028 |
- BIBLIOGRAPHY
- What is PMID?
- PI = Manufacturer's Package Insert
- 1 - Harvoni™ PI
- 2 - PMID 24725239
- 3 - PMID 24725238
- 4 - PMID 24720702