- ACRONYMS AND DEFINITIONS
- AASLD - American Association for the Study of Liver Diseases
- CP - Child-Pugh liver failure classification
- GT - Genotype
- HBV - Hepatitis B virus
- HCV - Hepatitis C virus
- IDSA - Infectious Diseases Society of America
- PegIFN - Pegylated interferon
- RBV - Ribavirin
- ULN - Upper limit of normal
- DRUGS IN CLASS
- 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 adults and pediatric patients ≥ 3 years of age
- HCV genotype 1
- No cirrhosis or Child-Pugh A: Harvoni alone
- Child-Pugh B/C and post-liver transplant: Harvoni + ribavirin
- HCV genotype 4
- No cirrhosis and Child-Pugh A: Harvoni alone
- Post-liver transplant without cirrhosis or with Child-Pugh A: Harvoni + ribavirin
- HCV genotype 5
- No cirrhosis or Child-Pugh A: Harvoni alone
- HCV genotype 6
- No cirrhosis or Child-Pugh A: Harvoni alone
- HEPATITIS C TREATMENT
| HCV cure rates for Harvoni ± ribavirin | ||
|---|---|---|
| Genotype | No cirrhosis or Child-Pugh A | Child-Pugh 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® for 12 weeks (N=539) |
Harvoni® for 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 for Harvoni
- If Harvoni is prescribed with ribavirin, the contraindications to ribavirin apply. See ribavirin for more.
- PRECAUTIONS
- Kidney disease
- No dosage adjustment of Harvoni is recommended in patients with any degree of renal impairment, including end-stage renal disease (ESRD) on dialysis
- 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 interpreting HBV screening results 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: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here 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.
- Ledipasvir and sofosbuvir
- See the Harvoni PI [sec 7] for a complete list of potential drug interactions
- Clearance of HCV and liver function - 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. Examples of drugs that may need to be adjusted after liver function improves include diabetes medications, drugs with narrow therapeutic index, warfarin, immunosuppressants, and others.
- 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.
- Digoxin - Harvoni® may increase digoxin levels.
- HIV antiretrovirals - See the Harvoni PI [sec 7] for recommendations on concomitant HIV antiretroviral medications
- 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
- Rosuvastatin (Crestor®) - Harvoni® can increase blood levels of rosuvastatin. Harvoni® and rosuvastatin should not be taken together.
- Warfarin (Coumadin®) - Fluctuations in INR levels may occur when Harvonia is taken with warfarin. Monitor INR levels closely.
- 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 clearance
- 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
- DOSING
- Dosage form
- Tablet
- 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.
- Oral pellets
- ledipasvir : sofosbuvir
- 33.75 mg : 150 mg packet
- 45 mg : 200 mg packet
- Comes in carton with 28 packets
- Pellets are sprinkled on food and swallowed whole
- Dosing
- Adults: One tablet once daily. May take without regard to food.
- See Harvoni PI [sec 2] for dosing in pediatric patients
| Harvoni treatment regimens | ||
|---|---|---|
| HCV GT | Patient population | Regimen |
| 1 |
|
May consider Harvoni for 8 weeks |
|
Harvoni for 12 weeks | |
|
Harvoni for 12 weeks | |
|
Harvoni for 24 weeks Harvoni + ribavirin for 12 weeks can also be considered |
|
|
Harvoni + ribavirin for 12 weeks | |
|
Harvoni + ribavirin for 12 weeks | |
| 4 |
|
Harvoni for 12 weeks |
|
Harvoni + ribavirin for 12 weeks | |
| 5 |
|
Harvoni for 12 weeks |
| 5 |
|
Harvoni for 12 weeks |
- LONG TERM SAFETY
- Harvoni® was FDA-approved in 2014
- There is no long-term safety data for the medication but it has been shown to be generally safe in a number of trials
- BIBLIOGRAPHY
- 1 - Harvoni® PI
- 2 - PMID 24725239
- 3 - PMID 24725238
- 4 - PMID 24720702