®
Manufacturer: Gilead Sciences
FDA Approval Date: 10/10/2014

Harvoni
®
- ledipasvir/sofosbuvir
Clinical Application
• Indication:
• Treatment of chronic hepatitis C (CHC) genotype 1 infection in adults.
• Place in therapy:
• One pill a day for convenient dosing and increased compliance
• Less adverse effects than the current treatment options for genotype 1

Harvoni
®
- ledipasvir/sofosbuvir
Clinical Application
• Contraindications:
• None
• Warnings and Precautions:
• P-gp inducers may reduce therapeutic effect of Harvoni.
• The use of Harvoni with other products containing sofosbuvir (Sovaldi) is not recommended.

Harvoni
®
- ledipasvir/sofosbuvir
Clinical Application
• Pregnancy:
• Category B
• Lactation:
• It is not known whether Harvoni can be found in human breast milk.

Harvoni
®
- ledipasvir/sofosbuvir
Drug Facts
• Pharmacology:
•
• Ledipasvir – inhibits the HCV NS5A protein necessary for viral replication
Sofosbuvir – prodrug converted to its active form (GS-461203), which inhibits
NS5B RNA-dependent RNA polymerase and acts as a chain terminator

Harvoni
®
- ledipasvir/sofosbuvir
Drug Facts
• Pharmacokinetics:
A
C max
4-4.5 hours
Well absorbed
>99.8% protein bound
D
M
E
Slow oxidative metabolism via an unknown mechanism
87% feces, 1% urine
T
1/2
47 hours

Harvoni
®
- ledipasvir/sofosbuvir
Drug Interactions
• Drug Interactions – Object Drugs:
•
•
•
•  digoxin
 tenofovir
 simeprevir
 rosuvastatin

Harvoni
®
- ledipasvir/sofosbuvir
Drug Interactions
• Drug Interactions – Precipitant Drugs:
•
•
•
•
• Acid reducing agents
 solubility of ledipasvir
Anticonvulsants

Harvoni
Antimycobacterials

Harvoni
HCV products
 ledipasvir
St. Johns wort

Harvoni

Harvoni
®
- ledipasvir/sofosbuvir
Adverse Effects
Fatigue
Headache
Nausea
Diarrhea
Insomnia
Harvoni
8 weeks
16%
11%
6%
4%
3%
Harvoni
12 weeks
13%
14%
7%
3%
5%
Harvoni
24 weeks
18%
17%
9%
7%
6%

Harvoni
®
- ledipasvir/sofosbuvir
Monitoring Parameters
• Efficacy Monitoring:
•
• Signs of clinical improvement
HCV RNA (viral load) at weeks 4 and 12
• Toxicity Monitoring:
• CBC, basic chemistry panel, liver enzyme levels, bilirubin levels at weeks 1-2, 4, and then monthly during treatment

Harvoni
®
- ledipasvir/sofosbuvir
Prescription Information
• Dosing:
• One tablet (90mg ledipasvir/400mg sofosbuvir) taken orally once daily with or without food
• Treatmentnaïve with or without cirrhosis: 12 weeks
• Treatment-experienced without cirrhosis: 12 weeks
• Treatment-experienced with cirrhosis:
24 weeks

Harvoni
®
- ledipasvir/sofosbuvir
Prescription Information
Duration of Treatment
8 Weeks
12 Weeks
24 Weeks
Estimated Cost
$63,000
$94,500
$189,000
*Estimated cost based on Wholesaler Acquisition Cost of $1125 per pill

Harvoni
®
- ledipasvir/sofosbuvir
Literature Review
ION-1
• Design: open-label, randomized, phase
3 trial
• 99 sites in the United States and Europe
• Interventions
• Fixed-dose combinations of ledipasvir/sofosbuvir +/- ribavirin for 12 or 24 weeks in treatmentnaïve patients with genotype 1 HCV
Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

Harvoni
®
- ledipasvir/sofosbuvir
Literature Review
ION-1
• Primary Endpoint: SVR at 12 weeks after the end of treatment
• Assessed in all patients who were randomized and received treatment
Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

Harvoni
®
- ledipasvir/sofosbuvir
Literature Review
ION-1
• Inclusion Criteria:
•
•
•
• Chronic HCV Genotype I (n=865)
18 years or older
No prior HCV treatment
Patients with cirrhosis accepted (up to
20% of patients)
Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

ION-1
Harvoni
®
- ledipasvir/sofosbuvir
Literature Review
12 week treatment
24 week treatment
Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

ION-1
Harvoni
®
- ledipasvir/sofosbuvir
Literature Review
*Subgroup results do not include patients who withdrew consent or were lost to follow-up
12 week treatment
24 week treatment
Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

Harvoni
®
- ledipasvir/sofosbuvir
Literature Review
ION-1
• Conclusions:
• “Once daily ledipasvir/sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection.”
Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

Harvoni
®
- ledipasvir/sofosbuvir
Summary
• Harvoni
® is indicated for the treatment of chronic hepatitis C genotype 1 infection in adults
• The use of Harvoni
® with P-gp inducers is not recommended
• Harvoni
® has a convenient dosing schedule which may increase compliance

Harvoni
®
- ledipasvir/sofosbuvir
References
2.
3.
1.
4.
Harvoni package insert. Gilead. October 2014. http://www.gilead.com/~/media/Files/pdfs/medici nes/liver-disease/harvoni/harvoni_pi.pdf
http://www.harvoni.com/ November 2014.
UPDATE 2 US FDA approves Gilead’s $94,500 hepatitis C drug. Reuters. October 2014.
(http://www.reuters.com/article/2014/10/10/gileadfda-hepatitis-idUSL2N0S51WN20141010)
Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:1889-98.