HARVONI is ledipasvir and sofosbuvir in one pill

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On October 10, 2014, FDA approved HARVONI a fixed-dose combination tablet of ledipasvir 90 mg, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir 400 mg, an HCV nucleotide analog NS5B polymerase inhibitor. Harvoni is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults. HARVONI is the first combination pill approved to treat chronic HCV genotype 1 infection. HARVONI is also the first approved regimen that does not require administration with interferon or ribavirin, two FDA-approved drugs also used to treat HCV infection.
Dosage and Administration:
The recommended dosage of HARVONI is one tablet taken orally once daily with or without food.
Recommended Treatment Duration for HARVONI in Patients with CHC Genotype 1

Patient Population	Recommended Treatment Duration
Treatment-naïve with or without cirrhosis	12 weeks*
Treatment-experienced** without cirrhosis	12 weeks
Treatment-experienced** with cirrhosis	24 weeks

* HARVONI for 8 weeks can be considered in treatment-naïve patients without cirrhosis who have pre-treatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14)].
** Treatment-experienced patients who have failed treatment with either peginterferon alfa + ribavirin or an HCV protease inhibitor + peginterferon alfa + ribavirin.

No dosage adjustment of HARVONI is required for patients with mild or moderate renal impairment. No dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate [eGFR] <30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite.
No dosage adjustment of HARVONI is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C). Safety and efficacy of HARVONI have not been established in patients with decompensated cirrhosis.
WARNINGS AND PRECAUTIONS

Risk of Reduced Therapeutic Effect Due to P-gp Inducers
The concomitant use of HARVONI and P-gp inducers (e.g., rifampin, St. John’s wort) may significantly decrease ledipasvir and sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of HARVONI. Therefore, the use of HARVONI with P-gp inducers (e.g., rifampin or St. John’s wort) is not recommended

Related Products Not Recommended
The use of HARVONI with other products containing sofosbuvir (SOVALDI®) is not recommended
Data to Support Approval:
Harvoni’s efficacy was evaluated in three clinical trials enrolling 1,518 subjects who had not previously received treatment for their infection (treatment-naive) or had not responded to previous treatment (treatment-experienced), including subjects with cirrhosis. Subjects were randomly assigned to receive Harvoni with or without ribavirin. The trials were designed to measure whether the hepatitis C virus was no longer detected in the blood at least 12 weeks after finishing treatment (sustained virologic response, or SVR), indicating that a subject’s HCV infection has been cured. See Clinical Studies below for additional details.

ADVERSE REACTIONS
The safety assessment of HARVONI was based on pooled data from three Phase 3 clinical trials of subjects with genotype 1 chronic hepatitis C (CHC) with compensated liver disease (with and without cirrhosis) including 215, 539, and 326 subjects who received HARVONI for 8, 12 and 24 weeks, respectively.
The most common adverse reactions (≥10%) were fatigue and headache in subjects treated with 8, 12, or 24 weeks of HARVONI.

The Table below lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in ≥5% of subjects receiving 8, 12, or 24 weeks treatment with HARVONI in clinical trials. Themajority of adverse reactions presented in Table 2 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 2 Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with HARVONI

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

Laboratory Abnormalities

Bilirubin Elevations: Bilirubin elevations of greater than 1.5xULN were observed in 3%, <1%, and 2% of subjects treated with HARVONI for 8, 12, and 24 weeks, respectively.

Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3xULN were observed in <1%, 2%, and 3% of subjects treated with HARVONI for 8, 12, and 24 weeks, respectively.

Creatine Kinase: Creatine kinase was not assessed in Phase 3 trials of HARVONI. Isolated, asymptomatic creatine kinase elevations (Grade 3 or 4) have been previously reported in subjects treated with sofosbuvir in combination with ribavirin or peginterferon/ribavirin in other clinical trials.

DRUG INTERACTIONS
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 or 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.
The Table below 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.

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

Concomitant Drug Class: Drug Name	Effect on Concentration^b	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 antagonistsc (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 inhibitorsc (e.g., omeprazole)		Proton-pump inhibitor doses comparable to omeprazole 20 mg or lower can be administered simultaneously with HARVONI under fasted conditions.
Antiarrhythmics: 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 oxcarbazepine	↓ ledipasvir ↓ sofosbuvir ↓ GS-331007	Coadministration of HARVONI with carbamazepine, phenytoin, phenobarbital, or oxcarbazepine is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of HARVONI. Coadministration is not recommended.
Antimycobacterials: rifabutin rifampinc rifapentine	↓ ledipasvir ↓ sofosbuvir ↓ GS-331007	Coadministration of HARVONI with rifabutin or rifapentine is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of HARVONI. Coadministration is not recommended. Coadministration of HARVONI with rifampin, a P-gp inducer, is not recommended [see Warnings and Precautions (5.1)].
HIV Antiretrovirals:
efavirenz, emtricitabine, tenofovir disoproxil fumarate (DF)	↑ tenofovir	Monitor for tenofovir-associated adverse reactions in patients receiving HARVONI concomitantly with the combination of efavirenz, emtricitabine and tenofovir DF. Refer to VIREAD, TRUVADA, or ATRIPLA prescribing information for recommendations on renal monitoring.
Regimens containing tenofovir DF and a HIV protease inhibitor/ritonavir atazanavir/ritonavir + emtricitabine/tenofovir DFc darunavir/ritonavir + emtricitabine/tenofovir DFc lopinavir/ritonavir + emtricitabine/tenofovir DF	↑ tenofovir	The safety of increased tenofovir concentrations in the setting of HARVONI and a HIV protease inhibitor/ritonavir 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 ↓ GS-331007	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^c	↑ 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 ↓ GS-331007	Coadministration of HARVONI with St. John’s wort, a P-gp inducer is not recommended [see Warnings and Precautions (5.1)].
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.

a. This table is not all inclusive.
b. ↓ = decrease, ↑ = increase

c. 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 individually: abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, lamivudine, methadone, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, tenofovir disoproxil fumarate, or verapamil. See Table above for use of HARVONI with certain HIV antiretroviral regimens.

Clinical Studies
Treatment-Naïve Adults without Cirrhosis - ION-3 (Study 0108)
ION-3 was a randomized, open-label trial in treatment-naïve non-cirrhotic subjects with genotype 1 CHC. Subjects were randomized in a 1:1:1 ratio to one of the following three treatment groups and stratified by HCV genotype (1a vs 1b): HARVONI for 8 weeks, HARVONI for 12 weeks, or HARVONI + ribavirin for 8 weeks.

Demographics and baseline characteristics were balanced across the treatment groups. Of the 647 treated subjects, the median age was 55 years (range: 20 to 75); 58% of the subjects were male; 78% were White; 19% were Black; 6% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 18 to 56 kg/m2); 81% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 80% had genotype 1a HCV infection; 73% had non-C/C IL28B alleles (CT or TT).

Table 6 presents the response rates for the HARVONI treatment groups in the ION-3 trial after 8 and 12 weeks of HARVONI treatment. Ribavirin was not shown to increase the response rates observed with HARVONI. Therefore, the HARVONI + ribavirin arm is not presented in Table 6.

Table 6 Study ION-3: Response Rates after 8 and 12 Weeks of Treatment in Treatment-Naïve Non-Cirrhotic Subjects with Genotype 1 CHC

Outcome for Subjects without SVR
	HARVONI 8 Weeks (N=215)	HARVONI 12 Weeks (N=216)
SVR	94% (202/215)	96% (208/216)
On-Treatment Virologic Failure	0/215	0/216
Relapse^a	5% (11/215)	1% (3/216)
Other^b	1% (2/215)	2% (5/216)
SVR by Genotype^c
Genotype 1a	93% (159/171)	96% (165/172)
Genotype 1b	98% (42/43)	98% (43/44)

a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment.
b. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).
c. One subject without a confirmed subtype for genotype 1 infection was excluded from this subgroup analysis.

The treatment difference between the 8-week treatment of HARVONI and 12-week treatment of HARVONI was –2.3% (97.5% confidence interval –7.2% to 2.5%). Among subjects with a baseline HCV RNA <6 million IU/mL, the SVR was 97% (119/123) with 8-week treatment of HARVONI and 96% (126/131) with 12-week treatment of HARVONI.

Relapse rates by baseline viral load are presented in Table 7.

Table 7 Study ION-3: Relapse Rates by Baseline Viral Load after 8 and 12 Weeks of Treatment in Treatment-Naïve Non-Cirrhotic Subjects with Genotype 1 CHC

Baseline HCV RNA^a
	HARVONI 8 Weeks (N=215)	HARVONI 12 Weeks (N=216)
Number of Responders at End of Treatment	215	216
HCV RNA <6 million IU/mL	2% (2/123)	2% (2/131)
HCV RNA ≥6 million IU/mL	10% (9/92)	1% (1/85)

a. HCV RNA values were determined using the Roche TaqMan Assay; a subject's HCV RNA may vary from visit to visit.

Treatment-Naïve Adults with or without Cirrhosis - ION-1 (Study 0102)
ION-1 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in 865 treatment-naïve subjects with genotype 1 CHC including those with cirrhosis. Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI + ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis and HCV genotype (1a vs 1b). The interim primary endpoint analysis for SVR included all subjects enrolled in the 12-week treatment groups (N=431). SVR rates for all subjects enrolled in the 24-week treatment groups (N=434) were not available at the time of interim analysis.

Demographics and baseline characteristics were balanced across the treatment groups. Of the 865 treated subjects, the median age was 54 years (range: 18 to 80); 59% of the subjects were male; 85% were White; 12% were Black; 12% were Hispanic or Latino; mean body mass index was 27 kg/m2 (range: 18 to 48 kg/m2); 79% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 67% had genotype 1a HCV infection; 70% had non-C/C IL28B alleles (CT or TT); and 16% had cirrhosis.
Table 8 presents the response rates for the treatment group of HARVONI for 12 weeks in the ION-1 trial. Ribavirin was not shown to increase response rates observed with HARVONI. Therefore, the HARVONI + ribavirin arm is not presented in Table 8.

Table 8 Study ION-1: Response Rates after 12 Weeks of Treatment in Treatment-Naïve Subjects with Genotype 1 CHC with and without Cirrhosis

Outcome for Subjects without SVR
	HARVONI 12 Weeks (N=214)
SVRa	99% (210/213)
On-Treatment Virologic Failure^a	0/213
Relapse^a,b	<1% (1/212)
Other^a,c	1% (2/213)

a. Excluding one subject with genotype 4 infection.
b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment.
c. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).

Response rates for selected subgroups are presented in Table 9.

Table 9 Study ION-1: SVR Rates for Selected Subgroups after 12 Weeks of Treatment in Treatment-Naïve Subjects with Genotype 1 CHC with and without Cirrhosis

Genotype^a
	HARVONI 12 Weeks (N=214)
Genotype 1a	98% (142/145)
Genotype 1b	100% (67/67)
Cirrhosis^b
No	99% (176/177)
Yes	94% (32/34)

a. One subject without a confirmed subtype for genotype 1 infection and one subject with genotype 4 infection were excluded from this subgroup analysis.
b. Subjects with missing cirrhosis status were excluded from this subgroup analysis.

14.3 Clinical Trials in Subjects Who Failed Prior Therapy
Previously-Treated Adults with or without Cirrhosis - ION-2 (Study 0109)
ION-2 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in genotype 1 HCV-infected subjects with or without cirrhosis who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor. Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI + ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis, HCV genotype (1a vs 1b) and response to prior HCV therapy (relapse/breakthrough vs nonresponse).

Demographics and baseline characteristics were balanced across the treatment groups. Of the 440 treated subjects, the median age was 57 years (range: 24 to 75); 65% of the subjects were male; 81% were White; 18% were Black; 9% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 19 to 50 kg/m2); 89% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 79% had genotype 1a HCV infection; 88% had non-C/C IL28B alleles (CT or TT); and 20% had cirrhosis. Forty‑seven percent (47%) of the subjects failed a prior therapy of pegylated interferon and ribavirin. Among these subjects, 49% were relapse/breakthrough and 51% were non-responder. Fifty-three percent (53%) of the subjects failed a prior therapy of pegylated interferon and ribavirin with an HCV protease inhibitor. Among these subjects, 62% were relapse/breakthrough and 38% were non-responder.

Table 10 presents the response rates for the HARVONI treatment groups in the ION-2 trial. Ribavirin was not shown to increase response rates observed with HARVONI. Therefore, the HARVONI + ribavirin arms are not presented in Table 10.

Table 10 Study ION-2: Response Rates after 12 and 24 Weeks of Treatment in Subjects with Genotype 1 CHC with or without Cirrhosis who Failed Prior Therapy

Outcome for Subjects without SVR
	HARVONI 12 Weeks (N=109)	HARVONI 24 Weeks (N=109)
SVR	94% (102/109)	99% (108/109)
On-Treatment Virologic Failure	0/109	0/109
Relapse^a	6% (7/108)	0/109
Other^b	0/109	1% (1/109)

Among the subjects with available SVR12 and SVR24 data (206/218), all subjects who achieved SVR12 in the ION-2 study also achieved SVR24.

Response rates and relapse rates for selected subgroups are presented in Tables 11 and 12.

Table 11 Study ION-2: SVR Rates for Selected Subgroups after 12 and 24 Weeks of Treatment in Subjects with Genotype 1 CHC who Failed Prior Therapy

Genotype
	HARVONI 12 Weeks (N=109)	HARVONI 24 Weeks (N=109)
Genotype 1a	95% (82/86)	99% (84/85)
Genotype 1b	87% (20/23)	100% (24/24)
Cirrhosis^a
No	95% (83/87)	99% (85/86)
Yes	86% (19/22)	100% (22/22)
Prior HCV Therapy
Peg-IFN + RBV	93% (40/43)	100% (58/58)
HCV protease inhibitor + Peg-IFN + RBV	94% (62/66)	98% (49/50)
Response to Prior HCV Therapy
Relapse/Breakthrough	95% (57/60)	100% (60/60)
Nonresponder	92% (45/49)	98% (48/49)

a. Subjects with missing cirrhosis status were excluded from this subgroup analysis.

Table 12 Study ION-2: Relapse Rates for Selected Subgroups after 12 and 24 Weeks of Treatment in Subjects with Genotype 1 CHC who Failed Prior Therapy

Cirrhosis^a
	HARVONI 12 Weeks (N=109)	HARVONI 24 Weeks (N=109)
Number of Responders at End of Treatment	108	109
No	5% (4/86)^b	0% (0/86)
Yes	14% (3/22)	0% (0/22)
Presence of Baseline NS5A Resistance-Associated Polymorphisms^c
No	2% (2/85)	0% (0/90)
Yes	22% (5/23)	0% (0/19)
IL28B Status
C/C	0% (0/10)	0% (0/16)
Non-C/C	7% (7/98)	0% (0/93)

a. Subjects with missing cirrhosis status were excluded from this subgroup analysis.
b. These 4 non-cirrhotic relapsers all had baseline NS5A resistance-associated polymorphisms.
c. NS5A resistance-associated polymorphisms include any change at NS5A positions 24, 28, 30, 31, 58, 92, or 93.

HARVONI is a product of Gilead Sciences, Inc..

The complete product label will be available soon at DailyMed or at Drugs@FDA.

Also see: FDA Press Release

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration

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