HARVONI - Product Monograph

FOSTER CITY, Calif.--(BUSINESS WIRE)--Oct. 10, 2014-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved Harvoni® (ledipasvir 90 mg/sofosbuvir 400 mg), the first once-daily single tablet regimen for the treatment of chronic hepatitis C genotype 1 infection in adults. Harvoni combines the NS5A inhibitor ledipasvir with the nucleotide analog polymerase inhibitor sofosbuvir, approved under the tradename Sovaldi® in December 2013. Harvoni’s efficacy has been established in patients with chronic hepatitis C virus (HCV) genotype 1 infection, with a treatment duration of eight, 12 or 24 weeks depending on prior treatment history, cirrhosis status and baseline viral load. Eight weeks of treatment with Harvoni can be considered for treatment-naïve patients without cirrhosis who have baseline HCV viral load below 6 million IU/mL - See more at: Gilead Sciences
About Jack Berlin

About Gilead Sciences - About Prizm Share
HARVONI ledipasvir sofosbuvir dose PATIENT HARVONI ledipasvir sofosbuvir DRUG daily ledipasvir sofosbuvir tablet tablet Product Monograph
About Jack Berlin

About Gilead Sciences - About Prizm Share
HARVONI ledipasvir sofosbuvir dose PATIENT HARVONI ledipasvir sofosbuvir DRUG daily ledipasvir sofosbuvir tablet tablet Product Monograph
<p> 
 
 
 
 
 
 
Product Monograph 
 
 
 
Pr HARVONI® 
(ledipasvir/sofosbuvir) Tablets 
90 mg/400 mg 
Antiviral Agent 
 
 
 
 
Gilead Sciences Inc. 
Foster City, CA 94404 
USA 
 
Gilead Sciences Canada, Inc. 
Mississauga, ON L5N 2W3 
Canada 
 
www.gilead.ca 
 
Submission Control No.: 194635 
Date of Preparation: 8 August 2016 
 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 2 of 71 
TABLE OF CONTENTS 
PART I: HEALTH PROFESSIONAL INFORMATION ............................................................................... 3 
SUMMARY PRODUCT INFORMATION ...................................................................................... 3 
INDICATIONS AND CLINICAL USE ............................................................................................ 3 
CONTRAINDICATIONS ................................................................................................................. 4 
WARNINGS AND PRECAUTIONS ............................................................................................... 4 
ADVERSE REACTIONS ................................................................................................................. 8 
DRUG INTERACTIONS ................................................................................................................ 12 
DOSAGE AND ADMINISTRATION ............................................................................................ 23 
OVERDOSAGE .............................................................................................................................. 25 
ACTION AND CLINICAL PHARMACOLOGY .......................................................................... 26 
STORAGE AND STABILITY ....................................................................................................... 32 
SPECIAL HANDLING INSTRUCTIONS ..................................................................................... 32 
DOSAGE FORMS, COMPOSITION AND PACKAGING ........................................................... 32 
PART II: SCIENTIFIC INFORMATION ...................................................................................................... 33 
PHARMACEUTICAL INFORMATION ....................................................................................... 33 
CLINICAL TRIALS ....................................................................................................................... 34 
DETAILED PHARMACOLOGY ................................................................................................... 50 
MICROBIOLOGY .......................................................................................................................... 56 
TOXICOLOGY ............................................................................................................................... 61 
REFERENCES ................................................................................................................................ 63 
PART III: PATIENT MEDICATION INFORMATION .............................................................................. 65 
 
 
 
 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 3 of 71 
 
HARVONI 
ledipasvir/sofosbuvir 
 
PART I: 
HEALTH PROFESSIONAL INFORMATION 
SUMMARY PRODUCT INFORMATION 
Route of 
Administration 
Dosage Form / Strength 
Clinically Relevant Nonmedicinal Ingredients 
oral 
tablet  
90 mg ledipasvir/400 mg 
sofosbuvir 
lactose monohydrate 
 
For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section. 
 
INDICATIONS AND CLINICAL USE 
HARVONI (ledipasvir/sofosbuvir) is indicated for the treatment of chronic hepatitis C virus 
(CHC) genotype 1 infection in adults.   
Geriatrics (≥ 65 years of age) 
Clinical studies of HARVONI included 132 patients (7.1% of total number of patients in 
clinical trials) aged 65 and over.  The response rates observed for patients over 65 years of 
age were similar to that of younger patients across treatment groups. HARVONI can be 
administered in geriatric patients (see ACTION AND CLINICAL PHARMACOLOGY).  
Pediatrics (< 18 years of age) 
Safety and effectiveness in pediatric patients have not been established (see WARNINGS 
AND PRECAUTIONS).  
Liver Transplant Recipients and/or Patients with Decompensated Cirrhosis: 
Efficacy with HARVONI + ribavirin (RBV) regimen has been established in liver transplant 
recipients without cirrhosis, with compensated cirrhosis (CPT A) and with decompensated 
CPT B and CPT C cirrhosis.   
Efficacy with HARVONI + RBV regimen has been established in CHC patients with 
decompensated cirrhosis, irrespective of transplantation status (see DOSAGE AND 
ADMINISTRATION and CLINICAL TRIALS). Safety and efficacy in liver transplant 
recipients with decompensated CPT C cirrhosis are based on the results seen in 17 patients.  
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 4 of 71 
Patients Co-infected with HIV-1 
Efficacy with HARVONI has been established in CHC patients, with or without cirrhosis, 
co-infected with HIV-1 (see DOSAGE AND ADMINISTRATION and CLINICAL 
TRIALS). 
CONTRAINDICATIONS 
HARVONI is contraindicated in patients with known hypersensitivity to any of the 
components of the product. For a complete listing, see the DOSAGE FORMS, 
COMPOSITION AND PACKAGING section of the Product Monograph. 
When HARVONI is administered with RBV, the contraindications to RBV also apply to this 
combination regimen. Refer to the RBV Product Monograph for a list of contraindications 
for RBV. 
The use of RBV is contraindicated in pregnant women and in men whose female partners are 
pregnant, may be pregnant, or plan to become pregnant because of the risks for birth defects 
and fetal death associated with RBV (see WARNINGS AND PRECAUTIONS, Special 
Populations, Pregnant Women). 
WARNINGS AND PRECAUTIONS 
General 
Treatment with HARVONI should be initiated and monitored by a physician experienced in 
the management of chronic hepatitis C (CHC). 
 
The safety and efficacy of HARVONI in combination with other anti-HCV medicines have 
not been studied. The sustained virologic response (SVR) of HARVONI is reduced in 
treatment-experienced patients with HCV containing certain NS5A baseline mutations (see 
MICROBIOLOGY).   
 
The safety and efficacy of HARVONI have not been studied in patients who have failed 
previous therapy with HARVONI. 
 
Use with Potent P-gp Inducers 
 
Medicinal products that are potent P-glycoprotein (P-gp) inducers [e.g. rifampin, St. John’s 
wort (Hypericum perforatum)] may significantly decrease ledipasvir and sofosbuvir plasma 
concentration leading to reduced therapeutic effect of HARVONI and potential loss of 
virologic response. Rifampin and St. John’s wort should not be used with HARVONI (see 
DRUG INTERACTIONS).  
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 5 of 71 
Cardiovascular 
Serious Symptomatic Bradycardia When Coadministered with Amiodarone  
Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and cases 
requiring pacemaker intervention have been reported when amiodarone is coadministered 
with HARVONI. Bradycardia has generally occurred within hours to days, but cases have 
been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta 
blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may 
be at increased risk for symptomatic bradycardia with coadministration of amiodarone. 
Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for 
this effect is unknown.  
Coadministration of amiodarone with HARVONI is not recommended. For patients taking 
amiodarone who have no other alternative, viable treatment options and who will be 
coadministered HARVONI:  
• Counsel patients about the risk of symptomatic bradycardia  
• Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is 
recommended, 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.  
Patients who are taking HARVONI who need to start amiodarone therapy due to no other 
alternative, viable treatment options should undergo similar cardiac monitoring as outlined 
above.  
Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting 
HARVONI should also undergo similar cardiac monitoring as outlined above.  
Patients who develop signs or symptoms of bradycardia should seek medical evaluation 
immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, 
malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or 
memory problems (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions 
and DRUG INTERACTIONS). 
Patients with Other HCV Genotypes 
The safety and efficacy of HARVONI have not been studied in patients infected with HCV 
genotype 2, 4, 5 or 6 and has not been fully established in patients infected with genotype 3 
(see CLINICAL TRIALS). 
Use with Certain HIV Antiretroviral Regimens 
HARVONI has been shown to increase tenofovir exposure when used together with an HIV 
regimen containing tenofovir disoproxil fumarate (tenofovir DF) (see DRUG 
INTERACTIONS). Patients receiving HARVONI concomitantly with tenofovir DF, 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 6 of 71 
particularly those at increased risk for renal dysfunction should be monitored for tenofovir-
associated adverse reactions. Refer to Product Monographs for tenofovir DF-containing 
products for recommendations on renal monitoring. 
Coadministration with Related Products 
HARVONI should not be administered concurrently with other medicinal products 
containing sofosbuvir (SOVALDI®). 
Hepatic 
Hepatic impairment studies have been conducted with the individual drugs, ledipasvir and 
sofosbuvir. HARVONI can be administered in patients with mild, moderate or severe hepatic 
impairment (Child-Pugh Class A, B or C) (see ACTION AND CLINICAL 
PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Safety and efficacy of 
HARVONI have been established in genotype 1 CHC patients with decompensated cirrhosis. 
Safety and efficacy in liver transplant recipients with decompensated CPT C cirrhosis are 
based on the results seen in 17 patients.  
Liver function monitoring (including direct bilirubin), when clinically indicated, is 
recommended for patients with decompensated cirrhosis receiving treatment with HARVONI 
+ RBV (see ADVERSE EVENTS and CLINICAL TRIALS). 
Gastrointestinal 
HARVONI contains lactose.  This medicine is not recommended for patients with rare 
hereditary problems of galactose intolerance (severe lactase deficiency or glucose-galactose 
malabsorption). 
Renal 
Renal impairment studies have been conducted with the individual drugs, ledipasvir and 
sofosbuvir. HARVONI can be administered in patients with mild or moderate renal 
impairment. The safety of HARVONI has not been established in patients with severe renal 
impairment (eGFR < 30 mL/min/1.73m2) or end stage renal disease (ESRD) requiring 
hemodialysis (see ACTION AND CLINICAL PHARMACOLOGY and DOSAGE AND 
ADMINISTRATION).  
Special Populations 
 
Pregnant Women   
Pregnancy should be avoided while taking HARVONI as there are no data on the use of 
HARVONI in pregnant women.  HARVONI should not be used during pregnancy unless the 
potential benefit justifies the potential risk to the fetus. Patients should be advised to notify 
their health care provider immediately in the event of a pregnancy. 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 7 of 71 
In the rat and rabbit, at ledipasvir AUC exposures 5- and 2-fold higher, respectively, than the 
human exposure at 90 mg dose, no effects on fetal development were observed (see 
TOXICOLOGY).  
In the ledipasvir rat pre- and postnatal study, at a maternally toxic dose, the developing rat 
offspring exhibited mean decreased body weight and body weight gain when exposed in 
utero (via maternal dosing) and during lactation (via maternal milk) at a maternal exposure 
approximately 4 times the exposure in humans at the recommended clinical dose.  There 
were no effects on survival, physical and behavioral development, and reproductive 
performance in the offspring at maternal exposures similar to the exposure in humans at the 
recommended clinical dose (see TOXICOLOGY).  
No effects on fetal development were observed in rats and rabbits at the highest doses of 
sofosbuvir tested. In the rat and rabbit, exposure to the predominant circulating metabolite 
GS-331007 at the highest dose was approximately 6-fold and 16-fold the exposure in humans 
at the recommended clinical dose, respectively (see TOXICOLOGY).  
Pregnancy and Concomitant Use with RBV 
Ribavirin may cause birth defects and/or death of the exposed fetus (see 
CONTRAINDICATIONS). Extreme care must be taken to avoid pregnancy in female 
patients and in female partners of male patients when HARVONI is administered in 
combination with RBV as significant teratogenic and/or embryocidal effects have been 
demonstrated in all animal species exposed to RBV. 
HARVONI in combination with RBV should not be started unless a report of a negative 
pregnancy test has been obtained immediately prior to initiation of therapy. Female patients 
of childbearing potential and their male partners as well as male patients and their female 
partners must use at least two effective forms of contraception during treatment and for at 
least 6 months after treatment has concluded. Routine monthly pregnancy tests must be 
performed during this time (see the RBV product monograph). 
Nursing Women   
It is not known whether ledipasvir, sofosbuvir and its metabolites are excreted in human 
breast milk. A risk to the newborn/infant cannot be excluded; therefore, nursing should be 
discontinued before treatment with HARVONI.  
When administered to lactating rats, ledipasvir was detected in the plasma of suckling rats 
likely due to excretion of ledipasvir via milk. Ledipasvir plasma AUC ratio in the suckling 
rats to the lactating female rats was 0.26 on Lactation Day 10. Ledipasvir had no effects on 
the nursing pups.  
Excretion of sofosbuvir in milk was studied in postpartum female rats after a single oral dose. 
The milk:plasma concentration ratios in the female rats were 0.1 at 1 hour post-dose and 0.8 
at 24 hours post-dose. The predominant circulating metabolite GS-331007 was the primary 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 8 of 71 
component observed in the milk of lactating rats, and the metabolite had no effect on the 
nursing pups.   
Pediatrics (< 18 years of age)  
The safety and efficacy of HARVONI in pediatric patients have not been established.  
Geriatrics (≥ 65 years of age)   
Clinical studies of HARVONI included 132 patients (7.1% of total number of patients in 
clinical trials) aged 65 and over.  The response rates observed for patients over 65 years of 
age were similar to that of younger patients across treatment groups. HARVONI can be 
administered in geriatric patients.  
Patients Coinfected with HBV/HCV: 
The safety and efficacy of HARVONI have not been established in patients coinfected with 
HBV. 
Patients Co-infected with HIV-1 
In a clinical trial in HIV-1 co-infected patients, the relapse rate in Black patients was 9% 
(10/115), all of whom were IL28B non-CC genotype, and none in non-Black patients 
(0/220). In 3 clinical trials in HCV mono-infected patients, relapse rates were 3% (10/305) in 
Black patients and 2% (26/1637) in non-Black patients. 
ADVERSE REACTIONS 
Adverse Drug Reaction Overview 
The overall safety profile of HARVONI was established in patients infected with HCV 
genotype 1 who were treatment-naïve or who failed prior treatments (PEG-IFN/RBV or PI + 
PEG-IFN/RBV), CHC patients co-infected with HIV-1, and CHC patients who are post-liver 
transplant and/or who have decompensated cirrhosis. 
The safety assessment of HARVONI in patients with genotype 1 CHC is based on pooled 
data of 1080 patients from three Phase 3 clinical trials (ION-3, ION-1 and ION-2) including 
215, 539 and 326 patients who received HARVONI for 8, 12 and 24 weeks, respectively.  
The proportion of patients who permanently discontinued treatment due to adverse events 
was 0%, <1% and 1% for patients receiving HARVONI for 8, 12 and 24 weeks, respectively. 
The proportion of Grade 3 adverse events considered related to study drug by site 
investigators was 0% and 0.4% for 8 and 12 weeks, respectively; no Grade 4 adverse events 
were reported. 
No adverse drug reactions specific to HARVONI have been identified. 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 9 of 71 
Clinical Trial Adverse Drug Reactions 
Because clinical trials are conducted under very specific conditions, the adverse reaction 
rates observed in the clinical trials may not reflect the rates observed in practice and should 
not be compared to the rates in the clinical trials of another drug. Adverse drug reaction 
information from clinical trials is useful for identifying drug-related adverse events and for 
approximating rates. 
The adverse reactions (Grades 2 to 4) observed in ≥ 2% of patients receiving 8, 12 or 24 
weeks treatment with HARVONI in clinical trials are listed in Table 1.  
Table 1. 
Adverse Reactions (Grades 2 – 4) Reported in ≥ 2% of Patients 
Receiving 8, 12, or 24 Weeks of HARVONIa from the Pooled Phase 
3 Studies (ION-1, ION-2, ION-3) 
 
HARVONI 
8 weeks 
HARVONI 
12 weeks 
HARVONI 
24 weeks 
N = 215 
N = 539 
N = 326 
Headache 
3% 
4% 
4% 
Fatigue 
2% 
2% 
5% 
a. Frequencies of adverse reactions are based on treatment-emergent adverse events, considered related to 
study drug by site investigators. 
Less Common Clinical Trial Adverse Drug Reactions (< 2%) 
Adverse reactions (Grades 2 to 4) occurring in less than 2% of patients receiving 8, 12 or 24 
weeks treatment with HARVONI in clinical trials are listed below by body system: 
Table 2.  
Adverse Reactions (Grades 2 – 4) Reported in < 2% of Patients 
Receiving 8, 12 or 24 Weeks of HARVONIa from the Pooled Phase 
3 Studies (ION-1, ION-2, ION-3) 
Body System 
HARVONI 
8, 12 or 24 Weeksb 
Blood And Lymphatic System 
Disorders 
Factor VIII inhibition 
Cardiac Disorders 
Palpitations 
Eye Disorders 
Visual impairment 
Gastrointestinal Disorders 
Abdominal discomfort, abdominal distension, abdominal pain, 
abdominal pain upper, constipation, diarrhoea, dyspepsia, 
gastrooesophageal reflux disease, mesenteric vein thrombosis, nausea, 
oral discomfort, vomiting 
General Disorders And 
Administration Site Conditions 
Asthenia, feeling abnormal, irritability, edema 
Hepatobiliary Disorders 
Hepatitis acute  
Infections And Infestations 
Conjunctivitis infective, salpingitis, sinusitis  
Injury, Poisoning And 
Procedural Complications 
Contusion, ligament sprain, meniscus injury, muscle strain 
Metabolism and Nutrition 
Disorders 
Abnormal loss of weight, decreased appetite, gout  
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 10 of 71 
Body System 
HARVONI 
8, 12 or 24 Weeksb 
Musculoskeletal and 
Connective Tissue Disorders 
Arthralgia, joint effusion, muscle spasms, muscular weakness 
Nervous System Disorders 
Disturbance in attention, dizziness, memory impairment, migraine, 
migraine with aura, parosmia, somnolence 
Psychiatric Disorders 
Affect lability, aggression, anxiety, depressed mood, depression, 
emotional disorder, insomnia, libido decreased, sleep disorder  
Renal And Urinary Disorders Urinary retention 
Reproductive System and 
Breast Disorders 
Erectile dysfunction, metrorrhagia 
Respiratory, Thoracic and 
Mediastinal Disorders 
Oropharyngeal pain, sinus congestion 
Skin And Subcutaneous Tissue 
Disorders 
Acne, alopecia, hyperhidrosis, prurigo, pruritus, rash 
Vascular Disorders 
Hemorrhage, hypertension 
a. Frequencies of adverse reactions are based on treatment-emergent adverse events, considered related to 
study drug by site investigators. 
b. Note: adverse events have not been distinguished by whether they occurred during 8, 12 or 24 weeks of 
therapy. 
Abnormal Hematologic and Clinical Chemistry Findings 
Laboratory Abnormalities 
The frequency of treatment-emergent laboratory abnormalities (Grades 2-4) occurring in at 
least 2% of patients receiving 8, 12 or 24 Weeks of Treatment with HARVONI are described 
in Table 3. 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 11 of 71 
Table 3. 
Laboratory Abnormalities (Grades 2-4) Reported in ≥ 2% of 
Patients Receiving 8, 12 or 24 Weeks of HARVONI from the 
Pooled Phase 3 Studies (ION-1, ION-2, ION-3) 
Laboratory Abnormality 
Parameters 
HARVONI 
8 weeks 
HARVONI 
12 weeks 
HARVONI 
24 weeks 
N = 215 
N = 538* 
N = 325* 
Neutrophils 
(<1.0 x 109/L) 
< 1% 
< 1% 
3% 
Platelets  
(< 100  x 109/L) 
0 
2% 
5% 
Lipase 
(> 1.5 x ULN) 
4% 
6% 
9% 
Serum glucose (Hyperglycemia)  
(> 160 mg/dL) 
9% 
10% 
12% 
Serum glucose (Hypoglycemia) 
(< 55 mg/dL) 
< 1% 
2% 
2% 
Total Bilirubin  
(> 1.5 x ULN) 
3% 
< 1% 
2% 
* One patient was dosed but did not have any post-baseline lab values and was therefore excluded from the 
analysis. 
ULN = Upper Limit of Normal 
 
All patients with grades 2 to 4 elevations in lipase were asymptomatic, and the elevations 
were generally transient, with no treatment emergent clinical events of pancreatitis.   
All patients with Grade 3 or 4 increased serum glucose had either a medical history of 
diabetes or glucose intolerance (HbA1c > 6.0%) at screening. 
 
Special Populations 
Liver Transplant Recipients and/or Patients with Decompensated Cirrhosis 
The safety of HARVONI+RBV was assessed in liver transplant recipients and/or patients 
with decompensated liver disease in two Phase 2 open-label trials in which patients received 
HARVONI+RBV for 12 (N=336) or 24 weeks (N=334).  
The observed adverse events were consistent with expected clinical sequelae of liver 
transplantation and/or decompensated liver disease, or the known toxicity profile of RBV. 
One adverse event of direct bilirubin increased, where drug induced liver injury (DILI) could 
not be excluded and which resulted in permanent discontinuation of HARVONI, was 
reported in a liver transplant recipient with decompensated CPT B cirrhosis. This event, 
however, occurred at Week 20 of treatment with HARVONI and RBV, which is past the 
recommended dosing period of 12 weeks (see WARNINGS AND PRECAUTIONS, 
Hepatic). 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 12 of 71 
Decreases in hemoglobin to less than 10 mg/dL and 8.5 mg/dL during treatment were 
experienced by 39% and 13% of patients treated with HARVONI+RBV, respectively. 
Ribavirin was discontinued in 15% of the patients.  
HIV-1 Co-infected Patients 
The safety of HARVONI was assessed in an open-label trial of 335 patients with HCV/HIV-
1 co-infection who were on stable antiretroviral therapy (see CLINICAL TRIALS). The 
safety profile in HCV/HIV-1 co-infected patients was similar to that observed in HCV mono-
infected patients. The most common adverse reactions occurring in at least 10% of patients 
were headache (20%) and fatigue (17%). No adverse reactions specific to HARVONI were 
identified. 
 
Post-Market Adverse Drug Reactions 
In addition to adverse reactions from clinical studies, 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 when amiodarone is coadministered with HARVONI (see 
WARNINGS AND PRECAUTIONS, Cardiovascular and DRUG INTERACTIONS). 
 
Skin and Subcutaneous Tissue Disorders 
Skin rashes, sometimes with blisters or angioedema-like swelling. 
 
DRUG INTERACTIONS 
Overview 
 
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. Hydrolytic prodrug cleavage and sequential 
phosphorylation steps result in formation of the pharmacologically active uridine nucleoside 
analog triphosphate. Dephosphorylation of nucleotide metabolites results in conversion to the 
predominant circulating metabolite GS-331007 that accounts for approximately 85% of total 
systemic exposure. In clinical pharmacology studies, both sofosbuvir and GS-331007 were 
monitored for purposes of pharmacokinetic analyses.  
 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 13 of 71 
Drug-Drug Interactions 
 
Potential for HARVONI to Affect Other Drugs 
Ledipasvir is a weak inhibitor of intestinal efflux drug transporter P-gp and breast cancer 
resistance protein (BCRP) and may increase intestinal absorption of coadministered 
substrates for these transporters. Ledipasvir is an inhibitor of hepatic uptake transporters 
OATP1B1, OATP1B3 and hepatic efflux transporter BSEP only at concentrations exceeding 
those achieved in clinic. Ledipasvir is not an inhibitor of renal efflux transporters MRP2, 
MRP4, MATE1, renal uptake transporters OCT2, OAT1, OAT3, and hepatic uptake transport 
OCT1. Ledipasvir inhibits UGT1A1 only at concentrations exceeding those achieved in the 
clinic. The drug-drug interaction potential of ledipasvir is primarily limited to the process of 
intestinal absorption.  
Sofosbuvir and GS-331007 are not relevant inhibitors of drug transporters P-gp, BCRP, 
MRP2, BSEP, OATP1B1, OATP1B3, OCT1 and GS-331007 is not an inhibitor of OAT1, 
OCT2 and MATE1 (see DETAILED PHARMACOLOGY).  
Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes.  
 
Potential for Other Drugs to Affect HARVONI 
Ledipasvir and sofosbuvir are substrates of efflux drug transporters P-gp and BCRP while 
GS-331007 is not. Drugs that are potent 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 potential loss of virologic response, and should not be used with 
HARVONI (see WARNINGS AND PRECAUTIONS). Coadministration with drugs that 
inhibit P-gp and/or BCRP may increase sofosbuvir and ledipasvir plasma concentrations 
without increasing GS-331007 plasma concentration; HARVONI may therefore be 
coadministered with P-gp and/or BCRP inhibitors. Neither ledipasvir nor sofosbuvir is a 
substrate for hepatic uptake transporters OCT1, OATP1B1 or OATP1B3.  GS-331007 is not 
a substrate for renal uptake transporters including organic anion transporter OAT1 or OAT3, 
or organic cation transporter OCT2.  
Ledipasvir is subject to slow oxidative metabolism via an unknown mechanism. In vitro, no 
detectable metabolism of ledipasvir by CYP enzymes has been observed. Biliary excretion of 
unchanged ledispavir is a major route of elimination. Sofosbuvir is not a substrate for CYP 
and UGT1A1 enzymes. Clinically significant drug interactions with HARVONI mediated by 
CYP or UGT1A1 enzymes are not expected.  
 
Table 4 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. The table is not all-inclusive (see 
ACTION AND CLINICAL PHARMACOLOGY). 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 14 of 71 
Table 4. 
Established and Potentially Significanta Drug Interactions  
Concomitant Drug Class:  
Drug Name 
Effect on 
Concentrationb 
Clinical Comment 
Acid Reducing Agents: 
 
 
 
Antacids (e.g. aluminum 
and magnesium hydroxide) 
 
H2-receptor antagonistsc 
(e.g. famotidine) 
 
 
 
Proton-pump inhibitorsc 
(e.g. omeprazole) 
↓ ledipasvir 
 
 
Ledipasvir solubility decreases as pH increases. Drugs 
that increase gastric pH are expected to decrease 
concentration of ledipasvir.  
 
It is recommended to separate antacid and HARVONI 
administration by 4 hours. 
 
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 inhibitor doses comparable to omeprazole 
20 mg can be administered simultaneously with 
HARVONI. Proton-pump inhibitors should not be taken 
before HARVONI. 
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, Cardiovascular and ADVERSE 
REACTIONS, Post-Market Adverse Drug 
Reactions). 
digoxin 
↑ digoxin 
Coadministration of HARVONI with digoxin may result 
in increased  plasma concentration of digoxin  due to 
intestinal inhibition of P-gp by LDV. Caution is 
warranted and therapeutic concentration monitoring of 
digoxin is recommended to obtain the desired clinical 
effect when coadministered with HARVONI. 
Anticonvulsants: 
carbamazepine  
phenytoin  
phenobarbital  
oxcarbazepine 
↓ ledipasvir 
↓ sofosbuvir 
 
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  
 
 
↓ ledipasvir 
↓ sofosbuvir 
 
Coadministration of HARVONI with rifabutin is 
expected to decrease the concentration of ledipasvir and 
sofosbuvir, leading to reduced therapeutic effect of 
HARVONI. Coadministration is not recommended. 
HARVONI should not be used with rifampin, a potent  
P-gp inducer (see WARNINGS AND 
PRECAUTIONS, General, Use with Potent P-gp 
Inducers) 
Antiretrovirals:  
Regimens containing 
tenofovir disoproxil 
fumarate (tenofovir DF)c 
 
↑ tenofovir 
 
HARVONI has been shown to increase tenofovir 
exposure. Patients receiving tenofovir DF and 
HARVONI concomitantly should be monitored for 
adverse reactions associated with tenofovir DF. Refer to 
the Product Monographs for tenofovir DF-containing 
products for recommendations on renal monitoring. 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 15 of 71 
Concomitant Drug Class:  
Drug Name 
Effect on 
Concentrationb 
Clinical Comment 
Other HIV Antiretrovirals 
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: 
simeprevirc 
↑ ledipasvir 
↑ simeprevir  
 
Concentrations of ledipasvir and simeprevir are 
increased significantly when simeprevir is 
coadministered with ledipasvir. Coadministration is not 
recommended. 
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. ↑ = increase, ↓ = decrease. 
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: abacavir, 
atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, dolutegravir, emtricitabine, efavirenz, 
lamivudine,  methadone, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, 
or verapamil. For use of HARVONI with certain HIV regimens containing tenofovir DF, see 
WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS, Table 4. 
 
Assessment of Drug Interactions 
The drug interaction studies described were conducted with HARVONI, or components of 
HARVONI (ledipasvir or sofosbuvir). 
The effects of coadministered drugs on the exposure of ledipasvir, sofosbuvir and 
GS-331007 are shown in Table 5. The effects of ledipasvir or sofosbuvir on the exposure of 
coadministered drugs are shown in Table 6.  
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 16 of 71 
Table 5. 
Drug Interactions: Changes in Pharmacokinetic Parameters for 
Ledipasvir, Sofosbuvir and the Predominant Circulating 
Metabolite GS-331007 in the Presence of the Coadministered 
Druga 
Co-
administered 
Drug 
Dose of Co-
administered 
Drug  
(mg) 
Ledi-
pasvir 
Dose 
(mg) 
Sofos-
buvir 
Dose 
(mg) 
N 
Mean Ratio (90% CI) of Ledipasvir, Sofosbuvir 
and GS-331007 PK With/Without 
Coadministered Drug 
No Effect=1.00 
 
Cmax 
AUC 
Cmin 
Anti-HCV Drugs 
 
 
 
 
 
 
 
Simeprevirh 
150 once daily 
30 once 
dailyg 
ND 
22 
ledipasvir 
1.81    
(1.69, 2.94) 
1.92    
(1.77, 2.07) 
NA 
Anti-HIV Drugs 
 
 
 
 
 
 
 
Abacavir/ 
lamivudine 
600/300 once 
daily 
90 once 
daily 
400 once 
daily 
13 
ledipasvir 
1.10     
(1.01, 1.19) 
1.18    
(1.10, 1.28) 
1.26    
(1.17, 1.36) 
sofosbuvir 
1.08     
(0.85, 1.35) 
1.21   
(1.09, 1.35) 
NA 
GS-331007 
1.00     
(0.94, 1.07) 
1.05   
(1.01, 1.09) 
1.08    
(1.01, 1.14) 
Atazanavir/ 
ritonavir 
300/100 once 
daily 
90 once 
daily 
400 once 
daily 
30 
ledipasvir 
1.98    
(1.78, 2.20) 
2.13   
(1.89, 2.40) 
2.36    
(2.08, 2.67) 
sofosbuvir 
0.96    
(0.88, 1.05) 
1.08    
(1.02, 1.15) 
NA 
GS-331007 
1.13   
(1.08, 1.19) 
1.23    
(1.18, 1.29) 
1.28    
(1.21, 1.36) 
Atazanavir/ 
ritonavir + 
emtricitabine/ 
tenofovir DF 
300/100/200/300 
once daily 
simultaneously 
with HARVONIb 
90 once 
daily 
400 once 
daily 
24 
ledipasvir 
1.68 (1.54, 
1.84) 
1.96 (1.74, 
2.21) 
2.18 (1.91, 
2.50) 
sofosbuvir 
1.01 (0.88, 
1.15) 
1.11 (1.02, 
1.21) 
NA 
GS-331007 
1.17 (1.12, 
1.23) 
1.31 (1.25, 
1.36) 
1.42 (1.34, 
1.49) 
Darunavir/ 
ritonavirh 
800/100 once 
daily 
90 once 
daily 
ND 
23 
ledipasvir 
1.45     
(1.34, 1.56) 
1.39    
(1.28, 1.49) 
1.39   
(1.29, 1.51) 
ND 
400 
single 
dose 
18 
sofosbuvir 
1.45    
(1.10, 1.92) 
1.34     
(1.12, 1.59) 
NA 
GS-331007 
0.97      
(0.90, 1.05) 
1.24     
(1.18, 1.30) 
NA 
Darunavir/ 
ritonavir + 
emtricitabine/ 
tenofovir 
disoproxil 
fumarate  
800/100/200/300 
once daily 
simultaneously 
with HARVONIb 
90 once 
daily 
400 once 
daily 
23 
ledipasvir 
1.11 (0.99, 
1.24) 
1.12 (1.00, 
1.25) 
1.17 (1.04, 
1.31) 
sofosbuvir 
0.63 (0.52, 
0.75) 
0.73 (0.65, 
0.82) 
NA 
GS-331007 
1.10 (1.04, 
1.16) 
1.20 (1.16, 
1.24) 
1.26 (1.20, 
1.32) 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 17 of 71 
Co-
administered 
Drug 
Dose of Co-
administered 
Drug  
(mg) 
Ledi-
pasvir 
Dose 
(mg) 
Sofos-
buvir 
Dose 
(mg) 
N 
Mean Ratio (90% CI) of Ledipasvir, Sofosbuvir 
and GS-331007 PK With/Without 
Coadministered Drug 
No Effect=1.00 
 
Cmax 
AUC 
Cmin 
Dolutegravir + 
emtricitabine/ 
tenofovir DF 
50 + 200/300 
once daily 
90 once 
daily  
400 once 
daily 
29 
ledipasvir 
0.85   
(0.81, 0.90) 
0.89   
(0.84, 0.95) 
0.89   
(0.84, 0.95) 
sofosbuvir 
1.06   
(0.92, 1.21)  
1.09   
(1.00, 1.19)  
NA  
GS-331007 
0.99   
(0.95, 1.03)  
1.06   
(1.03, 1.09)  
1.06   
(1.03, 1.10)  
Efavirenz/ 
emtricitabine/ 
tenofovir 
disoproxil 
fumaratec 
600/200/300 once 
daily 
90 once 
daily 
400 once 
daily 
14 
ledipasvir 
0.66    
(0.59, 0.75) 
0.66      
(0.59, 0.75) 
0.66   
(0.57, 0.76) 
sofosbuvir 
1.03    
(0.87, 1.23) 
0.94   
(0.81, 1.10) 
NA 
GS-331007 
0.86    
(0.76, 0.96) 
0.90   
(0.83, 0.97) 
1.07    
(1.02, 1.13) 
Elvitegravir + 
cobicistatd 
150/150 once 
daily 
90 once 
daily 
400 once 
daily 
29 
ledipasvir 
1.63    
(1.51, 1.75) 
1.78    
(1.64, 1.94) 
1.91    
(1.76, 2.08) 
sofosbuvir 
1.33     
(1.14, 1.56) 
1.36     
(1.21, 1.52) 
NA 
GS-331007 
1.33    
(1.22, 1.44) 
1.44     
(1.41, 1.48) 
1.53     
(1.47, 1.59) 
Emtricitabine/ 
rilpivirine/  
tenofovir 
disoproxil 
fumaratee 
200/25/300 once 
daily 
90 once 
daily 
400 once 
daily 
15 
ledipasvir 
1.01      
(0.95, 1.07) 
1.08   
(1.02, 1.15) 
1.16   
(1.08, 1.25) 
sofosbuvir 
1.05    
(0.93, 1.20) 
1.10    
(1.01, 1.21) 
NA 
GS-331007 
1.06     
(1.01, 1.11) 
1.15   
(1.11, 1.19) 
1.18   
(1.13, 1.24) 
 
Raltegravirh 
400 twice daily 
90 once 
daily 
ND 
28 
ledipasvir 
0.92    
(0.85, 1.00) 
0.91    
(0.84, 1.00) 
0.89    
(0.81, 0.98) 
ND 
400 
single 
dose 
19 
sofosbuvir 
0.87     
(0.71, 1.08) 
0.95    
(0.82, 1.09) 
NA 
GS-331007 
1.09      
(0.99, 1.19) 
1.02     
(0.97, 1.08) 
NA 
Anti-infectives 
 
 
 
 
 
 
 
 
Rifampinh 
600 once daily 
90 single 
dosef 
ND 
31 
ledipasvir 
0.65    
(0.56, 0.76) 
0.41   
(0.36, 0.48) 
NA 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 18 of 71 
Co-
administered 
Drug 
Dose of Co-
administered 
Drug  
(mg) 
Ledi-
pasvir 
Dose 
(mg) 
Sofos-
buvir 
Dose 
(mg) 
N 
Mean Ratio (90% CI) of Ledipasvir, Sofosbuvir 
and GS-331007 PK With/Without 
Coadministered Drug 
No Effect=1.00 
 
Cmax 
AUC 
Cmin 
ND 
400 
single 
dose 
17 
sofosbuvir 
0.23    
(0.19, 0.29) 
0.28   
(0.24, 0.32) 
NA 
GS-331007 
1.23   
(1.14, 1.34) 
0.95    
(0.88, 1.03) 
NA 
H2-Receptor Antagonists 
 
 
 
 
 
 
 
Famotidine 
40 single dose 
simultaneously 
with HARVONI 
90 single 
dose 
400 
single 
dose 
12 
ledipasvir 
0.80    
(0.69, 0.93) 
0.89    
(0.76, 1.06) 
NA 
sofosbuvir 
1.15    
(0.88, 1.50) 
1.11    
(1.00, 1.24) 
NA 
GS-331007 
1.06    
(0.97, 1.14) 
1.06      
(1.02, 1.11) 
NA 
40 single dose 12 
hours prior to 
HARVONI 
12 
ledipasvir 
0.83    
(0.69, 1.00) 
0.98          
(0.80, 1.20) 
NA 
sofosbuvir 
1.00     
(0.76, 1.32) 
0.95     
(0.82, 1.10) 
NA 
GS-331007 
1.13     
(1.07, 1.20) 
1.06    
(1.01, 1.12) 
NA 
Immunosuppressants 
 
 
 
 
 
 
 
Cyclosporineh 
600 single dose 
ND 
400 
single 
dose 
19 
sofosbuvir 
2.54 
(1.87, 3.45) 
4.53 
(3.26, 6.30) 
NA 
GS-331007 
0.60    
(0.53, 0.69) 
1.04    
(0.90, 1.20) 
NA 
Tacrolimush 
5 single dose 
ND 
400 
single 
dose 
16 
sofosbuvir 
0.97   
(0.65, 1.43) 
1.13   
(0.81, 1.57) 
NA 
GS-331007 
0.97     
(0.83, 1.14) 
1.00   
(0.87, 1.13) 
NA 
Opiate Agonist 
 
 
 
 
 
 
 
Methadoneh 
30 to 130 daily 
ND 
400 once 
daily 
14 
sofosbuvir 
0.95   
(0.68, 1.33) 
1.30   
(1.00, 1.69) 
NA 
GS-331007 
0.73    
(0.65, 0.83) 
1.04   
(0.89, 1.22) 
NA 
Proton Pump Inhibitors 
 
 
 
 
 
 
 
Omeprazole 
20 once daily 
simultaneously 
with HARVONI 
90 single 
dose 
400 
single 
dose 
16 
ledipasvir 
0.89    
(0.61, 1.30) 
0.96    
(0.66, 1.39) 
NA 
sofosbuvir 
1.12     
(0.88, 1.42) 
1.00    
(0.80, 1.25) 
NA 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 19 of 71 
Co-
administered 
Drug 
Dose of Co-
administered 
Drug  
(mg) 
Ledi-
pasvir 
Dose 
(mg) 
Sofos-
buvir 
Dose 
(mg) 
N 
Mean Ratio (90% CI) of Ledipasvir, Sofosbuvir 
and GS-331007 PK With/Without 
Coadministered Drug 
No Effect=1.00 
 
Cmax 
AUC 
Cmin 
GS-331007 
1.14,    
(1.01, 1.29) 
1.03   
(0.96, 1.12) 
NA 
 
20 once daily 2 
hours prior to 
ledipasvir 
30 single 
dose 
ND 
17 
ledipasvir 
0.52   
(0.41, 0.66) 
0.58   
(0.48, 0.71) 
NA 
NA = not available/not applicable, ND = not dosed.  
a 
All interaction studies conducted in healthy volunteers. 
b 
Staggered administration (12 hours apart) of atazanavir/ritonavir+emtricitabine/tenofovir DF or 
darunavir/ritonavir+emtricibatine/tenofovir DF and HARVONI provided similar results. 
c 
Administered as ATRIPLA®. 
d 
This study was conducted to support the use of STRIBILD. 
e 
Administered as COMPLERA®. 
f 
This study was conducted in the presence of two other investigational HCV direct-acting agents. 
g 
Ledipasvir dose administered in this study is 30 mg which is lower than the ledipasvir dose of 90 mg when 
administered as HARVONI. 
h 
These studies have not been performed with HARVONI; they were conducted with either ledipasvir or sofosbuvir 
administered as single agents. 
 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 20 of 71 
Table 6. 
Changes in Pharmacokinetic Parameters for Coadministered 
Drug in the Presence of Ledipasvir, Sofosbuvir, or HARVONIa 
Co-
administered 
Drug 
Dose of Co-
administered 
Drug (mg) 
Ledi-
pasvir 
dose (mg) 
Sofos-
buvir 
Dose (mg) N 
Mean Ratio (90% CI) of 
Coadministered drug PK 
With/Without Ledipasvir, 
Sofosbuvir or HARVONI 
No Effect=1.00 
Cmax 
AUC 
Cmin 
Anti-HCV 
 
 
 
 
 
 
 
Simeprevirf 
150 once daily 
30 once 
dailye 
ND 
28 
2.61          
(2.39, 2.86) 
2.69       
(2.44, 2.96) 
NA 
Anti-HIV 
 
 
 
 
 
 
 
Abacavir 
/lamivudine 
abacavir 600 
once daily 
90 once 
daily 
400 once 
daily 
15 
0.92     
(0.87, 0.97) 
0.90         
(0.85, 0.94) 
NA 
lamivudine 300 
once daily 
0.93      
(0.87, 1.00) 
0.94       
(0.90, 0.98) 
1.12    
(1.05, 1.20) 
Atazanavir/ 
ritonavirg 
atazanavir 300 
once daily 
90 once 
daily 
400 once 
daily 
30 
1.07        
(1.00, 1.15) 
1.33       
(1.25, 1.42) 
1.75        
(1.58, 1.93) 
ritonavir 100 
once daily 
0.93     
(0.84, 1.02)  
1.05   
(0.98, 1.11)  
1.56   
(1.42, 1.71)  
Atazanavir/ 
ritonavir + 
emtricitabine/ 
tenofovir 
disoproxil 
fumarateg 
simultaneously 
with HARVONIh 
atazanavir 300 
once dailyi 
90 once 
daily 
400 once 
daily 
24 
1.07 (0.99, 
1.14) 
1.27 (1.18, 
1.37) 
1.63 (1.45, 
1.84) 
ritonavir 100 
once daily 
0.86 
(0.79, 0.93) 
0.97 
(0.89, 1.05) 
1.45 
(1.27, 1.64) 
emtricitabine 
200 once dailyi 
0.98 (0.94, 
1.02) 
1.00 (0.97, 
1.04) 
1.04 (0.96, 
1.12) 
enofovir 
disoproxil 
fumarate 300 
once dailyi 
1.47 (1.37, 
1.58) 
1.35 (1.29, 
1.42) 
1.47 (1.38, 
1.57) 
Darunavir            
(boosted by 
ritonavirf,g) 
800/100 once 
daily 
90 once 
daily 
ND 
23 
1.02        
(0.88, 1.19) 
0.96      
(0.84, 1.11) 
0.97   
(0.86, 1.10) 
ND  
400 single 
dose 
18 
0.97       
(0.94, 1.01) 
0.97     
(0.94, 1.00) 
0.86        
(0.78, 0.96) 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 21 of 71 
Co-
administered 
Drug 
Dose of Co-
administered 
Drug (mg) 
Ledi-
pasvir 
dose (mg) 
Sofos-
buvir 
Dose (mg) N 
Mean Ratio (90% CI) of 
Coadministered drug PK 
With/Without Ledipasvir, 
Sofosbuvir or HARVONI 
No Effect=1.00 
Cmax 
AUC 
Cmin 
Darunavir/ 
ritonavir + 
emtricitabine/ 
tenofovir 
disoproxil 
fumarate 
simultaneously 
with HARVONIh 
darunavir 800 
once dailyj 
90 once 
daily 
400 once 
daily 
23 
1.01 (0.96, 
1.06) 
1.04 (0.99, 
1.08) 
1.08 (0.98, 
1.20) 
ritonavir 100 
once daily 
1.17j     
(1.01, 1.35) 
1.25j   
(1.15, 1.36) 
1.48j   
(1.34, 1.63) 
emtricitabine 
200 once dailyj 
1.02 (0.96, 
1.08) 
1.04 (1.00, 
1.08) 
1.03 (0.97, 
1.10) 
tenofovir 
disoproxil 
fumarate 300 
once dailyj 
1.64 (1.54, 
1.74) 
1.50 (1.42, 
1.59) 
1.59 (1.49, 
1.70) 
Dolutegravir + 
emtricitabine/ 
tenofovir DFk 
dolutegravir 50 
once daily 
90 once 
daily 
400 once 
daily 
29 
1.15     
(1.07, 1.23)  
1.13   
(1.06, 1.20)  
1.13   
(1.06, 1.21)  
emtricitabine 
200 once daily 
1.02     
(0.95, 1.08)  
1.07   
(1.04, 1.10)  
1.05   
(1.02, 1.09)  
tenofovir DF 
300 once daily 
1.61     
(1.51, 1.72)  
1.65    
(1.59, 1.71)  
2.15    
(2.05, 2.26)  
Efavirenz/ 
emtricitabine/ 
tenofovir 
disoproxil 
fumarateb 
efavirenz 600 
once daily 
90 once 
daily 
400 once 
daily 
15 
0.87       
(0.79, 0.97) 
0.90       
(0.84, 0.96) 
0.91       
(0.83, 0.99) 
emtricitabine 
200 once daily 
1.08        
(0.97, 1.21) 
1.05       
(0.98, 1.11) 
1.04        
(0.98, 1.11) 
tenofovir 
disoproxil 
fumarate 300 
once daily 
1.79        
(1.56, 2.04) 
1.98       
(1.77, 2.23) 
2.63       
(2.32, 2.97) 
Elvitegravir + 
cobicistatc 
elvitegravir 150 
once daily 
90 once 
daily 
400 once 
daily 
29 
0.88        
(0.82, 0.95) 
1.02       
(0.95, 1.09) 
1.36        
(1.23, 1.49) 
cobicistat 150 
once daily 
1.25        
(1.18, 1.32) 
1.59       
(1.49, 1.70) 
4.25        
(3.47, 5.22) 
Emtricitabine/ 
rilpivirine/ 
tenofovir 
disoproxil 
fumarated 
emtricitabine 
once 200 daily 
90 once 
daily 
400 once 
daily 
14 
1.02        
(0.98, 1.06) 
1.05       
(1.02, 1.08) 
1.06        
(0.97, 1.15) 
rilpivirine 25 
once daily 
0.97        
(0.88, 1.07) 
1.02       
(0.94, 1.11) 
1.12        
(1.03, 1.21) 
tenofovir 
disoproxil 
fumarate 300 
once daily 
1.32       
(1.25, 1.39) 
1.40       
(1.31, 1.50) 
1.91        
(1.74, 2.10) 
Raltegravirf 
400 twice daily 
90 once 
daily 
ND 
28 
0.82        
(0.66, 1.02) 
0.85       
(0.70, 1.02) 
1.15       
(0.90, 1.46) 
ND 
400 single 
dose 
19 
0.57       
(0.44, 0.75) 
0.73     
(0.59, 0.91) 
0.95        
(0.81, 1.12) 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 22 of 71 
Co-
administered 
Drug 
Dose of Co-
administered 
Drug (mg) 
Ledi-
pasvir 
dose (mg) 
Sofos-
buvir 
Dose (mg) N 
Mean Ratio (90% CI) of 
Coadministered drug PK 
With/Without Ledipasvir, 
Sofosbuvir or HARVONI 
No Effect=1.00 
Cmax 
AUC 
Cmin 
Estrogen-based Contraceptives 
 
 
 
 
 
 
Norelgestromin 
Norgestimate 
0.180/0.215/0.2
50/ ethinyl 
estradiol 0.025 
once dailyf 
90 once 
daily 
ND 
15 
1.02          
(0.89, 1.16) 
1.03        
(0.90, 1.18) 
1.09             
(0.91, 1.31) 
ND 
400 once 
daily 
1.07                         
(0.94, 1.22) 
1.06        
(0.92, 1.21) 
1.07              
(0.89, 1.28) 
Norgestrel 
90 once 
daily 
ND 
1.03        
(0.87, 1.23) 
0.99        
(0.82, 1.20) 
1.00      
(0.81, 1.23) 
ND 
400 once 
daily 
1.18       
(0.99, 1.41) 
1.19       
(0.98, 1.45) 
1.23      
(1.00, 1.51) 
Ethinyl estradiol 
90 once 
daily 
ND 
1.40         
(1.18, 1.66) 
1.20        
(1.04, 1.39) 
0.98              
(0.79, 1.22) 
ND 
400 once 
daily 
1.15          
(0.97, 1.36) 
1.09        
(0.94, 1.26) 
0.99              
(0.80, 1.23) 
Immunosuppressants 
 
 
 
 
 
 
Cyclosporinef 
600 single dose 
ND 
400 single 
dose 
19 
1.06       
(0.94, 1.18) 
0.98     
(0.85, 1.14) 
NA 
Tacrolimusf 
5 single dose 
ND 
400 single 
dose 
16 
0.73       
(0.59, 0.90) 
1.09    
(0.84, 1.40) 
NA 
Opiate Agonists   
 
 
 
 
 
 
R-Methadonef 
30 to 130 daily 
ND 
400 once 
daily 
14 
0.99       
(0.85, 1.16) 
1.01    
(0.85, 1.21) 
0.94        
(0.77, 1.14) 
S-Methadonef 
0.95       
(0.79, 1.13) 
0.95    
(0.77, 1.17) 
0.95        
(0.74, 1.22) 
NA = not available/not applicable, ND = not dosed. 
a 
All interaction studies conducted in healthy volunteers. 
b 
Administered as ATRIPLA. 
c 
This study was conducted to support the use of STRIBILD. 
d 
Administered as COMPLERA. 
e 
Ledipasvir dose administered in this study was  30 mg which is lower than the ledipasvir  dose of 90 mg  when 
administered as HARVONI. 
f 
These studies have not been performed with HARVONI; they were conducted with either ledipasvir or sofosbuvir 
administered as single agents. 
g 
Ledipasvir leads to moderate increases of ritonavir plasma exposures. 
h 
Staggered administration (12 hours apart) of atazanavir/ritonavir+emtricitabine/tenofovir DF or 
darunavir/ritonavir+emtricitabine/tenofovir DF and HARVONI provided similar results. 
i 
Comparison based on exposures when administered as atazanavir/ritonavir+emtricitabine/tenofovir DF. 
j 
Comparison based on exposures when administered as darunavir/ritonavir+emtricitabine/tenofovir DF. 
k 
Comparison based on exposures when administered as dolutegravir + emtricitabine/tenofovir DF 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 23 of 71 
Drug-Food Interactions 
The response rates in Phase 3 trials were similar in HCV-infected patients who received 
HARVONI with food or without food. HARVONI can be administered without regard to 
food. 
Relative to fasting conditions, the administration of a single dose of HARVONI with a 
moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal did not 
substantially affect the sofosbuvir Cmax and AUCinf. The exposures of GS-331007 and 
ledipasvir were not altered in the presence of either meal type. (see DOSAGE AND 
ADMINISTRATION, ACTION AND CLINICAL PHARMACOLOGY, 
Pharmacokinetics and DETAILED PHARMACOLOGY).  
 
Drug-Herb Interactions 
St. John’s wort should not be used with HARVONI. 
Coadministration of St. John’s wort, a potent P-gp inducer, may decrease ledipasvir and 
sofosbuvir plasma concentrations, which may result in loss of therapeutic effect. See 
WARNINGS AND PRECAUTIONS, General, Use with Potent Pgp Inducers. 
Drug-Laboratory Interactions 
Interactions of HARVONI with laboratory tests have not been established. 
DOSAGE AND ADMINISTRATION 
Dosing Considerations 
The treatment duration of HARVONI is fixed and is not guided by a patient’s HCV RNA 
levels (i.e., no response guided therapy). 
Recommended Dose and Dosage Adjustment 
HARVONI is a fixed dose single tablet regimen. No dosage adjustments are possible for 
HARVONI. 
The recommended dose of HARVONI is one tablet of 90 mg/400 mg ledipasvir/sofosbuvir, 
taken orally, once daily with or without food (see ACTION AND CLINICAL 
PHARMACOLOGY, Pharmacokinetics).   
The recommended dose and treatment duration for HARVONI is provided in Table 7. 
 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 24 of 71 
Table 7 
Treatment Dose and Duration for HARVONI in HCV Mono-
infected and HCV/HIV-1 Co-infected Patientsa 
Patient Population 
Treatment Regimen and Duration 
Treatment-naïveb with or without 
cirrhosisc  
HARVONI 8 or 12 weeksd 
Treatment-experiencede without 
cirrhosisc  
HARVONI 12 weeks 
Treatment-experiencede with 
cirrhosisc 
HARVONI 24 weeks 
Treatment-naïveb and treatment-
experiencede  liver transplant 
recipients without cirrhosis, or with 
compensated cirrhosis (Child-Pugh 
A) 
HARVONI + RBVf 12 weeks 
Treatment-naïveb and treatment-
experiencede with decompensated 
cirrhosis (Child-Pugh B or C) 
HARVONI + RBVg 12 weeks 
a. Refer to Tables 4-6 for dosing recommendations with HIV-1 antiviral agents and for observed drug 
exposure levels when co-administered with HIV antiviral agents. (DRUG INTERACTIONS, Drug-Drug 
Interactions) 
b. Treatment-naïve is defined as no prior exposure to any interferon, RBV, or other approved or experimental 
HCV-specific direct-acting antiviral agent at the time of treatment initiation.  
c. Cirrhosis is defined as any one of the following: Liver biopsy showing cirrhosis (eg, Metavir score = 4 or 
Ishak score ≥ 5); or Fibroscan (in countries where locally approved) showing cirrhosis or results > 12.5 
kPa; or FibroTest® score of > 0.75 and an aspartate aminotransferase (AST): platelet ratio index (APRI) of 
> 2.  
d. HARVONI for 8 weeks can be considered in treatment-naïve genotype 1 patients without cirrhosis who 
have pre-treatment HCV RNA less than 6 million IU/mL (see CLINICAL TRIALS). 
e. Treatment-experienced is defined as those who failed prior therapy with an interferon-based regimen, 
including regimens containing an HCV protease inhibitor. 
f. The daily dose of RBV is weight based (<75 kg = 1000 mg; ≥75 kg = 1200 mg) and administered orally in 
two divided doses with food. Refer to RBV PM for information on dose modification. 
g. Administer ribavirin at a starting daily dosage of 600 mg in two divided doses with food. If the starting 
dosage is well-tolerated, the dosage can be titrated up to a maximum of 1000-1200 mg daily divided (<75 
kg = 1000 mg; ≥75 kg = 1200 mg) and administered twice daily with food If the starting dosage is not well-
tolerated, the dosage should be reduced as clinically indicated based on hemoglobin levels. Refer to RBV 
PM for information on dose modifications. 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 25 of 71 
Special Populations 
Pediatrics (<18 Years of age) 
HARVONI is not indicated for use in pediatric patients < 18 years of age.  
Geriatrics (> 65 years of age) 
HARVONI can be administered in elderly patients (see ACTION AND CLINICAL 
PHARMACOLOGY).  
Renal Impairment 
Renal impairment studies have been conducted with the individual drugs, ledipasvir and 
sofosbuvir. HARVONI can be administered in patients with mild or moderate renal 
impairment. The safety of HARVONI has not been established in patients with severe renal 
impairment (eGFR < 30 mL/min/1.73m2) or end stage renal disease (ESRD) requiring 
hemodialysis (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL 
PHARMACOLOGY).  
Hepatic Impairment 
Hepatic impairment studies have been conducted with the individual drugs, ledipasvir and 
sofosbuvir. HARVONI can be administered in patients with mild, moderate or severe hepatic 
impairment (Child-Pugh Class A, B or C) (see WARNINGS AND PRECAUTIONS and 
ACTION AND CLINICAL PHARMACOLOGY). Safety and efficacy of HARVONI have  
been established in genotype 1 CHC patients with decompensated cirrhosis.  
Missed Dose 
If a patient misses a dose of HARVONI within 18 hours of the time it is usually taken, the 
patient should take HARVONI as soon as possible, and then take the next dose of 
HARVONI at the regularly scheduled time. 
If a patient misses a dose of HARVONI and it is after 18 hours of the time it is usually taken, 
the patient should not take the missed dose, but resume the usual dosing schedule.  A double 
dose of HARVONI must not be taken. 
If a patient vomits less than 5 hours after taking a dose of HARVONI, the patient should take 
another dose of HARVONI.  If a patient vomits more than 5 hours after taking a dose of 
HARVONI, the patient should take the next dose at the regularly scheduled time. 
OVERDOSAGE 
For management of a suspected drug overdose, contact your regional Poison Control Centre. 
 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 26 of 71 
No specific antidote is available for overdose with HARVONI. If overdose occurs the patient 
must be monitored for evidence of toxicity. Hemodialysis is unlikely to result in significant 
removal of ledipasvir since ledipasvir is highly bound to plasma protein. Hemodialysis can 
efficiently remove (53% extraction ratio) the predominant circulating metabolite GS-331007.  
Administration of activated charcoal may also be used to aid in the removal of unabsorbed 
active substance.  General supportive measures including monitoring of vital signs as well as 
observation of the clinical status of the patient are recommended. 
The highest documented doses of ledipasvir and sofosbuvir were 120 mg twice daily for 10 
days and a single dose of 1200 mg, respectively.  In these trials, there were no untoward 
effects observed at this dose level, and adverse events were similar in frequency and severity 
to those reported in the placebo groups. The effects of higher doses/exposures are not known. 
ACTION AND CLINICAL PHARMACOLOGY 
Description 
Ledipasvir is an HCV NS5A inhibitor. Sofosbuvir is a nucleotide analog pan-genotypic 
NS5B polymerase inhibitor. 
Mechanism of Action 
HARVONI 
HARVONI is a fixed-dose single tablet regimen of ledipasvir and sofosbuvir.  
Both sofosbuvir and ledipasvir exhibit high potency and specificity as individual agents 
against HCV as compounds that target the HCV NS5B and NS5A proteins, respectively. 
Both compounds display low cytotoxicity in a number of distinct cell lines and display no 
significant antiviral activity against other viruses tested. In vitro combination studies using 
both sofosbuvir and ledipasvir showed an additive effect as measured by in vitro cell based 
genotype 1a and 1b HCV replicon assays. As individual components, both sofosbuvir and 
ledispasvir showed additive to synergistic activity with all other anti-HCV agents. 
Ledipasvir 
Ledipasvir is a direct acting anti-viral agent that inhibits HCV RNA replication and virion 
production by targeting the HCV NS5A protein. The NS5A protein is thought to play 
multiple roles in mediating viral replication, host-cell interactions, and viral pathogenesis. As 
a nonstructural (NS) protein with no apparent enzymatic activity, NS5A functions through 
interaction with other viral and cellular proteins. The protein NS5A protein is critical for 
HCV viability and the rapid viral load (HCV RNA) decline produced by NS5A inhibitors has 
been postulated to be due to inhibition of viral replication (as with NS3 and NS5B inhibitors) 
and additional inhibition of virion assembly or secretion from infected cells. The HCV NS5A 
protein is phosphorylated on multiple sites by host cell kinases and interacts with host cell 
membranes. While no known enzymatic function has been ascribed to NS5A, it is an 
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 27 of 71 
essential component of the HCV replicase. In vitro resistance selection and cross-resistance 
studies also indicate ledipasvir targets NS5A as its mode of action.  
Sofosbuvir 
Sofosbuvir is a pan-genotypic polymerase inhibitor of the HCV NS5B RNA-dependent RNA 
polymerase (RdRp). HCV NS5B is the essential initiating and catalytic subunit of the 
membrane-associated multiprotein complex that mediates HCV RNA replication and is 
critical for the viral replication cycle. There is no human homolog for HCV NS5B RdRp. 
Sofosbuvir is a monophosphorylated pyrimidine nucleotide prodrug that undergoes 
intracellular metabolism to form the pharmacologically active uridine analog triphosphate 
(GS-461203).  Incorporation of GS-461203 into nascent RNA strongly reduces the efficiency 
of further RNA elongation by RdRp, resulting in premature termination of RNA synthesis. 
The stopping of viral replication leads to a rapid decline of HCV viral load and clearing of 
HCV levels in the body.  
Pharmacodynamics 
Effect on Electrocardiogram 
The thorough QT studies have been conducted with the individual drugs, ledipasvir and 
sofosbuvir.  
The effect of ledipasvir 120 mg twice daily for 10 days on QTc interval was evaluated in a 
randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) three 
period crossover thorough QT trial in 59 healthy subjects.  
 
The effects of sofosbuvir at the therapeutic dose (400 mg) and 3-fold above therapeutic dose 
(1200 mg) on QTc interval were evaluated in a randomized, single-dose, placebo-, and 
active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 
healthy subjects.  
These trials demonstrated a lack of effect of ledipasvir or sofosbuvir on prolongation of the 
QTcF interval. The upper bounds of the two-sided 90% confidence interval for the largest 
placebo-adjusted, baseline-corrected QTc based on Fridericia correction method (QTcF) 
were below 10 ms.  
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 28 of 71 
Pharmacokinetics 
Ledipasvir AUC is dose proportional over the dose range of 3 to 100 mg. Sofosbuvir and 
GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg. 
The pharmacokinetic properties of ledipasvir, sofosbuvir and the predominant circulating 
metabolite GS-331007 have been evaluated in healthy adult subjects and in patients with 
chronic hepatitis C following oral administration of HARVONI.  
The pharmacokinetics of HARVONI are shown in Table 8. 
Table 8. 
Summary of Once-Daily Administration of HARVONI in Healthy 
Adult Subjects and HCV-Infected Patients  
 
PK 
Parameters  
 
Healthy Subjectsa 
HARVONI 
N=192 
Geometric Mean (Range) 
HCV-Infected Patientsb 
HARVONI 
N=2113 
Geometric Mean (Range) 
LDVc 
SOF 
GS-331007 
LDV 
SOFd 
GS-331007 
AUC0-24 
(ng·h/mL) 
9600  
(1160, 36800) 
1170  
(505, 2470) 
11400  
(5660, 21300) 
7290  
(416, 49100) 
1320  
(511, 6690) 
12000  
(1790, 32000) 
Cmax 
(ng/mL) 
476  
(56.9, 1590) 
563  
(156, 1290) 
826  
(492, 1730) 
323  
(19.6, 1910) 
618  
(87.7, 2540) 
707  
(83.1, 1690) 
Cmin 
(ng/mL) 
283 
(33.5, 1180) 
ND 
ND 
211 
(13.4, 1550) 
ND 
ND 
a.  
Population PK analysis from Phase 1 studies. 
b. 
Population PK analysis from Phase 2 and 3 studies. 
c.  
N=191, one subject did not have estimable PK parameters for LDV 
d.  
N=1542; 571 subjects did not have estimable PK parameters for SOF 
ND: not determined 
 
Relative to healthy subjects, ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, 
respectively in HCV-infected patients.  Sofosbuvir and GS-331007 AUC0-24 and Cmax were 
similar in healthy adult subjects and patients with HCV infection. 
Based on population PK analyses, age, race, BMI, treatment status (treatment-naive or 
treatment-experienced), presence of RBV in the treatment regimen, or the presence or 
absence of cirrhosis had no clinically relevant effects on the exposure of SOF, GS-331007, or 
LDV. 
Absorption   
The pharmacokinetic properties of ledipasvir, sofosbuvir and the predominant circulating 
metabolite GS-331007 have been evaluated in healthy adult subjects and in patients with 
chronic hepatitis C. Following oral administration of HARVONI, ledipasvir median peak 
concentrations were observed 4.0 to 4.5 hours post-dose. Sofosbuvir was absorbed quickly 
and the peak median plasma concentration was observed ~ 0.8 to 1 hour post-dose. Median 
peak plasma concentration of GS-331007 was observed between 3.5 to 4 hours post-dose.  
HARVONI (ledipasvir/sofosbuvir) Tablets 
Product Monograph 
 
 
 
Page 29 of 71 
Effects of Food  
The response rates in Phase 3 trials were similar in HCV-infected patients who received 
HARVONI with food or without food. Relative to fasting conditions, the administration of a 
single dose of HARVONI with a moderate fat (~600 kcal, 25% to 30% fat) or high fat 
(~1000 kcal, 50% fat) meal did not alter the exposures of ledipasvir or GS-331007. Either 
meal type did not substantially affect the sofosbuvir Cmax and AUCinf. HARVONI can be 
administered without regard to food.  
 
Distribution   
Ledipasvir is >99.8% bound to human plasma proteins. After a single 90 mg dose of [14C]-
ledipasvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity ranged between 
0.51 and 0.66, indicating radioactivity exclusion from erythocytes.  
Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is 
independent of drug concentration over the range of 1 µg/mL to 20 µg/mL. Protein binding 
of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir 
in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.  
Metabolism   
In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, 
CYP2C9, CYP 2C19, CYP2D6 and CYP3A4. Evidence of slow oxidative metabolism via an 
unknown mechanism has been observed.  Following a single dose of 90 mg [14C]-LDV, 
systemic exposure was almost exclusively to the parent drug (> 98%). Unchanged ledipasvir 
is the major species present in feces. 
  
Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active 
nucleoside analog triphosphate GS-461203. The metabolic activation pathway 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 
biosysthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite 
GS-331007 that cannot be efficiently rephosphorylated and</p>