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

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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




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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.
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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).
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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,
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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.
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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
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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.
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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
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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.
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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).
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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.

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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).
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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.
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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.
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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)
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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
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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
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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.

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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)
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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)
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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
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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.

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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.
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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.

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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
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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.
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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.
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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