DRUG INTERACTIONS

•  Coadministration with amiodarone may result in serious symptomatic bradycardia. Use of HARVONI with amiodarone is not recommended 

• P-gp inducers (e.g., rifampin, St. John’s wort): May alter concentrations of ledipasvir and sofosbuvir. Use of HARVONI with P-gp inducers is not recommended   

 • Consult the full prescribing information prior to use for potential drug interactions

ADVERSE REACTIONS

­ The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed with treatment with HARVONI for 8, 12, or 24 weeks are fatigue and headache

WARNINGS AND PRECAUTIONS

­ • Bradycardia with amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with HARVONI is not recommended. In patients without alternative, viable treatment options, cardiac monitoring is recommended. 

• Use with other drugs containing sofosbuvir, including SOVALDI, is not recommended 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Drug Interactions                                                                                                           Inform patients that HARVONI may interact with other drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products including St. John’s wort

Hepatitis C Virus Transmission                                                                                     Inform patients that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus during treatment or in the event of treatment failure should be taken. 

Administration                                                                                                               Advise patients that HARVONI should be taken once daily on a regular dosing schedule with or without food.                                                                                                           

If a patient did not take HARVONI at the regular time, it should be taken as soon as they remember on the same day. 

Resume the usual dosing schedule the next day. Advise the patient not to take more than 1 tablet of HARVONI in a day.

Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404 Harvoni, Complera, Sovaldi,

 CLINICAL PHARMACOLOGY

1. Mechanism of Action                                                                                            HARVONI is a fixed-dose combination of ledipasvir and sofosbuvir which are directacting antiviral agents against the hepatitis C virus [see Microbiology (12.4)].

2. Pharmacodynamics                                                                                                     Cardiac Electrophysiology                                                                                         Thorough QT studies have been conducted for ledipasvir and sofosbuvir. The effect of ledipasvir 120 mg twice daily (2.67 times the maximum recommended dosage) 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.

3. Pharmacokinetics

Absorption                                                                                                                       The pharmacokinetic properties of ledipasvir, sofosbuvir, and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C.

Following oral administration of HARVONI, ledipasvir median peak concentrations were observed 4 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.  

Effect of 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 increased sofosbuvir AUC0-inf by approximately 2-fold, but did not significantly affect sofosbuvir Cmax. The exposures of GS-331007 and ledipasvir were not altered in the presence of either meal type.

The response rates in Phase 3 trials were similar in HCVinfected subjects who received HARVONI with food or without food. 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. 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.

 Metabolism                                                                                                                       In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Evidence of slow oxidative metabolism via an unknown mechanism has been observed. Following a single dose of 90 mg [14C]-ledipasvir, 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.

Elimination                                                                                                                Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [ 14C]-radioactivity in feces and urine was approximately 87%, with most of the radioactive dose recovered from feces (approximately 86%).

Unchanged ledipasvir excreted in feces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose. 

The median terminal half-lives of sofosbuvir and GS-331007 following administration of HARVONI were 0.5 and 27 hours, respectively.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy                                                                                                        Pregnancy Category B                                                                                                 There are no adequate and well-controlled studies with HARVONI in pregnant women. Because animal reproduction studies are not always predictive of human response, HARVONI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

2. Nursing Mothers                                                                                                              It is not known whether HARVONI and its metabolites are present in human breast milk. When administered to lactating rats, ledipasvir was detected in the plasma of suckling rats likely due to the presence of ledipasvir in milk

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HARVONI and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

3.Pediatric Use                                                                                                                Safety and effectiveness of HARVONI have not been established in pediatric patients. 

4.Geriatric Use                                                                                                                Clinical trials of HARVONI included 117 subjects aged 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

No dosage adjustment of HARVONI is warranted in geriatric patients..

5. Renal Impairment                                                                                                         No dosage adjustment of HARVONI is required for patients with mild or moderate renal impairment. The safety and efficacy of HARVONI have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73m2 ) or ESRD requiring hemodialysis.

6.Hepatic Impairment                                                                                                        No dosage adjustment of HARVONI is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C). Safety and efficacy of HARVONI have not been established in patients with decompensated cirrhosis  .

OVERDOSAGE                                                                                                                No specific antidote is available for overdose with HARVONI. If overdose occurs the patient must be monitored for evidence of toxicity. 

Treatment of overdose with HARVONI consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

Hemodialysis is unlikely to result in significant removal of ledipasvir since ledipasvir is highly bound to plasma protein.Hemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%.