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<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>
