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Prescription drug Drug Classification No. 629 Harvoni tab.


Dosage Forms and strength

Each tablet contains
Sofosbuvir ……….……………………………………………………………………………………… 400 mg Additives(tar colorant) : Yellow #5
Form

A orange, diamond-shaped, film-coated tablet, debossed with "GSI" on one side
and "7985" on the other side
Indication

For the treatment of genotype 1 chronic hepatitis C (CHC) in adults, as
monotherapy or in combination with other medicinal products
Dosage and Administration

This drug treatment should be initiated and monitored by a physician experienced
in the management of patients with CHC.

Posology
The recommended dose of this drug is one tablet once daily with or without food.

Table 1: Recommended treatment duration for this drug and the recommended
use of co-administered ribavirin for certain subgroups Patient population Patients with genotype 1 CHC* 8 weeks may be considered in previously This drug untreated genotype 1-infected patients with a pretreatment HCV RNA of <6 million 24 weeks may be considered for patients deemed at high risk of clinical disease subsequent retreatment options. 12 weeks may be considered for patients deemed at low risk for clinical disease progression and who have subsequent retreatment options. decompensated cirrhosis or who are pre-/post- + liver transplant ※ Plasma HCV RNA values were measured during the clinical studies using the Roche COBAS® TaqMan® and the value for limit of detection (LOD) was 10 IU/mL and lower limit of quantification (LLOQ) was 25 IU/mL. * Treatment-naïve patients and patients who have failed treatment with previous treatments (including peginterferon alfa/ribavirin or HCV protease inhibitor+ peginterferon alfa/ribavirin) a. In patients with decompensated cirrhosis, ribavirin should be administered at a starting dose of 600 mg given in a divided daily dose. If the starting dose is well-tolerated, the dose is titrated to weight-based dose. The daily dose is 1000 mg for subjects weighing < 75 kg or 1200 mg for subjects weighing ≥ 75kg with food. If the starting dose is not well-tolerated, the dose should be reduced based on haemoglobin levels and other adverse reaction of ribavirin. Ribavirin is administered with food.
Dose modification of ribavirin in patients
If this drug is used in combination with ribavirin and a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Refer to ribavirin PI for guidelines on dose modifications and discontinuation based on the patient's haemoglobin concentration and cardiac status.
Special patient populations
1) Elderly
No dose adjustment is warranted for elderly patients.
2) Renal impairment
No dose adjustment of this drug is required for patients with mild or moderate renal impairment. The safety of ledipasvir/sofosbuvir has not been assessed in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) or end stage renal disease (ESRD) requiring haemodialysis. When this drug is used in combination with ribavirin refer also to the ribavirin PI for patients with creatinine clearance (CrCl) < 50 mL/min.
3) Hepatic impairment
No dose adjustment of this drug is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh-Turcotte [CPT] class A, B or C).
4) Paediatric population
The safety and efficacy of this drug in children and adolescents aged less than 18 years have not been evaluated.
Method of administration
For oral use. Patients should be instructed to swallow the tablet whole with or without food. Due to the bitter taste, it is recommended that the film-coated tablet is not chewed or crushed. Patients should be instructed that if vomiting occurs within 5 hours of dosing an additional tablet should be taken. If vomiting occurs more than 5 hours after dosing, no further dose is needed. If a dose is missed and it is within 18 hours of the normal time, patients should be instructed to take the tablet as soon as possible and then patients should take the next dose at the usual time. If it is after 18 hours then patients should be instructed to wait and take the next dose at the usual time. Patients should be instructed not to take a double dose.
Precautions in Use

1. WARNINGS
1) This drug should not be administered concomitantly with other medicinal
products containing sofosbuvir.
2) 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 This drug. 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 this drug is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered this drug: Counsel patients about the risk of serious 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 this drug 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 this drug 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 Undesirable effects (4), Drug Interactions (6)]. 3) Pregnancy and concomitant use with ribavirin
When this drug is used in combination with ribavirin, women of childbearing potential or their male partners must use an effective form of contraception during treatment and for a period of time after the treatment as recommended in the PI for ribavirin. Refer to the PI for ribavirin for additional information. 4) Use with potent P-gp inducers
Medicinal products that are potent P-glycoprotein (P-gp) inducers (e.g. rifampicin, carbamazepine and phenytoin) may significantly decrease ledipasvir and sofosbuvir plasma concentration which may lead to reduced therapeutic effect of this drug. Such medicinal products should not be used with this drug. 5) Use with certain HIV antiretroviral regimens
This drug has been shown to increase tenofovir exposure, especially when used together with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in the setting of this drug and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of this drug with the fixed-dose combination tablet containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving this drug concomitantly with elvitegravir/cobicistat/ emtricitabine/tenofovir disoproxil fumarate or with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for tenofovir-associated adverse reactions. Refer to tenofovir emtricitabine/tenofovir elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate PI for recommendations on renal monitoring. 6) Use with HMG-CoA reductase inhibitors
Co-administration of this drug and HMG-CoA reductase inhibitors (statins) can significantly increase the concentration of the statin, which increases the risk of myopathy and rhabdomyolysis. 2. Do not administer to the following patients
1) Hypersensitivity to the active substances or to any of the excipients of this drug. 2) Co-administration with rosuvastatin or St. John's wort (Hypericum perforatum). 3) It also contains lactose. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. 4) As this drug is used in combination with other drugs, all contraindications to the combined drugs are also applied to this drug combination therapy. For the contraindications, refer to the PI for a relevant product (refer to the PI of ribavirin). 5) When used in combination with ribavirin, pregnant women and their male partners, or women suspected to be pregnant. 3. Carefully administer to the following patients
1) Treatment-experienced patients In patients who fail treatment with ledipasvir/sofosbuvir, selection of NS5A resistance mutations that substantially reduce the susceptibility to ledipasvir is seen in the majority of cases. Limited data indicate that such NS5A mutations do not revert on long-term follow-up. There are presently no data to support ledipasvir/sofosbuvir with a subsequent regimen that contains an NS5A inhibitor. Similarly, there are presently no data to support the effectiveness of NS3/4A protease inhibitors in patients who previously failed prior therapy that included an NS3/4A protease inhibitor. Such patients may therefore be dependent on other drug classes for clearance of HCV infection. Consequently, consideration should be given to longer treatment for patients with uncertain subsequent retreatment options. 2) As this drug contains Yellow no. 5 (Sunset yellow FCF), it should be carefully administered to the patients who have hypersensitivity or history of allergic reaction to this ingredient. 4. UNDESIRABLE EFFECTS
1) Experience from clinical studies
Summary of the safety profile
The safety assessment of ledipasvir/sofosbuvir is based on pooled data from three Phase 3 clinical studies including 215, 539 and 326 patients who received ledipasvir/sofosbuvir for 8, 12 and 24 weeks, respectively; and 216, 328 and 328 patients who received ledipasvir/sofosbuvir + ribavirin combination therapy for 8, 12 and 24 weeks, respectively. These studies did not include any control group not receiving ledipasvir/sofosbuvir. Further data include a double-blind comparison of the safety of ledipasvir/sofosbuvir (12 weeks) and placebo in 155 cirrhotic patients. The proportion of patients who permanently discontinued treatment due to adverse events was 0%, < 1% and 1% for patients receiving ledipasvir/sofosbuvir for 8, 12 and 24 weeks, respectively; and < 1%, 0%, and 2% for patients receiving ledipasvir/sofosbuvir + ribavirin combination therapy for 8, 12 and 24 weeks, respectively. In clinical studies, fatigue and headache were more common in patients treated with ledipasvir/sofosbuvir compared to placebo. When ledipasvir/sofosbuvir was studied with ribavirin, the most frequent adverse drug reactions to ledipasvir/sofosbuvir + ribavirin combination therapy were consistent with the known safety profile of ribavirin, without increasing the frequency or severity of the expected adverse drug reactions. The following adverse drug reactions have been identified with this drug (Table 2). The adverse reactions are listed below by body system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) or very rare (< 1/10,000).
Table 2: Adverse drug reactions identified with this drug
Nervous system disorders: Very common General disorders: Very common 2) Postmarketing experiences
In addition to adverse reactions from clinical studies, the following possible adverse reactions were also identified during postapproval use of this drug. Because these reactions were reported voluntarily from a population of unknown size, estimates of frequency cannot be made.
Cardiac disorders
Symptomatic bradycardia (when amiodarone is coadministered with this drug) [see section 1. Warnings in Precautions: Symptomatic bradycardia when coadministered with amiodarone]
5. GENERAL PRECAUTIONS
1) This drug should not be administered concomitantly with other medicinal
products containing sofosbuvir. 2) HCV/HBV (hepatitis B virus) co infection
The safety and efficacy of this drug in patients with HCV/HBV co infection have not been investigated. 3) Resistance
In cell culture HCV replicons with reduced susceptibility to ledipasvir have been selected in cell culture for genotype 1a and 1b. Reduced susceptibility to ledipasvir was associated with the primary NS5A substitution Y93H in both genotype 1a and 1b. Additionally a Q30E substitution developed in genotype 1a replicons. Site- directed mutagenesis of NS5A RAVs showed that substitutions conferring a fold-change > 100 and ≤ 1,000 in ledipasvir susceptibility are Q30H/R, L31I/M/V, P32L and Y93T in genotype 1a and P58D and Y93S in genotype 1b; and substitutions conferring a fold-change > 1,000 are M28A/G, Q30E/G/K, H58D, Y93C/H/N/S in genotype 1a and A92K and Y93H in genotype 1b. HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the viral replication capacity by 89% to 99% compared to the corresponding wild-type. In clinical studies In a pooled analysis of patients who received ledipasvir/sofosbuvir in Phase 3 studies, 37 patients (29 with genotype 1a and 8 with genotype 1b) qualified for resistance analysis due to virologic failure or early study drug discontinuation and having HCV RNA > 1,000 IU/mL. Post-baseline NS5A and NS5B deep sequencing data (assay cut off of 1%) were available for 37/37 and 36/37 patients, respectively. NS5A resistance-associated variants (RAVs) were observed in post-baseline isolates from 29/37 patients (22/29 genotype 1a and 7/8 genotype 1b) not achieving sustained virologic response (SVR). Of the 29 genotype 1a patients who qualified for resistance testing, 22/29 (76%) patients harboured one or more NS5A RAVs at positions K24, M28, Q30, L31, S38 and Y93 at failure, while the remaining 7/29 patients had no NS5A RAVs detected at failure. The most common variants were Q30R, Y93H and L31M. Of the 8 genotype 1b patients who qualified for resistance testing, 7/8 (88%) harboured one or more NS5A RAVs at positions L31 and Y93 at failure, while 1/8 patients had no NS5A RAVs at failure. The most common variant was Y93H. Among the 8 patients who had no NS5A RAVs at failure, 7 patients received 8 weeks of treatment (n = 3 with ledipasvir/sofosbuvir; n = 4 with ledipasvir/sofosbuvir + ribavirin) and 1 patient received ledipasvir/sofosbuvir for 12 weeks. In phenotypic analyses, post- baseline isolates from patients who harboured NS5A RAVs at failure showed 20- to at least a 243-fold (the highest dose tested) reduced susceptibility to ledipasvir. Site-directed mutagenesis of the Y93H substitution in both genotype 1a and 1b as well as the Q30R and L31M substitution in genotype 1a conferred high levels of reduced susceptibility to ledipasvir (fold-change in EC50 ranging from 544-fold to 1,677-fold). The sofosbuvir resistance-associated substitution S282T in NS5B was not detected in any virologic failure isolate from the Phase 3 studies. However, the NS5B S282T substitution in combination with NS5A substitutions L31M, Y93H and Q30L were detected in one patient at failure following 8 weeks of treatment with ledipasvir/sofosbuvir from a Phase 2 study (LONESTAR). This patient was subsequently retreated with ledipasvir/sofosbuvir + ribavirin for 24 weeks and achieved SVR following retreatment. Effect of baseline HCV resistance-associated variants on treatment outcome Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and treatment outcome. In the pooled analysis of the Phase 3 studies, 16% of patients had baseline NS5A RAVs identified by population or deep sequencing irrespective of subtype. Baseline NS5A RAVs were overrepresented in patients who experienced relapse in the Phase 3 studies (see "Clinical efficacy and safety"). Following 12 weeks of treatment with ledipasvir/sofosbuvir (without ribavirin) in treatment experienced patients (arm 1 of ION-2 study) 4/4 patients with baseline NS5A RAVs conferring a ledipasvir fold-change of ≤ 100 achieved SVR. For the same treatment arm, patients with baseline NS5A RAVs conferring a fold-change of > 100, relapse occurred in 4/13 (31%), as compared to 3/95 (3%) in those without any baseline RAVs or RAVs conferring a fold-change of ≤ 100. The group of NS5A RAVs that conferred > 100-fold shift and was observed in patients were the following substitutions in genotype 1a (M28A, Q30H/R/E, L31M/V/I, H58D, Y93H/N/C) or in genotype 1b (Y93H). The proportion of such baseline NS5A RAVs seen with deep sequencing varied from very low (cut off for assay = 1%) to high (main part of the plasma population). The sofosbuvir resistance-associated substitution S282T was not detected in the baseline NS5B sequence of any patient in Phase 3 studies by population or deep sequencing. SVR was achieved in all 24 patients (n = 20 with L159F+C316N; n = 1 with L159F; and n = 3 with N142T) who had baseline variants associated with resistance to NS5B nucleoside inhibitors. Cross-resistance Ledipasvir was fully active against the sofosbuvir resistance-associated substitution S282T in NS5B while all ledipasvir resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir. Both sofosbuvir and ledipasvir were fully active against substitutions associated with resistance to other classes of direct-acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. NS5A substitutions conferring resistance to ledipasvir may reduce the antiviral activity of other NS5A inhibitors. 6. DRUG INTERACTIONS
As this drug contains ledipasvir and sofosbuvir, any interactions that have been identified with these active substances individually may occur with this drug.
1) Potential for This drug to affect other medicinal products
Ledipasvir is an in vitro inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of co-administered substrates for these transporters. In vitro data indicate that ledipasvir may be a weak inducer of metabolising enzymes such as CYP3A4, CYP2C and UGT1A1. Compounds that are substrates of these enzymes may have decreased plasma concentrations when co-administered with ledipasvir/sofosbuvir. In vitro ledipasvir inhibits intestinal CYP3A4 and UGT1A1. Medicinal products that have a narrow therapeutic range and which are metabolised by these isoenzymes should be used with caution and carefully 2) Potential for other medicinal products to affect This drug
Ledipasvir and sofosbuvir are substrates of drug transporter P-gp and BCRP while GS-331007 is not. Medicinal products that are potent P-gp inducers (e.g. rifampicin, St. John's wort, carbamazepine and phenytoin) may decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of ledipasvir/sofosbuvir and should not be used with this drug. Co-administration with medicinal products that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; this drug may be co-administered with P-gp and/or BCRP inhibitors. Clinically significant medicinal product interactions with ledipasvir/sofosbuvir mediated by CYP450s or UGT1A1 enzymes are not 3) Interactions with other medicinal products
Table 3 provides a listing of established or potentially clinically significant medicinal product interactions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratio were within "↔", extended above "↑", or extended below "↓" the predetermined equivalence boundaries). The medicinal product interactions described are based on studies conducted with either ledipasvir/sofosbuvir or ledipasvir and sofosbuvir as individual agents, or are predicted medicinal product interactions that may occur with ledipasvir/sofosbuvir. The table is not all-inclusive. Table 3: Interactions between this drug and other medicinal products
Medicinal product by Effects medicinal Recommendation therapeutic areas co-administration with this drug confidence interval) for AUC, C max, C min a, b ACID REDUCING AGENTS Ledipasvir solubility decreases as pH increases. Medicinal products that increase gastric pH are expected to decrease concentration of ledipasvir. or Interaction not studied. It is recommended to separate antacid and magnesium hydroxide; this drug administration by 4 hours. calcium carbonate (Increase in gastric pH) Antiarrhythmics Amiodarone amiodarone, Coadministration of amiodarone with this ledipasvir and sofosbuvir drug concentrations unknown bradycardia. The mechanism of this effect is Coadministration amiodarone with this drug is not recommended: if coadministration is required, recommended (see section 1.Warnings in Precautions: Symptomatic bradycardia when coadministrated with amiodarone) H2-receptor antagonists Famotidine (40 mg single dose)/ ↓ C max 0.80 (0.69, 0.93) administered simultaneously with or ledipasvir (90 mg single ↔ AUC 0.89 (0.76, 1.06) staggered from this drug at a dose that does not exceed doses comparable to (400 mg single dose)c, d Sofosbuvir famotidine 40 mg twice daily. dosed ↑ C max 1.15 (0.88, 1.50) with ↔ AUC 1.11 (1.00, 1.24) ↔ C max 1.06 (0.97, 1.14) ↔ AUC 1.06 (1.02, 1.11) (Increase in gastric pH) (40 mg single dose)/ ↓ C max 0.83 (0.69, 1.00) ledipasvir (90 mg single ↔ AUC 0.98 (0.80, 1.20) (400 mg single dose)c, d Sofosbuvir ↔ C max 1.00 (0.76, 1.32) dosed ↔ AUC 0.95 (0.82, 1.10) 12 hours prior to This GS-331007 ↔ C max 1.13 (1.07, 1.20) ↔ AUC 1.06 (1.01, 1.12) (Increase in gastric pH) Proton pump inhibitors Proton pump inhibitor doses comparable to (20 mg once daily)/ ↓ C max 0.89 (0.61, 1.30) omeprazole 20 mg can be administered ledipasvir (90 mg single ↓ AUC 0.96 (0.66, 1.39) simultaneously with this drug. Proton pump inhibitors should not be taken before (400 mg single dose)c ↔ C max 1.12 (0.88, 1.42) dosed ↔ AUC 1.00 (0.80, 1.25) simultaneously with this drug ↔ C max 1.14 (1.01, 1.29) ↔ AUC 1.03 (0.96, 1.12) (Increase in gastric pH) Esomeprazolee
ANTIARRHYTHMICS
Digoxin
Interaction not studied. Co-administration of this drug with digoxin may increase the concentration of digoxin. (Inhibition of P-gp) Caution is warranted and therapeutic concentration monitoring of digoxin is recommended when co-administered with ANTICOAGULANTS Dabigatran etexilate Interaction not studied. Co administration of this drug with dabigatran etexilate may increase the (Inhibition of P-gp) concentration of dabigatran. Clinical monitoring, looking for signs of bleeding and anaemia, is recommended when dabigatran etexilate is co-administered with this drug. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure. ANTICONVULSANTS Carbamazepine Interaction not studied. Co-administration of this drug with carbamazepine, phenytoin, phenobarbital (Induction of P-gp) or oxcarbazepine is expected to decrease the concentration of ledipasvir and sofosbuvir which may lead to reduced therapeutic effect of this drug. This drug should not be used with carbamazepine, phenytoin, ANTIMYCOBACTERIALS Rifampicin (600 mg Ledipasvir This drug should not be used with once daily)/ ledipasvir ↓ C max 0.65 (0.56, 0.76) rifampicin, a potent P-gp inducer. (90 mg single dose)d ↓ AUC 0.41 (0.36, 0.48) (Induction of P-gp) (600 mg Sofosbuvir once daily)/ sofosbuvir ↓ C max 0.23 (0.19, 0.29) (400 mg single dose)d ↓ AUC 0.28 (0.24, 0.32) ↔ C max 1.23 (1.14, 1.34) ↔ AUC 0.95 (0.88, 1.03) (Induction of P-gp) Interaction not studied. Co-administration of this drug with rifabutin or rifapentine is expected to (Induction of P-gp) decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of this drug. Such co-administration is not recommended. HCV PRODUCTS Simeprevir (150 mg Simeprevir Concentrations of ledipasvir, sofosbuvir once daily)/ ledipasvir ↑ C max 2.61 (2.39, 2.86) and simeprevir are increased when (30 mg once daily) ↑ AUC 2.69 (2.44, 2.96) simeprevir is co-administered with this Co-administration ↑ C max 1.81 (1.69, 2.94) ↑ AUC 1.92 (1.77, 2.07) Simeprevir ↔ C max 0.96 (0.71, 1.30) ↔ AUC 0.94 (0.67, 1.33) Sofosbuvir ↑ C max 1.91 (1.26, 2.90) ↑ AUC 3.16 (2.25, 4.44) GS-331007 ↓ C max 0.69 (0.52, 0.93) ↔ AUC 1.09 (0.87, 1.37) HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS Efavirenz/ No dose adjustment of this drug or emtricitabine/ tenofovir ↔ C max 0.87 (0.79, 0.97) efavirenz/ disoproxil fumarate ↔ AUC 0.90 (0.84, 0.96) disoproxil fumarate is required. 300 mg/ once daily)/ min 0.91 (0.83, 0.99) This drug has been shown to increase ledipasvir (90 mg once Emtricitabine tenofovir exposure. Patients receiving tenofovir DF and this drug concomitantly ↔ C max 1.08 (0.97, 1.21) (400 mg once daily)c, d should be monitored for adverse reactions ↔ AUC 1.05 (0.98, 1.11) associated with tenofovir. Refer to the ↔ C min 1.04 (0.98, 1.11) tenofovir-containing product's prescribing information for recommendations on renal ↑ C max 1.79 (1.56, 2.04) ↑ AUC 1.98 (1.77, 2.23) ↑ C min 2.63 (2.32, 2.97) Ledipasvir ↓ C max 0.66 (0.59, 0.75) ↓ AUC 0.66 (0.59, 0.75) ↓ C min 0.66 (0.57, 0.76) Sofosbuvir ↔ C max 1.03 (0.87, 1.23) ↔ AUC 0.94 (0.81, 1.10) GS-331007 ↔ C max 0.86 (0.76, 0.96) ↔ AUC 0.90 (0.83, 0.97) ↔ C min 1.07 (1.02, 1.13) No dose adjustment of this drug or tenofovir ↔ C max 1.02 (0.98, 1.06) emtricitabine/ disoproxil fumarate ↔ AUC 1.05 (1.02, 1.08) disoproxil fumarate is required. 300 mg once daily)/ min 1.06 (0.97, 1.15) This drug has been shown to increase ledipasvir (90 mg once Rilpivirine tenofovir exposure. Patients receiving tenofovir DF and this drug concomitantly ↔ C max 0.97 (0.88, 1.07) (400 mg once daily)c, d should be monitored for adverse reactions ↔ AUC 1.02 (0.94, 1.11) associated with tenofovir. Refer to the ↔ C min 1.12 (1.03, 1.21) tenofovir-containing product's prescribing information for recommendations on renal ↔ C max 1.32 (1.25, 1.39) ↑ AUC 1.40 (1.31, 1.50) ↑ C min 1.91 (1.74, 2.10) Ledipasvir ↔ C max 1.01 (0.95, 1.07) ↔ AUC 1.08 (1.02, 1.15) ↔ C min 1.16 (1.08, 1.25) ↔ C max 1.05 (0.93, 1.20) ↔ AUC 1.10 (1.01, 1.21) GS-331007 ↔ C max 1.06 (1.01, 1.11) ↔ AUC 1.15 (1.11, 1.19) ↔ C min 1.18 (1.13, 1.24) Abacavir/ lamivudine No dose adjustment of this drug or (600 mg/ 300 mg once ↔ C max 0.92 (0.87, 0.97) abacavir/ lamivudine is required. ledipasvir ↔ AUC 0.90 (0.85, 0.94) (90 mg once daily)c / sofosbuvir (400 mg Lamivudine ↔ C max 0.93 (0.87, 1.00) ↔ AUC 0.94 (0.90, 0.98) ↔ C min 1.12 (1.05, 1.20) Ledipasvir ↔ C max 1.10 (1.01, 1.19) ↔ AUC 1.18 (1.10, 1.28) ↔ C min 1.26 (1.17, 1.36) Sofosbuvir ↔ C max 1.08 (0.85, 1.35) ↔ AUC 1.21 (1.09, 1.35) GS-331007 ↔ C max 1.00 (0.94, 1.07) ↔ AUC 1.05 (1.01, 1.09) ↔ C min 1.08 (1.01, 1.14) HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS Atazanavir boosted with Atazanavir No dose adjustment of this drug or ↔ C max 1.07 (1.00, 1.15) atazanavir (ritonavir boosted) is required. (300 mg/ 100 mg once ↔ AUC 1.33 (1.25, 1.42) ↑ C min 1.75 (1.58, 1.93) (90 mg once daily)c / tenofovir/emtricitabine (400 mg Ledipasvir atazanavir/ritonavir, please see below. ↑ C max 1.98 (1.78, 2.20) ↑ AUC 2.13 (1.89, 2.40) ↑ C min 2.36 (2.08, 2.67) Sofosbuvir ↔ C max 0.96 (0.88, 1.05) ↔ AUC 1.08 (1.02, 1.15) GS-331007 ↔ C max 1.13 (1.08, 1.19) ↔ AUC 1.23 (1.18, 1.29) ↔ C min 1.28 (1.21, 1.36) Atazanavir boosted with Atazanavir When given with tenofovir disoproxil (300 mg/ ↔ C max 1.07 (0.99, 1.14) fumarate used in conjunction with once ↔ AUC 1.27 (1.18, 1.37) atazanavir/ritonavir, This drug increased daily) + emtricitabine/ the concentration of tenofovir. min 1.63 (1.45, 1.84) (200 mg/ Ritonavir The safety of tenofovir disoproxil fumarate 300 mg once daily)/ in the setting of this drug and a ↔ C max 0.86 (0.79, 0.93) ledipasvir (90 mg once ↔ AUC 0.97 (0.89, 1.05) pharmacokinetic enhancer (e.g. ritonavir sofosbuvir ↑ C min 1.45 (1.27, 1.64) or cobicistat) has not been established. (400 mg once daily)c, d The combination should be used with caution with frequent renal monitoring, if Dosed simultaneouslyf ↔ C max 0.98 (0.94, 1.02) other alternatives are not available. ↔ AUC 1.00 (0.97, 1.04) ↔ C min 1.04 (0.96, 1.12) increased, with a risk for an increase in bilirubin levels/icterus. That risk is even ↑ C max 1.47 (1.37, 1.58) higher if ribavirin is used as part of the ↔ AUC 1.35 (1.29, 1.42) ↑ C min 1.47 (1.38, 1.57) Ledipasvir ↑ C max 1.68 (1.54, 1.84) ↑ AUC 1.96 (1.74, 2.21) ↑ C min 2.18 (1.91, 2.50) Sofosbuvir ↔ C max 1.01 (0.88, 1.15) ↔ AUC 1.11 (1.02, 1.21) GS-331007 ↔ C max 1.17 (1.12, 1.23) ↔ AUC 1.31 (1.25, 1.36) ↑ C min 1.42 (1.34, 1.49) Darunavir boosted with Darunavir No dose adjustment of this drug or ↔ C max 1.02 (0.88, 1.19) darunavir (ritonavir boosted) is required. (800 mg/ 100 mg once ↔ AUC 0.96 (0.84, 1.11) ↔ C min 0.97 (0.86, 1.10) (90 mg once daily)d tenofovir/emtricitabine darunavir/ritonavir, please see below. ↑ C max 1.45 (1.34, 1.56) ↑ AUC 1.39 (1.28, 1.49) ↑ C min 1.39 (1.29, 1.51) Darunavir boosted with Darunavir ritonavir ↔ C max 0.97 (0.94, 1.01) (800 mg/ 100 mg once ↔ AUC 0.97 (0.94, 1.00) (400 mg once daily) min 0.86 (0.78, 0.96) Sofosbuvir ↑ C max 1.45 (1.10, 1.92) ↑ AUC 1.34 (1.12, 1.59) GS-331007 ↔ C max 0.97 (0.90, 1.05) ↔ AUC 1.24 (1.18, 1.30) Darunavir boosted with Darunavir When given with darunavir/ritonavir used (800 mg/ ↔ C max 1.01 (0.96, 1.06) in conjunction with tenofovir disoproxil once ↔ AUC 1.04 (0.99, 1.08) daily) + emtricitabine/ concentration of tenofovir. min 1.08 (0.98, 1.20) (200 mg/ Ritonavir The safety of tenofovir disoproxil fumarate 300 mg once daily)/ in the setting of this drug and a ledipasvir (90 mg once ↔ C max 1.17 (1.01, 1.35) pharmacokinetic enhancer (e.g. ritonavir ↔ AUC 1.25 (1.15, 1.36) sofosbuvir ↑ C min 1.48 (1.34, 1.63) or cobicistat) has not been established. (400 mg once daily)c, d The combination should be used with caution with frequent renal monitoring, if Dosed simultaneouslyf ↔ C max 1.02 (0.96, 1.08) other alternatives are not available. ↔ AUC 1.04 (1.00, 1.08) ↔ C min 1.03 (0.97, 1.10) Tenofovir ↑ C max 1.64 (1.54, 1.74) ↑ AUC 1.50 (1.42, 1.59) ↑ C min 1.59 (1.49, 1.70) Ledipasvir ↔ C max 1.11 (0.99, 1.24) ↔ AUC 1.12 (1.00, 1.25) ↔ C min 1.17 (1.04, 1.31) Sofosbuvir ↓ C max 0.63 (0.52, 0.75) ↓ AUC 0.73 (0.65, 0.82) GS-331007 ↔ C max 1.10 (1.04, 1.16) ↔ AUC 1.20 (1.16, 1.24) ↔ C min 1.26 (1.20, 1.32) Lopinavir boosted with Interaction not studied. When given with lopinavir/ritonavir used in ritonavir + emtricitabin tenofovir disoproxil e/ tenofovir disoproxil fumarate, this drug is expected to increase the concentration of tenofovir. The safety of tenofovir disoproxil fumarate in the setting of this drug and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established. The combination should be used with caution with frequent renal monitoring, if other alternatives are not available. Tipranavir boosted with Interaction not studied. Co-administration of this drug with tipranavir (ritonavir boosted) is expected (Induction of P-gp) ledipasvir, leading to reduced therapeutic effect of This drug. Co-administration is not recommended. HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS Raltegravir No dose adjustment of this drug or (400 mg twice daily)/ ↓ C max 0.82 (0.66, 1.02) raltegravir is required. ledipasvir (90 mg once ↔ AUC 0.85 (0.70, 1.02) ↑ C min 1.15 (0.90, 1.46) Ledipasvir ↔ C max 0.92 (0.85, 1.00) ↔ AUC 0.91 (0.84, 1.00) ↔ C min 0.89 (0.81, 0.98) (400 mg twice daily)/ ↓ C max 0.57 (0.44, 0.75) (400 mg ↓ AUC 0.73 (0.59, 0.91) ↔ C min 0.95 (0.81, 1.12) Sofosbuvir ↔ C max 0.87 (0.71, 1.08) ↔ AUC 0.95 (0.82, 1.09) GS-331007 ↔ C max 1.09 (0.99, 1.19) ↔ AUC 1.02 (0.97, 1.08) Elvitegravir/ cobicistat/ Elvitegravir When given with elvitegravir/ cobicistat/ emtricitabine/ tenofovir ↔ C max 0.88 (0.82, 0.95) emtricitabine/ disoproxil fumarate ↔ AUC 1.02 (0.95, 1.09) fumarate, this drug is expected to increase the concentration of tenofovir. 200 mg/ 300 mg once min 1.36 (1.23, 1.49) ledipasvir Cobicistat The safety of tenofovir disoproxil fumarate (90 mg once daily)c / in the setting of this drug and a max 1.25 (1.18, 1.32) pharmacokinetic enhancer (e.g. ritonavir ↑ AUC 1.59 (1.49, 1.70) or cobicistat) has not been established. ↑ C min 4.25 (3.47, 5.22) The combination should be used with caution with frequent renal monitoring, if ↑ C max 1.63 (1.51, 1.75) other alternatives are not available. ↑ AUC 1.78 (1.64, 1.94) ↑ C min 1.91 (1.76, 2.08) Sofosbuvir ↑ C max 1.33 (1.14, 1.56) ↑ AUC 1.36 (1.21, 1.52) GS-331007 ↑ C max 1.33 (1.22, 1.44) ↑ AUC 1.44 (1.41, 1.48) ↑ C min 1.53 (1.47, 1.59) Interaction not studied. No dose adjustment required. HERBAL SUPPLEMENTS St. John's wort Interaction not studied. Co-administration of this drug with (Induction of P-gp) St. John's wort is contraindicated. HMG-CoA REDUCTASE INHIBITORS Rosuvastating ↑ Rosuvastatin Co-administration of this drug with rosuvastatin may significantly increase the drug concentration of rosuvastatin (several fold- transporters OATP and increase in AUC) which is associated with BCRP) increased risk of myopathy, including rhabdomyolysis. Co-administration of this drug with rosuvastatin is contraindicated. Co-administration of this drug with pravastatin may significantly increase the concentration of pravastatin which is associated myopathy. Clinical and biochemical control is recommended in these patients and a dose adjustment may be needed. Interactions cannot be excluded with other HMG-CoA reductase inhibitors. When co-administered with this drug, a reduced dose of statins should be considered and careful monitoring for statin adverse reactions should be undertaken. NARCOTIC ANALGESICS Methadone Interaction not studied. No dose adjustment of this drug or methadone is required. ↔ C max 0.99 (0.85, 1.16) therapy ↔ AUC 1.01 (0.85, 1.21) [30 to 130 mg/daily])/ ↔ C min 0.94 (0.77, 1.14) S-methadone ↔ C max 0.95 (0.79, 1.13) ↔ AUC 0.95 (0.77, 1.17) ↔ C min 0.95 (0.74, 1.22) Sofosbuvir ↓ C max 0.95 (0.68, 1.33) ↑ AUC 1.30 (1.00, 1.69) GS-331007 ↓ C max 0.73 (0.65, 0.83) ↔ AUC 1.04 (0.89, 1.22) IMMUNOSUPPRESSANTS Ciclosporing Interaction not studied. No dose adjustment of this drug or ciclosporin is required. (600 mg single dose)/ ↔ C max 1.06 (0.94, 1.18) (400 mg ↔ AUC 0.98 (0.85, 1.14) Sofosbuvir ↑ C max 2.54 (1.87, 3.45) ↑ AUC 4.53 (3.26, 6.30) GS-331007 ↓ C max 0.60 (0.53, 0.69) ↔ AUC 1.04 (0.90, 1.20) Interaction not studied. No dose adjustment of this drug or tacrolimus is required. (5 mg single dose)/ ↓ C max 0.73 (0.59, 0.90) (400 mg ↑ AUC 1.09 (0.84, 1.40) Sofosbuvir ↓ C max 0.97 (0.65, 1.43) ↑ AUC 1.13 (0.81, 1.57) GS-331007 ↔ C max 0.97 (0.83, 1.14) ↔ AUC 1.00 (0.87, 1.13) ORAL CONTRACEPTIVES Norgestimate/ ethinyl Norelgestromin No dose adjustment of oral contraceptives estradiol (norgestimate ↔ C max 1.02 (0.89, 1.16) is required. 0.180 mg/ 0.215 mg/ ↔ AUC 1.03 (0.90, 1.18) min 1.09 (0.91, 1.31) ledipasvir (90 mg once Norgestrel ↔ C max 1.03 (0.87, 1.23) ↔ AUC 0.99 (0.82, 1.20) ↔ C min 1.00 (0.81, 1.23) Ethinyl estradiol ↑ C max 1.40 (1.18, 1.66) ↔ AUC 1.20 (1.04, 1.39) ↔ C min 0.98 (0.79, 1.22) ethinyl Norelgestromin estradiol (norgestimate ↔ C max 1.07 (0.94, 1.22) 0.180 mg/ 0.215 mg/ ↔ AUC 1.06 (0.92, 1.21) min 1.07 (0.89, 1.28) (400 mg Norgestrel ↔ C max 1.18 (0.99, 1.41) ↑ AUC 1.19 (0.98, 1.45) ↑ C min 1.23 (1.00, 1.51) Ethinyl estradiol ↔ C max 1.15 (0.97, 1.36) ↔ AUC 1.09 (0.94, 1.26) ↔ C min 0.99 (0.80, 1.23) a. Mean ratio (90% CI) of co-administered drug pharmacokinetics of study medicinal products alone
or in combination. No effect = 1.00.
b. All interaction studies conducted in healthy volunteers.
c. Administered as this drug (Harvoni).
d. Lack of pharmacokinetics interaction bounds 70-143%.
e. These are drugs within class where similar interactions could be predicted.
f. Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir
disoproxil fumarate or darunavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate and this drug
(Harvoni) provided similar results.
g. This study was conducted in the presence of another two direct-acting antiviral agents.
h. Bioequivalence/Equivalence boundary 80-125%.
7. USE IN PREGNANT WOMEN AND NURSING MOTHERS
1) Women of childbearing potential / contraception in males and females
When this drug is used in combination with ribavirin, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Women of childbearing potential or their male partners must use an effective form of contraception during treatment and for a period of time after the treatment has concluded as recommended in the PI for ribavirin. Refer to the PI for ribavirin for additional information regarding use in pregnant women. 2) Pregnancy
There are no or limited amount of data (less than 300 pregnancy outcomes) There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ledipasvir, sofosbuvir or this drug in pregnant women. Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. No significant effects on foetal development have been observed with ledipasvir or sofosbuvir in rats and rabbits. However, it has not been possible to fully estimate exposure margins achieved for sofosbuvir in the rat relative to the exposure in humans at the recommended clinical dose. As a precautionary measure, it is preferable to avoid the use of this drug during pregnancy. When this drug is used in combination with ribavirin, it must not be used in women who are pregnant or suspected to be pregnant and their partners. Refer to the PI for ribavirin for additional information regarding use in pregnant 3) Breast-feeding
It is unknown whether ledipasvir or sofosbuvir and its metabolites are excreted in human milk. Available pharmacokinetic data in animals has shown excretion of ledipasvir and metabolites of sofosbuvir in milk. A risk to the newborns/infants cannot be excluded. Therefore, this drug should not be used during breast-feeding. 4) Fertility
No human data on the effect of this drug on fertility are available. Animal studies do not indicate harmful effects of ledipasvir or sofosbuvir on fertility. If ribavirin is co-administered with this drug, the contraindications regarding use of ribavirin during pregnancy and breast-feeding apply (see also the PI for 8. USE IN PEDIATRICS
The safety and efficacy of this drug in children and adolescents aged <18 years
have not yet been established. No data are available.

9. USE IN GERIATRICS

No dose adjustment is warranted for elderly patients.
USE IN RENAL IMPAIRMENT
No dose adjustment of this drug is required for patients with mild or moderate renal impairment. The safety of ledipasvir/sofosbuvir has not been assessed in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) or end stage renal disease (ESRD) requiring haemodialysis. When this drug is used in combination with ribavirin refer also to the PI for ribavirin for patients with creatinine clearance (CrCl) < 50 mL/min. USE IN HEPATIC IMPAIRMENT
No dose adjustment of this drug is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh-Turcotte [CPT] class A, B or C). Safety and efficacy of ledipasvir/sofosbuvir have been established in patients with decompensated cirrhosis. MANAGEMENT OF OVERDOSAGE
The highest documented doses of ledipasvir and sofosbuvir were 120 mg twice daily for 10 days and a single dose of 1,200 mg, respectively. In these healthy volunteer studies, there were no untoward effects observed at these dose levels, and adverse reactions were similar in frequency and severity to those reported in the placebo groups. The effects of higher doses are not known. No specific antidote is available for overdose with this drug. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with this drug consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Haemodialysis is unlikely to result in significant removal of ledipasvir as ledipasvir is highly bound to plasma protein. Haemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%. STORAGE AND HANDLING
1) Keep out of reach of children. 2) Store in the original container.
Storage
Store in a tight container at room temperature (1 30C )
Date of preparation: 13 Oct 2015 ※ You can find the latest labelling and more information on online drug library site of Ministry of Food and Drug Safety .

Source: http://www.gilead.co.kr/~/media/korea/pdfs/website-%20harvoni_eng_20151013.pdf?la=en