Holkira Pak Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

HOLKIRA PAK (ombitasvir/paritaprevir/ritonavir and dasabuvir) is indicated for the treatment of adults with genotype 1 chronic hepatitis C (CHC) infection, including those with compensated cirrhosis:

• with ribavirin in non-cirrhotic and cirrhotic patients with genotype 1a infection;
• without ribavirin in non-cirrhotic and cirrhotic patients with genotype 1b infection

Geriatrics (> 65 years of age):

In Phase 3 clinical trials, 8.5% (174/2053) of patients were age 65 or over. No overall differences in safety or effectiveness were observed between these patients and younger patients (see WARNINGS AND PRECAUTIONS).

HCV Patients Co-Infected with HIV-1:

Efficacy and safety of HOLKIRA PAK has been established in patients with hepatitis C virus (HCV) genotype 1 co-infected with HIV-1 (see DOSAGE AND ADMINISTRATION and CLINICAL TRIALS).

Post-Liver Transplant Recipients:

Efficacy and safety of HOLKIRA PAK with ribavirin has been established in liver transplant recipients with normal hepatic function and Metavir fibrosis score of ≤ 2, regardless of the HCV genotype 1 subtype (see DOSAGE AND ADMINISTRATION and CLINICAL TRIALS).

Pediatrics (< 18 years of age):

Safety and effectiveness of HOLKIRA PAK in children less than 18 years of age have not been established (see WARNINGS AND PRECAUTIONS).

CONTRAINDICATIONS

• Patients who are hypersensitive to the medicinal ingredients of HOLKIRA PAK

  (ombitasvir, paritaprevir, ritonavir and dasabuvir) or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

• Patients with known hypersensitivity (e.g. toxic epidermal necrolysis (TEN) or Stevens-

  Johnson syndrome) to ritonavir.

• If HOLKIRA PAK is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen (see the ribavirin Product Monograph for a list of contraindications for ribavirin).
• The use of ribavirin 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 ribavirin (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).
• HOLKIRA PAK is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C) due to risk of potential toxicity.

• The following categories of drugs are contraindicated with HOLKIRA PAK:

  ○ Drugs for which elevated plasma concentrations are associated with serious adverse events and that are sensitive cytochrome P450 (CYP) 3A substrates;

  ○ Drugs that are strong CYP2C8 inhibitors, which may increase dasabuvir plasma concentrations;

  ○ Drugs that are moderate or strong inducers of CYP3A, which may result in substantial lowering of plasma concentrations of paritaprevir, ombitasvir and dasabuvir.

  ○ Drugs that are strong inducers of CYP2C8, which may result in substantial lowering of plasma concentrations of dasabuvir.

Table 1. Drugs that Are Contraindicated with HOLKIRA PAK

Drug Class Drug Name

Alpha1-adrenoreceptor antagonist alfuzosin HCl

Antiarrhythmic disopyramide, dronedarone

Antibiotic fusidic acid (oral formulation)*

Anticonvulsants carbamazepine, phenytoin, phenobarbital

Anti-gout colchicine in patients with renal and/or hepatic impairment

Antihistamine astemizole, terfenadine*

Antihyperlipidemic gemfibrozil

Antimycobacterial rifampin

Antipsychotic lurasidone

Antiviral efavirenz-containing regimens, including Atripla, etravirine, nevirapine

Benzodiazepines oral midazolam, triazolam

Endothelin receptor agonist bosentan

Ergot derivatives ergotamine, dihydroergotamine, ergonovine*, methylergonovine*

GI Motility Agent cisapride*

Herbal Product St. John’s Wort (Hypericum perforatum)

Hormonal Product ethinyl estradiol-containing medications such as combined oral contraceptives

HMG-CoA Reductase Inhibitors atorvastatin, lovastatin, simvastatin

Long-acting beta-adrenoceptor

agonist salmeterol

Neuroleptics pimozide

PDE5 enzyme inhibitor sildenafil only when used for the treatment of pulmonary arterial hypertension

(PAH)

Others modafinil

* Drugs not sold in Canada.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• Potential for Hepatitis B virus (HBV) reactivation: Screen all patients for evidence of current or prior HBV infection before initiating HOLKIRA PAK therapy. Cases of HBV reactivation, including those resulting in fulminant hepatitis, hepatic failure, and death, have been reported during HCV treatment and/or post-treatment with regimens containing direct-acting HCV antivirals (DAAs) in patients co-infected with HBV. (See WARNINGS AND PRECAUTIONS, Potential for Hepatitis B Virus Reactivation)

General

If HOLKIRA PAK (ombitasvir/paritaprevir/ritonavir and dasabuvir) is administered with ribavirin, the warnings and precautions for ribavirin also apply to this combination regimen (see the ribavirin Product Monograph).

HOLKIRA PAK contains ritonavir and should not be co-administered with additional ritonavir or ritonavir-containing regimens.

Co-administration of HOLKIRA PAK with other direct-acting antivirals (DAAs) against HCV has not been studied and therefore cannot be recommended.

As a fixed dose combination formulation, no dosage adjustments for HOLKIRA PAK are possible.

Retreatment of patients previously treated with HOLKIRA PAK or other DAAs is not recommended since the efficacy in these patients has not been established.

Transaminase Elevations with Concomitant Drugs

Clinically significant transaminase elevations were observed when HOLKIRA PAK was co-administered with efavirenz- or ethinyl estradiol-containing regimens and therefore these drugs are contraindicated with HOLKIRA PAK (see CONTRAINDICATIONS and DRUG INTERACTIONS, Table 5). When HOLKIRA PAK is co-administered with other drugs known to cause elevations of transaminases, caution should be exercised and monitoring of transaminase levels should be considered. If transaminase elevations occur, consideration should be given to whether the other drug may be discontinued. Discontinuation of HOLKIRA PAK should be considered if there are clinical signs of liver inflammation that are accompanied by persistent elevations in ALT, direct bilirubin or international normalized ratio (INR) (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, ALT Elevations). Use with Tacrolimus, Sirolimus and Everolimus

Co-administration of HOLKIRA PAK with systemic tacrolimus, sirolimus, or everolimus increases the concentrations of the immunosuppressant via CYP3A inhibition (see DRUG INTERACTIONS, Table 9). Serious and/or life threatening adverse events have been observed with co-administration of HOLKIRA PAK with systemic tacrolimus and a similar risk can be expected with sirolimus and everolimus. Avoid concomitant use of tacrolimus or sirolimus with HOLKIRA PAK unless the benefits outweigh the risks.

If tacrolimus or sirolimus and HOLKIRA PAK are used concomitantly, caution is advised. Refer to the DRUG INTERACTIONS section for recommended doses and monitoring strategies. Everolimus cannot be used due to lack of suitable dose strength for dose adjustments.

Tacrolimus or sirolimus whole blood concentrations should be monitored upon initiation and throughout co-administration with HOLKIRA PAK and the dose and/or dosing frequency should be adjusted as needed. Patients should be monitored frequently for any changes in renal function or tacrolimus or sirolimus-associated adverse events. Refer to the tacrolimus or sirolimus Product Monograph for additional dosing and monitoring instructions.

Use with Fluticasone (and other glucocorticoids metabolized by CYP3A)

Use caution when administering HOLKIRA PAK with fluticasone or other glucocorticoids that are metabolized by CYP3A4 (see DRUG INTERACTIONS, Table 7). Concomitant use of inhaled glucocorticoids metabolized by CYP3A can increase systemic exposures of the glucocorticoids, and cases of Cushing’s syndrome and subsequent adrenal suppression have been reported with ritonavir-containing regimens. Concomitant use of HOLKIRA PAK and glucocorticoids, particularly long-term use, should only be initiated if the potential benefit of treatment outweighs the risk of systemic corticosteroid effects.

Use with Quetiapine

The use of HOLKIRA PAK with quetiapine, a CYP3A4 substrate, is not recommended due to an expected increase in quetiapine exposure. If co-administration is necessary, reduce the quetiapine dose and monitor for quetiapine-associated adverse reactions (see DRUG INTERACTIONS, Table 6 and the quetiapine Product Monograph for the recommendations on adverse reaction monitoring).

Use with Rilpivirine

Concomitant use of HOLKIRA PAK with rilpivirine, a CYP3A4 substrate, significantly increased rilpivirine exposure by 243%. Co-administration of HOLKIRA PAK with rilpivirine is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine (see DRUG INTERACTIONS, Table 6).

Use with HMG-CoA Reductase Inhibitors

Cardiovascular

QTc Prolongation

HOLKIRA PAK was associated with concentration-dependent QTc prolongation. At therapeutic plasma concentrations, the maximum mean difference from placebo in the QTc interval was reported to be < 5 ms, with a 95% CI upper limit of < 10 ms (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, Effects on Electrocardiogram).

Caution should be exercised when drugs that prolong QTc are co-administered with HOLKIRA PAK (see DRUG INTERACTIONS).

Hepatic/Biliary/Pancreatic

Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis

Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported from postmarketing sources in patients treated with HOLKIRA PAK with and without ribavirin. Most patients with these severe outcomes had evidence of advanced or decompensated cirrhosis prior to initiating therapy. Reported cases typically occurred within one to four weeks of initiating therapy and were characterized by the acute onset of rising direct serum bilirubin levels without ALT elevations in association with clinical signs and symptoms of hepatic decompensation. Because these events 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.

HOLKIRA PAK is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C) (see CONTRAINDICATIONS; DOSAGE AND ADMINISTRATION, Special Populations, Hepatic Impairment; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency). For patients with cirrhosis:

• Monitor for clinical signs and symptoms of hepatic decompensation (such as ascites, hepatic encephalopathy, variceal hemorrhage).
• Hepatic laboratory testing including direct bilirubin levels should be performed at baseline, during the first 4 weeks of starting treatment and as clinically indicated thereafter.
• Discontinue treatment in patients who develop evidence of hepatic decompensation.

ALT Elevations

During clinical trials with HOLKIRA PAK with or without ribavirin, transient, asymptomatic elevations of alanine transaminase (ALT) to greater than 5 times the upper limit of normal (ULN) occurred in approximately 1% of all patients (see ADVERSE REACTIONS, Abnormal Hematologic and Clinical Chemistry Findings, Laboratory Abnormalities). These ALT elevations were significantly more frequent in female patients who were using ethinyl estradiol-containing medications such as combined oral contraceptives or contraceptive vaginal rings (see CONTRAINDICATIONS). ALT elevations typically occurred during the first 4 weeks of treatment and declined within approximately two weeks of onset with continued dosing of HOLKIRA PAK with or without ribavirin.

Ethinyl estradiol-containing medications must be discontinued prior to starting therapy with HOLKIRA PAK (see CONTRAINDICATIONS). Alternative contraceptive agents or methods of contraception (e.g, progestin only contraception or non-hormonal methods) are recommended during HOLKIRA PAK therapy. Ethinyl estradiol-containing medications can be restarted approximately 2 weeks following completion of treatment with HOLKIRA PAK.

Patients using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy, had a rate of ALT elevation similar to those not receiving any estrogens (1%). However, due to the limited number of patients taking these other estrogens (n=87), caution is warranted for co-administration with HOLKIRA PAK.

Patients should be instructed to consult their health care professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and discolored feces. If elevated liver chemistries are identified, careful follow-up is recommended. HOLKIRA PAK should be discontinued if there are clinical signs of liver inflammation that are accompanied by persistent elevations in ALT, direct bilirubin or international normalized ratio (INR).

Potential for Hepatitis B Virus Reactivation

Cases of hepatitis B virus (HBV) reactivation, including those resulting in fulminant hepatitis, hepatic failure, and death have been reported in HCV/HBV–coinfected patients who were undergoing, or completed treatment with DAA. To decrease the risk of HBV reactivation in patients co-infected with HBV, HBV screening should be performed in all patients prior to initiation of HCV treatment. Patients with positive HBV serology (HBsAg positive) and patient with serologic evidence of resolved HBV infection (i.e. HBsAg negative and anti-HBc positive) should be monitored and treated according to current clinical practice guidelines to manage potential for HBV reactivation (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Renal

No dose adjustment of HOLKIRA PAK is required in patients with mild, moderate, or severe renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).

HOLKIRA PAK has not been studied in patients on dialysis. For patients that require ribavirin, refer to the ribavirin Product Monograph for information regarding use in patients with renal impairment.

Sexual Function/Reproduction

Fertility

There are no studies on the effect of HOLKIRA PAK on human fertility.

No effects on fertility were observed in animal studies with the components of HOLKIRA PAK (see NON-CLINICAL TOXICOLOGY, Fertility).

Use with Ribavirin in Females and Males of Reproductive Potential

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 HOLKIRA PAK is administered in combination with ribavirin as significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin.

HOLKIRA PAK in combination with ribavirin 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. See additional information on specific hormonal contraceptives in CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS,

Hepatic/Biliary/Pancreatic, ALT Elevations; and DRUG INTERACTIONS, Table 5. Routine monthly pregnancy tests must be performed during this time (see the ribavirin Product Monograph).

Special Populations

Pregnant Women

HOLKIRA PAK with Ribavirin

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; therefore, ribavirin is contraindicated in women who are pregnant and in men whose female partners are pregnant (see CONTRAINDICATIONS and the ribavirin Product Monograph).

HOLKIRA PAK

There are no studies with HOLKIRA PAK in pregnant women.

No effects on embryo-fetal development have been noted in studies in animals with paritaprevir/ritonavir, ombitasvir and its major inactive human metabolites (M29, M36) or dasabuvir. For paritaprevir/ritonavir, the highest doses tested produced exposures equal to 98-fold (mouse) or 8-fold (rat) the exposures in humans at the recommended clinical dose. For ombitasvir, the highest dose tested produced exposures equal to 28-fold (mouse) or 4-fold (rabbit) the exposure in humans at the recommended clinical dose. The highest doses of the major, inactive human metabolites similarly tested produced exposures approximately 26 times higher in mice than in humans at the recommended clinical dose. For dasabuvir, the highest dose tested produced exposures equal to 24-fold (rat) or 6-fold (rabbit) the exposure in humans at the recommended clinical dose.

Ombitasvir, paritaprevir and dasabuvir were minimally transferred through the placenta of pregnant rats.

Nursing Women

It is not known whether paritaprevir/ritonavir, ombitasvir or dasabuvir and their metabolites are excreted in human breast milk. Paritaprevir and its hydrolysis product M13, unchanged ombitasvir and dasabuvir were the predominant components observed in the milk of lactating rats, without effect on nursing pups. A risk to the newborn cannot be excluded; therefore nursing must be discontinued prior to initiation of treatment with HOLKIRA PAK. Physicians prescribing ribavirin should also refer the patient to the Product Monograph for ribavirin.

Pediatrics (< 18 years of age)

Safety and effectiveness of HOLKIRA PAK in children less than 18 years of age have not been established.

Geriatrics (> 65 years of age)

No dose adjustment of HOLKIRA PAK is needed in geriatric patients. In Phase 3 clinical trials, 8.5% (174/2053) of patients were age 65 or over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

HCV-HBV Co-infection

The safety and efficacy of HOLKIRA PAK have not been established in HCV patients co-infected with HBV. HBV reactivation has been reported during treatment and post-treatment with DAAs in patients co-infected with HBV who were not undergoing treatment for HBV infection (see WARNINGS AND PRECAUTIONS, Potential for Hepatitis B Virus Reactivation).

HCV-HIV Co-infection

The ritonavir component of HOLKIRA PAK is also an HIV-1 protease inhibitor and can select for HIV-1 protease inhibitor resistance-associated substitutions. Any HCV/HIV-1 co-infected patients treated with HOLKIRA PAK should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance.

HOLKIRA PAK is contraindicated with efavirenz-containing regimens (see CONTRAINDICATIONS and DRUG INTERACTIONS, Table 5).

Other HCV Genotypes

The safety and efficacy of HOLKIRA PAK has not been established in patients with HCV genotypes other than genotype 1.

Use in Patients Who Have Failed Previous Therapy with Direct-Acting Antivirals against HCV

HOLKIRA PAK efficacy has not been studied in patients who have previously failed therapy with other direct-acting antiviral (DAA) agents.

Monitoring and Laboratory Tests

For patients with cirrhosis, hepatic laboratory testing including direct bilirubin levels should be performed at baseline, during the first 4 weeks of starting treatment and as clinically indicated thereafter. Discontinue treatment in patients who develop evidence of hepatic decompensation.

Refer to WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic for additional information.

Clearance of HCV may lead to increased replication of HBV in patients who are HCV/HBV coinfected. Co-infected patients should be monitored for clinical and laboratory signs (e.g. HBsAg, anti-HBc, HBV DNA, serum aminotransferase levels, bilirubin) for hepatitis flare or HBV reactivation during and at post-treatment follow-up as clinically appropriate (see WARNINGS AND PRECAUTIONS, Potential for Hepatitis B Virus Reactivation).

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The safety summary is based on pooled data from phase 2 and 3 clinical trials in more than 2,600 patients who received HOLKIRA PAK with or without ribavirin.

In patients receiving HOLKIRA PAK with ribavirin, the most commonly reported treatment emergent adverse events considered related to study drug by site investigator (greater than 10% of patients) were fatigue, headache, nausea, pruritus and insomnia. The proportion of patients who permanently discontinued treatment due to related adverse events was 0.8% (17/2,044). 0.5% (11/2,044) of patients interrupted treatment due to related adverse events. 3.5% (72/2,044) of patients had ribavirin dose reductions due to related adverse events.

The safety profile of HOLKIRA PAK and ribavirin in patients with cirrhosis was similar to that of patients without cirrhosis.

In patients receiving HOLKIRA PAK without ribavirin, the most commonly reported treatment emergent adverse events considered related to study drug by site investigator (greater than 10% of patients) were fatigue and headache. No patients permanently discontinued treatment due to a related adverse event and no patients had a treatment interruption due to a related adverse event.

In patients with genotype 1b infection and compensated cirrhosis receiving HOLKIRA PAK without ribavirin, the most commonly reported treatment emergent adverse event considered related to study drug by site investigator (greater than 10% of patients) was fatigue. One patient (2%) had a serious adverse event. One patient (2%) interrupted treatment due to a related adverse event and no patients permanently discontinued treatment due to adverse events. Post-baseline Grade 2 increases in total bilirubin occurred in 12/60 (20%) patients.

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.

Table 2 lists adverse drug reactions (Grades 2 to 4) observed in ≥ 3% of patients in the Phase 3 trials.

The majority of adverse events in the Phase 3 clinical trials were of grade 1 severity. The safety profile of HOLKIRA PAK with ribavirin was consistent with the known safety profile of ribavirin.

Table 2. Side-by-Side Tabulation of Adverse Reactions (Grade 2 – 4) in ≥ 3% of Patients in Phase 3*

TURQUOISE

III

(patients with cirrhosis)

Adverse Reaction

HOLKIRA PAK

12 Weeks N = 60 n (%)

Fatigue

4 (6.7)

Nausea

0

Asthenia

0

Headache

3 (5.0)

* Frequencies of adverse events are based on treatment-emergent adverse events considered at least possibly related to study drug by site investigators.

HCV-HIV-1 Co-infected Patients

The overall safety profile in HCV genotype 1/HIV-1 co-infected patients was similar to that observed in HCV genotype 1 mono-infected patients. Transient elevations in total bilirubin > 3 × ULN (mostly indirect) occurred in 17/63 (27.0%) patients; 15 of these patients were receiving atazanavir. None of the patients with hyperbilirubinemia had concomitant elevations of aminotransferases.

Liver Transplant Recipients

The type of adverse events experienced by HCV genotype 1 infected liver transplant recipients who were treated with HOLKIRA PAK and ribavirin (in addition to their immunosuppressant medications) was similar to those experienced by patients treated with HOLKIRA PAK with ribavirin in Phase 3 clinical trials; however some events were increased in frequency. Adverse events occurring in > 20% of post-liver transplant patients included fatigue 50.0% (17/34), headache 44.1% (15/34), cough 32.4% (11/32), diarrhea 26.5% (9/34), insomnia 26.5% (9/34), asthenia 23.5% (8/34), nausea 23.5% (8/34), anemia 20.6% (7/34), muscle spasms 20.6% (7/34), and rash 20.6% (7/34). Ten patients (29.4%) had at least one post-baseline hemoglobin value of less than 10 g/dL. Ten of 34 patients (29.4%) had dose modified due to decrease in hemoglobin and 2.9% (1/34) had an interruption of ribavirin. Ribavirin dose modification did not impact SVR rates. Five patients required erythropoietin, all of whom initiated ribavirin at the starting dose of 1000 to 1200 mg daily. No patient received a blood transfusion. Less Common Clinical Trial Adverse Drug Events (< 3%)

Treatment emergent adverse events (Grades 2 to 4) considered at least possibly related to study drug by site investigators which occurred in less than 3% of patients in Phase 3 trials are listed below by system organ class (Table 3).

Table 3. Adverse Events (Grade 2 – 4) in < 3% of Patients in Phase 3

Body System Adverse Events

Blood and lymphatic system

disorders:

anaemia, leukopenia, neutropenia

Cardiac disorders: extrasystoles, palpitations, sinus tachycardia, tachycardia, ventricular extrasystoles

Ear and labyrinth disorders: tinnitus

Endocrine disorders: goitre, hypothyroidism, thyroiditis, adrenal insufficiency Eye disorders: blepharitis, ulcerative keratitis, visual impairment Gastrointestinal disorders: abdominal discomfort, abdominal pain, abdominal pain upper, anorectal discomfort, constipation, dental caries, diarrhoea, dry mouth, dyspepsia, dysphagia, frequent bowel movements, gastrointestinal disorder, gastrooesophageal reflux disease, haemorrhoids, hyperchlorhydria, lip ulceration, pancreatitis, retching, vomiting

General disorders and

administration site conditions:

chest discomfort, chills, energy increased, exercise tolerance decreased, hunger, inflammation, influenza like illness, irritability, malaise, oedema peripheral, pain, pre-existing condition improved, product taste abnormal, pyrexia, swelling

Hepatobiliary disorders: hyperbilirubinaemia, jaundice

Immune system disorders: seasonal allergy

Infections and infestations: abscess, bronchitis, cellulitis, ear infection, gastroenteritis, gingival infection, herpes simplex, lower respiratory tract infection, nasopharyngitis, oral herpes, sinusitis, skin infection, upper respiratory tract infection, tooth abscess

Investigations: alanine aminotransferase increased, blood bilirubin increased, blood bilirubin unconjugated increased, irritability, malaise, electrocardiogram abnormal, haemoglobin decreased, neutrophil count increased, reticulocyte count increased, transaminases increased, weight decreased, white blood cell count decreased

Metabolism and nutrition

disorders:

decreased appetite, diabetes mellitus, gout, hyperphosphataemia, hypertriglyceridaemia, hypophosphataemia, increased appetite, lactic acidosis Musculoskeletal and connective

tissue disorders:

arthralgia, arthritis, axillary mass, back pain, bone pain, bursitis, muscle spasms, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, neck pain, pain in extremity, sensation of heaviness, tendonitis

Nervous system disorders: ataxia, cerebrovascular accident, disturbance in attention, dizziness, dysgeusia, hyperaesthesia, intention tremor, lethargy, memory impairment, migraine, neuralgia, paraesthesia, presyncope, restless legs syndrome, somnolence, syncope, tension headache, tremor

Body System Adverse Events

Psychiatric disorders: abnormal dreams, affect lability, agitation, anger, anxiety, anxiety disorder, depressed mood, depression, emotional disorder, euphoric mood, insomnia, libido decreased, mental status changes, mood altered, mood swings, nervousness, nightmare, sleep disorder, suicidal ideation, tearfulness, terminal insomnia

Reproductive system and breast

disorders:

amenorrhoea, menorrhagia, metrorrhagia

Respiratory thoracic and

mediastinal disorders:

acute respiratory failure, chronic obstructive pulmonary disease, cough, dyspnoea, dyspnoea exertional, hypoxia, respiratory depression, sleep apnoea syndrome

Skin and subcutaneous tissue

disorders:

alopecia, blister, cold sweat, dandruff, dry skin, erythema, night sweats, photodermatosis, photosensitivity reaction, pruritus, pruritus generalised, rash, rash erythematous, rash generalised, rash papular, rash pruritic, skin odour abnormal, skin reaction

Vascular disorders: flushing, hot flush, hypertension, hypotension

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory Abnormalities

Changes in selected laboratory parameters are described in Table 4. A side-by-side tabulation is provided to simplify presentation; direct comparisons should not be made across trials that differ in design.

Table 4. Selected Treatment Emergent Laboratory Abnormalities of at Least Moderate Intensity

(Grades 2-4)

Laboratory

Parameters

TURQUOISE III (patients with cirrhosis)

HOLKIRA

PAK 12 Weeks N = 60 n (%)

ALT

> 5-20 × ULN*

(Grade 3)

1/60 (1.7%)

> 20 × ULN (Grade 4)

0

Hemoglobin

< 10-8 g/dL (Grade 2)

1/60 (1.7%)

< 8-6.5 g/dL (Grade 3)

0

< 6.5 g/dL (Grade 4)

0

Total

Bilirubin

> 3-10 ×

ULN (Grade

3)

0

> 10 × ULN (Grade 4)

0

* ULN: Upper Limit of Normal according to testing laboratory.

Serum ALT Elevations

During clinical trials with HOLKIRA PAK with and without ribavirin, less than 1% of patients who were not on ethinyl estradiol-containing medications experienced transient serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment (see CONTRAINDICATIONS). These elevations were asymptomatic, generally occurred during the first 4 weeks of treatment and resolved with ongoing therapy. Increases in ALT were not associated with simultaneous increases in bilirubin levels. Cirrhosis was not a risk factor for elevated ALT. No specific monitoring of liver chemistries is required for the majority of patients (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, ALT Elevations). Serum Bilirubin Elevations

Transient elevations in bilirubin (predominantly indirect) were observed in patients receiving HOLKIRA PAK with ribavirin, related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and ribavirin-induced hemolysis. Bilirubin elevations occurred after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were not associated with aminotransferase elevations. The frequency of indirect bilirubin elevations was lower among patients who did not receive ribavirin.

Post-Market Adverse Drug Reactions

The following adverse reactions have been identified during post approval use of HOLKIRA PAK. Because these 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.

Hepatobiliary Disorders: Hepatic decompensation, hepatic failure (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Immune System Disorders: Anaphylactic reactions and other hypersensitivity reactions (including tongue and lip swelling).

Skin and Subcutaneous Tissue Disorders: Erythema multiforme.

DRUG INTERACTIONS

Drug-Drug Interactions

Potential for HOLKIRA PAK to Affect Other Drugs

Ritonavir is a strong inhibitor of CYP3A. Co-administration of HOLKIRA PAK (ombitasvir/paritaprevir/ritonavir and dasabuvir) with drugs primarily metabolized by CYP3A may result in increased plasma concentrations of these drugs. Drugs that are highly dependent on CYP3A for clearance and for which elevated plasma levels are associated with serious events are contraindicated (see CONTRAINDICATIONS).

Paritaprevir is an inhibitor of the hepatic uptake transporters OATP1B1 and OATP1B3, and paritaprevir and ritonavir are inhibitors of OATP2B1. Paritaprevir, ritonavir and dasabuvir are inhibitors of BCRP. Co-administration of HOLKIRA PAK with drugs that are substrates of OATP1B1, OATP1B3, OATP2B1 or BCRP may increase plasma concentrations of these transporter substrates, potentially requiring dose adjustment/clinical monitoring.

While paritaprevir, ritonavir and dasabuvir are in vitro inhibitors of P-gp, only slight increase was observed in the exposure of the P-gp substrate, digoxin, when administered with HOLKIRA PAK. Monitoring for plasma concentrations of drugs that are sensitive for changed intestinal P-gp activity is recommended.

Ombitasvir, paritaprevir and dasabuvir are inhibitors of UGT1A1. Co-administration of HOLKIRA PAK with drugs that are primarily metabolized by UGT1A1 is expected to result in increased plasma concentrations of such drugs; consider clinical monitoring for narrow therapeutic index drugs (i.e. levothyroxine). See also Table 7 for specific advice on raltegravir and buprenorphine, which have been evaluated in drug interaction studies.

Co-administration of HOLKIRA PAK can decrease exposures of drugs that are primarily metabolized by CYP2C19 (e.g., omeprazole). Clinical monitoring and/or dose increases might be needed for CYP2C19 substrates when administered with HOLKIRA PAK.

HOLKIRA PAK did not affect the exposures of the CYP2C9 substrate, warfarin, or CYP2D6/CYP1A2 substrate, duloxetine. Dose adjustment is not required for CYP2C9 or CYP2D6 or CYP1A2 substrates when administered with HOLKIRA PAK.

Ombitasvir, paritaprevir, ritonavir, and dasabuvir do not inhibit organic anion transporter (OAT1) in vivo as shown by the lack of interaction with tenofovir (OAT1 substrate). In vitro studies show that ombitasvir, paritaprevir, ritonavir and dasabuvir are not inhibitors of organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations. Therefore, HOLKIRA PAK is not expected to affect drugs which are primarily excreted by the renal route via these transporters.

Ombitasvir, paritaprevir, ritonavir, and dasabuvir are not expected to inhibit organic cation transporter 1 (OCT1) at clinically relevant concentrations.

Caution should be exercised when drugs that prolong QTc are co-administered with HOLKIRA PAK.

If HOLKIRA PAK is coadministered with vitamin K antagonist, close monitoring of International Normalised Ratio (INR) is recommended. This is due to liver function changes during treatment with HOLKIRA PAK.

Potential for Other Drugs to Affect HOLKIRA PAK

Paritaprevir and ritonavir are primarily metabolized by CYP3A, and dasabuvir is primarily metabolized by CYP2C8.

Strong inhibitors of CYP3A may significantly increase paritaprevir and ritonavir exposures when co-administered with HOLKIRA PAK. Drugs that potently inhibit CYP2C8 may significantly increase dasabuvir plasma concentrations; the co-administration of HOLKIRA PAK with a weak CYP2C8 inhibitor trimethoprim did not meaningfully affect dasabuvir exposure.

Drugs that induce CYP3A are expected to decrease dasabuvir, paritaprevir, ombitasvir and ritonavir plasma concentrations significantly and reduce their therapeutic effect. Drugs that induce CYP2C8 are expected to decrease dasabuvir plasma concentrations significantly and reduce its therapeutic effect. Drugs that are strong CYP2C8 inhibitors, CYP3A inducers or CYP2C8 inducers are contraindicated with HOLKIRA PAK (see CONTRAINDICATIONS).

Paritaprevir, dasabuvir, ritonavir and ombitasvir are substrates of P-gp. Paritaprevir and dasabuvir are substrates of BCRP. Paritaprevir is a substrate of OATP1B1 and OATP1B3. Inhibition of P-gp, BCRP, OATP1B1 or OATP1B3 may significantly increase exposures of the various components of HOLKIRA PAK.

Paritaprevir is a substrate of CYP3A and transport proteins. Caution is advised if co-administering HOLKIRA PAK with products that are both moderate inhibitors of CYP3A4 and inhibitors of multiple transporters (P-gp, BCRP and/or OATP1B1/ OATP1B3) as it can result in clinically relevant increases in paritaprevir exposures.

Drugs that Are Contraindicated with HOLKIRA PAK

The drugs that are contraindicated with HOLKIRA PAK are listed in Table 5.

Table 5. Drugs that Are Contraindicated with HOLKIRA PAK

Drug Class: Specific

Drugs

Mechanism of

Interaction

Clinical Comment

ALPHA1-ADRENORECEPTOR ANTAGONISTS

alfuzosin HCL CYP3A inhibition by

ritonavir

Potential for increased alfuzosin concentrations which can result in hypotension.

ANTIARRHYTHMICS

disopyramide,

dronedarone

CYP3A inhibition by ritonavir

Potential for serious and/or life-threatening reactions such as cardiac arrhythmias

ANTIBIOTICS

fusidic acid (oral

formulation)*

CYP3A4 inhibition by ritonavir

Potential for increased fusidic acid concentrations with risk of adverse events such as hepatotoxicity.

ANTICONVULSANTS

carbamazepine,

phenytoin, phenobarbital

CYP3A4 induction by carbamazepine,

phenytoin, phenobarbital

Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of HOLKIRA PAK.

Drug Class: Specific

Drugs

Mechanism of

Interaction

Clinical Comment

ANTI-GOUT

colchicine CYP3A4 inhibition by

ritonavir

Contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions.

For recommendations concerning patients with normal renal and hepatic function see Table 7.

ANTIHISTAMINES

astemizole, terfenadine* CYP3A4 inhibition by

ritonavir

Potential for cardiac arrhythmias.

ANTIHYPERLIPIDEMICS

gemfibrozil CYP2C8 inhibition by

gemfibrozil

Increased risk of QT prolongation due to 10-fold increase in dasabuvir AUC

ANTIMYCOBACTERIALS

rifampin CYP3A4/CYP2C8

induction by rifampin

Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of HOLKIRA PAK.

ANTIPSYCHOTICS

lurasidone CYP3A inhibition by

ritonavir

Potential for serious and/or life-threatening reactions.

BENZODIAZEPINES

oral midazolam,

triazolam

CYP3A4 inhibition by ritonavir

Potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.

ERGOT DERIVATIVES

ergotamine,

dihydroergotamine,

ergonovine*,

methylergonovine*

CYP3A4 inhibition by ritonavir

Acute ergot toxicity characterized by vasospasm and tissue ischemia has been associated with co-administration of ritonavir and ergonovine, ergotamine, dihydroergotamine, or methylergonovine.

GI MOTILITY AGENTS

cisapride* CYP3A4 inhibition by

ritonavir

Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

HERBAL PRODUCTS

St. John’s Wort

(Hypericum perforatum)

CYP3A4 induction by St. John's Wort

Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of HOLKIRA PAK.

Drug Class: Specific

Drugs

Mechanism of

Interaction

Clinical Comment

HIV-ANTIVIRAL AGENTS

efavirenz-containing

regimens, such as

Atripla

Co-administration of efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla) with paritaprevir, ritonavir and dasabuvir was poorly tolerated and resulted in liver enzyme elevations and early study termination.

nevirapine, etravirine

CYP3A4 induction by nevirapine or etravirine

Ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of HOLKIRA PAK.

HORMONAL PRODUCTS

ethinyl estradiol-

containing drugs

(combined oral

contraceptives,

contraceptive vaginal

rings, contraceptive

patch)

possibly due to UGT inhibition by ombitasvir and paritaprevir

Potential for ALT elevations.

HMG CoA REDUCTASE INHIBITORS

lovastatin, simvastatin,

atorvastatin

CYP3A4 and OATP1B inhibition by ritonavir and paritaprevir,

respectively

Potential for serious reactions such as myopathy including rhabdomyolysis.

LONG-ACTING BETA-ADRENOCEPTOR AGONISTS

salmeterol CYP3A4 inhibition by

ritonavir

Potential for QT prolongation, palpitations and sinus tachycardia.

NEUROLEPTICS

pimozide CYP3A4 inhibition by

ritonavir

Potential for cardiac arrhythmias.

PDE5 ENZYME INHIBITORS

sildenafil only at the

doses used daily for the

treatment of pulmonary

arterial hypertension

CYP3A4 inhibition by ritonavir

Potential for sildenafil-associated adverse events such as visual disturbances, hypotension, priapism, and syncope.

OTHER

modafinil CYP3A4 induction by

modafinil

Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of HOLKIRA PAK.

* Drugs not sold in Canada

Drugs that Should Not be Co-administered with HOLKIRA PAK

The drugs that should not be co-administered with HOLKIRA PAK are listed in Table 6.

Table 6. Drugs that Should Not be Co-administered with HOLKIRA PAK

Established and Other Potential Drug Interactions

Table 7 lists clinically relevant drug interactions where patient monitoring and/or dose adjustment are recommended. The pharmacokinetic data relevant to these drug interactions are shown in Table 8 and Table 9.

Table 7. Established and Other Potentially Significant Drug Interactions

Drugs with No Observed Interactions with HOLKIRA PAK

Drug interaction studies in patients reveal no clinically significant interaction between HOLKIRA PAK and the following commonly co-prescribed medications. No dose adjustments are required when co-administering these drugs with HOLKIRA PAK: abacavir, acetaminophen, dolutegravir, duloxetine, emtricitabine, escitalopram, lamivudine, metformin, methadone, naloxone, norethindrone, sofosbuvir, sulfamethoxazole, tenofovir disoproxil fumarate, trimethoprim, zolpidem.

Pharmacokinetic Parameters for Clinically Relevant Drug Interactions

Change in pharmacokinetic parameters for drug interaction for drug interactions resulting in contraindications, dose modification or clinical monitoring is presented in Table 8 and Table 9. Table 8 provides the magnitude of interaction on the concomitant medication. For information regarding clinical recommendations, see Table 7.

Table 8. Drug Interactions: Change in Pharmacokinetic Parameters of the Individual Components of

HOLKIRA PAK in the Presence of co-administered Drug

Co-administered

Drug

Ratio (with/without co-administered drug) of DAA Pharmacokinetic Parameters (90% CI);

No Effect = 1.00

Cmin ANTIARRHYTHMICS

digoxin

0.99

(0.92-1.07)

0.99

(0.96-1.02)

0.92

(0.82-1.02)

0.96

(0.89, 1.04) ANTICOAGULANTS

warfarin

1.03

(0.94-1.13)

0.98

(0.95-1.02)

0.96

(0.85-1.09)

1.10

(1.03, 1.17) ANTICONVULSANTS

carbamazepine

NA

NA

NA

NA

ANTIFUNGALS

ketoconazole

NA

NA

NA

NA

ANTIHYPERLIPIDEMIC AGENT

gemfibrozil^a

NA

NA

NA Co-administered

Drug

Ratio (with/without co-administered drug) of DAA Pharmacokinetic Parameters (90% CI);

No Effect = 1.00

Cmin

NA

CALCIUM CHANNEL BLOCKERS

amlodipine

0.95

(0.89, 1.01)

1.00

(0.97, 1.04)

0.88

(0.80, 0.95)

0.95

(0.89, 1.01) CONTRACEPTIVES

ethinylestradiol/

norgestimate

0.53

(0.30- 0.95)

1.00

(0.88- 1.12)

0.87

(0.67-1.14)

0.79

(0.68, 0.93) nor-ethindrone (progestin

only pill)

0.95

(0.80-1.13)

0.97

(0.90-1.03)

1.43

(1.13-1.80)

1.27

(1.06, 1.51) DIURETICS

furosemide

1.06

(0.98, 1.14)

1.12

(1.08, 1.16)

1.26

(1.16, 1.38)

1.07

(0.99, 1.17) HIV-ANTIVIRAL AGENTS

atazanavir/

ritonavir^c

Atazanavir 300 and ritonavir 100 once daily in the

evening

11

0.80

(0.65, 0.98)

1.00

(0.89, 1.13)

11.95

(8.94, 15.98) Co-administered

Drug

Ratio (with/without co-administered drug) of DAA Pharmacokinetic Parameters (90% CI);

No Effect = 1.00

Cmin

24.65

(18.64, 32.60) darunavir^d

0.90

(0.76, 1.06)

0.87

(0.82, 0.92)

1.30

(1.09, 1.54)

1.07

(0.93, 1.23) darunavir/ ritonavir^e

0.54

(0.49, 0.61)

0.73

(0.64, 0.83)

0.83

(0.69, 1.01)

0.88

(0.79, 0.99) darunavir/ ritonavir^f

0.65

(0.58, 0.72)

0.87

(0.80, 0.95)

1.59

(1.23, 2.05)

14.15

(11.66, 17.18) lopinavir/ ritonavir

0.68

(0.57, 0.80)

1.24

(1.14, 1.34)

2.36

(1.00, 5.55)

5.25

(3.33, 8.28) lopinavir/ ritonavir^g

800/200 once daily 12

0.47

(0.39, 0.58)

1.11

(1.06, 1.16)

8.23

(5.18, 13.07)

19.46

(15.93, 23.77) Co-administered

Drug

Ratio (with/without co-administered drug) of DAA Pharmacokinetic Parameters (90% CI);

No Effect = 1.00

Cmin

rilpivirine

1.10

(0.89, 1.37)

1.05

(1.01, 1.08)

0.95

(0.84, 1.07)

0.97

(0.91, 1.04) HMG CoA REDUCTASE INHIBITORS

pravastatin

1.03

(0.91, 1.15)

0.94

(0.89-0.99)

1.39

(1.21, 1.59)

1.08

(0.98, 1.19) rosuvastatin

1.15

(1.05, 1.25)

0.88

(0.83, 0.94)

1.43

(1.22, 1.68)

1.00

(0.90, 1.12) IMMUNOSUPPRESSANTS

cyclosporine

0.76

(0.71, 0.82)

1.15

(1.08, 1.23)

1.85

(1.58, 2.18)

1.49

(1.28, 1.74) tacrolimus 2 single dose 12

1.01

(0.91, 1.11)

0.94

(0.91, 0.96)

0.73

(0.66, 0.80) ritonavir 0.76

(0.63, 0.91)

0.87

(0.79, 0.97)

1.03

(0.89, 1.19) Co-administered

Drug

Ratio (with/without co-administered drug) of DAA Pharmacokinetic Parameters (90% CI);

No Effect = 1.00

Cmin

MUSCLE RELAXANTS

carisoprodol

1.00

(0.92, 1.10)

0.96

(0.92, 0.99)

1.14

(1.02, 1.27)

0.95

(0.89, 1.03) cyclobenzaprine

1.13

(1.07, 1.18)

1.01

(0.98, 1.04)

1.13

(1.01, 1.25)

1.13

(1.05, 1.21) NARCOTIC ANALGESICS

hydrocodone/

acetaminophen

1.16

(1.08, 1.25)

0.93

(0.90, 0.97)

1.10

(0.97, 1.26)

1.01

(0.93, 1.10) PROTON PUMP INHIBITORS

omeprazole 40 once daily 11

1.05

(0.93, 1.19)

1.04

(0.98, 1.11)

0.92

(0.76, 1.12) ritonavir 1.04

(0.96, 1.12)

1.02

(0.97, 1.08)

0.97

(0.89, 1.05) Co-administered

Drug

Ratio (with/without co-administered drug) of DAA Pharmacokinetic Parameters (90% CI);

No Effect = 1.00

Cmin SEDATIVES/HYPNOTICS

alprazolam

1.00

(0.87, 1.15)

0.98

(0.93, 1.04)

1.12

(1.02, 1.23)

1.01

(0.94, 1.09)

a. Study was conducted with paritaprevir, ritonavir and dasabuvir.

b. N = 3 for dasabuvir

c. Atazanavir plus 100 mg ritonavir administered in the evening, 12 hours after morning dose of the components of

HOLKIRA PAK.

d. Darunavir administered with the components of HOLKIRA PAK in the morning was compared to darunavir administered with 100 mg ritonavir in the morning.

e. Darunavir administered with the components of HOLKIRA PAK in the morning and with 100 mg ritonavir in the evening was compared to darunavir administered with 100 mg ritonavir in the morning and evening. f. Darunavir plus 100 mg ritonavir administered in the evening, 12 hours after the morning dose of the components of

HOLKIRA PAK compared to darunavir administered with 100 mg ritonavir in the evening. g. Lopinavir/ritonavir administered in the evening, 12 hours after morning dose of the components of HOLKIRA PAK. h. Similar increases were observed when rilpivirine was dosed in the evening with food or 4 hours after food. i. 30 mg cyclosporine was administered with the components of HOLKIRA PAK in the test arm and 100 mg cyclosporine was administered in the reference arm without the components of HOLKIRA PAK. NA: not available/not applicable; DAA: Direct-acting antiviral agent; CI: Confidence interval Doses of dasabuvir were 250 mg or 400 mg (both doses showed similar exposures). Doses of ombitasvir, paritaprevir, and ritonavir were 25 mg, 150 mg and 100 mg.

Dasabuvir was dosed twice daily and ombitasvir, paritaprevir and ritonavir were dosed once daily in all the above studies except studies with gemfibrozil, ketoconazole and carbamazepine that used single doses.

Table 9 summarizes the effects of HOLKIRA PAK on the pharmacokinetics of co-administered drugs which showed clinically relevant changes. For information regarding clinical recommendations, see Table 7.

Table 9. Drug Interactions: Change in Pharmacokinetic Parameters for Co-administered Drug in the

Presence of Components of HOLKIRA PAK

Co-administered

Drug

Ratio (with or without Components of HOLKIRA PAK) of Co-administered Drug

Pharmacokinetic Parameters (90% CI); No Effect = 1.00

Ctrough alprazolam

NA amlodipine

NA buprenorphine

3.12

(2.29, 4.27)^c naloxone

NA carisoprodol

NA carisoprodol’s metabolite, mepobramate

NA cyclobenzaprine

NA cyclobenzaprine’s metabolite

norcyclobenzaprine

NA cyclosporine

15.80 (13.81, 18.09)^{a, b} everolimus

16.10

(14.5, 17.9)^g darunavir

0.52

(0.47, 0.58)^d darunavir/ ritonavir^e

0.54

(0.48, 0.62)^d darunavir/ ritonavir^d

0.57 (0.48, 0.67)^b

Co-administered

Drug

Ratio (with or without Components of HOLKIRA PAK) of Co-administered Drug

Pharmacokinetic Parameters (90% CI); No Effect = 1.00

Ctrough diazepam

NA diazepam's metabolite nordiazepam

NA digoxin

1.01

(0.97,1.05) ethinylestradiol

1.12

(0.94,1.33)

norgestimate

2.93

(2.39,3.57) norgestimate metabolites: norgestrel and norelgestromin

3.11

(2.51,3.85)

furosemide

NA hydrocodone

NA ketoconazole

NA lopinavir/ ritonavir

1.15

(0.93, 1.42)^d lopinavir/ ritonavir

3.18

(2.49, 4.06)^d omeprazole

NA pravastatin

NA rilpivirine

3.62 (3.12, 4.21)

2.87

(2.28, 3.62)

3.73

(3.16, 4.40)

rosuvastatin

0.59

(0.51, 0.69) Co-administered

Drug

Ratio (with or without Components of HOLKIRA PAK) of Co-administered Drug

Pharmacokinetic Parameters (90% CI); No Effect = 1.00

Ctrough sirolimus

19.55 (16.7, 22.9)

c, b tacrolimus

16.56 (12.97, 21.16)^{a, b}

R-warfarin

0.94

(0.84,1.05) S-warfarin

0.95

(0.88,1.02)

NA: Not available

a. Dose normalized parameters reported.

b. C₂₄: concentration at 24 hours following single dose of cyclosporine, digoxin, sirolimus or tacrolimus. c. Atazanavir or darunavir or lopinavir parameters are reported.

d. Darunavir administered with HOLKIRA^TM PAK in the morning was compared to darunavir administered with 100 mg ritonavir in the morning.

e. 0.5 mg sirolimus was administered with ombitasvir/paritaprevir/ritonavir plus dasabuvir in the test arm and 2 mg sirolimus was administered in the reference arm without ombitasvir/paritaprevir/ritonavir plus dasabuvir.

f. C₁₂: concentration at 12 hours following single dose of everolimus.

g. 30 mg cyclosporine was administered with ombitasvir/paritaprevir/ritonavir plus dasabuvir in the test arm and 100 mg cyclosporine was administered in the reference arm without ombitasvir/paritaprevir/ritonavir plus dasabuvir.

Drug-Food Interactions

Food increased the exposure (AUC) of paritaprevir, ombitasvir, ritonavir, and dasabuvir by up to 211%, 82%, 49%, and 30% respectively relative to the fasting state. The increase in exposure was similar regardless of meal type (e.g., high-fat versus moderate-fat) or calorie content (approximately 600 Kcal versus approximately 1000 Kcal). To maximize absorption, HOLKIRA PAK should be taken with food without regard to fat or calorie content (see DOSAGE AND ADMINISTRATION).

Drug-Herb Interactions

Co-administration of St. John’s wort (Hypericum perforatum), a potent hepatic and intestinal CYP3A4 and/or P-gp inducer, may decrease HOLKIRA PAK plasma concentrations, which may result in loss of therapeutic effect.

St. John’s wort (Hypericum perforatum) is contraindicated with HOLKIRA PAK (see CONTRAINDICATIONS).

Drug-Laboratory Interactions

Interactions of HOLKIRA PAK with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

• HOLKIRA PAK (ombitasvir/paritaprevir/ritonavir and dasabuvir) is

  ombitasvir/paritaprevir/ritonavir fixed dose combination tablets copackaged with dasabuvir tablets. Ombitasvir/paritaprevir/ritonavir tablets must be administered with dasabuvir tablets.

• HOLKIRA PAK is used in combination with ribavirin in patients with genotype 1a infection. HOLKIRA PAK is used without ribavirin in patients with genotype 1b infection (see Table 10).

• Prior to initiation of therapy, assess for laboratory and clinical evidence of hepatic decompensation (see WARNINGS AND PRECAUTIONS,

  Hepatic/Biliary/Pancreatic).

• Prior to initiation of therapy, HBV screening should be performed in all patients to decrease the risk of HBV reactivation in patients co-infected with HBV.

Recommended Dose and Dosage Adjustment

The recommended oral dose of HOLKIRA PAK is two ombitasvir/paritaprevir/ritonavir 12.5/75/50 mg tablets once daily (in the morning) and one dasabuvir 250 mg tablet twice daily (morning and evening). HOLKIRA PAK is used in combination with ribavirin in certain patient populations (see Table 10).

As a fixed dose combination formulation, no dosage adjustments for HOLKIRA PAK are possible.

HOLKIRA PAK tablets should be swallowed whole, with water if required, and not chewed, broken, or crushed. To maximize absorption, HOLKIRA PAK should be taken with food without regard to fat or calorie content (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption, Effects of Food on Oral Absorption).

Table 10 shows the recommended treatment regimen and duration based on patient population. Table 10. Treatment Regimen and Duration by Patient Population

Patient Population

Duration

HCV mono-infected subjects

Or

HCV patients co-infected with HIV

12 weeks

12 weeks

Liver transplant

recipients: Only patients with normal hepatic function and Metavir fibrosis score ≤ 2

24 weeks

HCV genotype 1a with cirrhosis and with

previous null response to pegylated interferon (pegIFN) and ribavirin

24 weeks

Note: HOLKIRA PAK with ribavirin is recommended in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection.

For specific dosage instructions for ribavirin, including dose modification, refer to the ribavirin Product Monograph.

HOLKIRA PAK should be taken as directed for the prescribed duration, without interruption or dose modification. If HOLKIRA PAK is used in combination with ribavirin, ribavirin should be administered for the same duration as HOLKIRA PAK.

Special Populations

Pediatrics (< 18 years of age)

Safety and effectiveness of HOLKIRA PAK in children less than 18 years of age have not been established.

Geriatrics (≥ 65 years of age)

No dose adjustment of HOLKIRA PAK is warranted in geriatric patients (see INDICATIONS AND CLINICAL USE; WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

HCV-HIV-1 Co-infection

For patients with HCV-HIV-1 co-infection, follow the dosage recommendations in Table 10. Refer to DRUG INTERACTIONS for dosage recommendations for concomitant HIV-1 antiviral drugs.

Liver Transplant Recipients

HOLKIRA PAK in combination with ribavirin is recommended for 24 weeks in liver transplant recipients. Lower ribavirin dose at initiation may be appropriate. In the post liver transplant study, ribavirin dosing was individualized and most patients received 600 to 800 mg per day (see CLINICAL TRIALS). For dosing recommendations with calcineurin inhibitors refer to DRUG INTERACTIONS.

Hepatic Impairment

No dose adjustment of HOLKIRA PAK is required in patients with mild hepatic impairment (Child-Pugh A). HOLKIRA PAK is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C) (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

Renal Impairment

No dose adjustment of HOLKIRA PAK is required in patients with mild, moderate or severe renal impairment (see WARNINGS AND PRECAUTIONS, Renal and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency)

Missed Dose

Patients should be informed that in case a dose of ombitasvir/paritaprevir/ritonavir is missed, the prescribed dose can be taken within 12 hours of the scheduled time for the dose that was missed.

In case a dose of dasabuvir is missed, the prescribed dose can be taken within 6 hours of the scheduled time for the dose that was missed.

If more than 12 hours has passed since ombitasvir/paritaprevir/ritonavir is usually taken or more than 6 hours has passed since dasabuvir is usually taken, the missed dose should NOT be taken and the patient should take the next dose as per the usual dosing schedule.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

The highest documented single dose administered to healthy subjects was 350 mg for ombitasvir, 400 mg for paritaprevir (with 100 mg ritonavir), 200 mg for ritonavir (with 100 mg paritaprevir), and 2000 mg for dasabuvir. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted immediately. ECG monitoring is recommended.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

HOLKIRA PAK (ombitasvir/paritaprevir/ritonavir and dasabuvir) combines three direct-acting hepatitis C virus antiviral agents with distinct mechanisms of action, and non-overlapping resistance profiles, to target HCV at multiple steps in the viral lifecycle (see MICROBIOLOGY, Mechanism of Action).

Paritaprevir is an inhibitor of HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. Ombitasvir is an inhibitor of HCV NS5A which is essential for viral replication. Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome. The stopping of viral replication leads to a rapid decline of HCV viral load and clearing of HCV levels in the body.

Ritonavir is not active against HCV. Ritonavir is a pharmacokinetic enhancer that increases peak and trough plasma drug concentrations of paritaprevir and overall drug exposure (i.e., area under the curve).

Pharmacodynamics

Effects on Electrocardiogram

Pharmacokinetics

The pharmacokinetic properties of the combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir have been evaluated in healthy adult subjects and in patients with chronic hepatitis C. Table 11 shows mean C_max and AUC of ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily with dasabuvir 250 mg twice daily following multiple doses with food in healthy subjects.

Table 11. Geometric Mean C_max, C_trough, AUC of Multiple Doses of Ombitasvir/Paritaprevir/Ritonavir

25/150/100 mg Once Daily with Dasabuvir 250 mg Twice Daily with Food in HCV-Infected Patients and Healthy Subjects

Compound/Population C_max (ng/mL) C_trough (ng/mL) AUC (ng*hr/mL)

HCV-Infected Patients^a

Ombitasvir 68 24 1000 Paritaprevir 262 22 2220 Dasabuvir 667 74 3240 Ritonavir 682 35 6180

Healthy Subjects^b

Ombitasvir 127 29 1420 Paritaprevir 1470 20 6990 Dasabuvir 1030 269 6840 Ritonavir 1600 33 9470 a. median values

b. geometric mean values

Absorption

Ombitasvir/paritaprevir/ritonavir and dasabuvir were absorbed after oral administration with mean T_max of approximately 4 to 5 hours. While ombitasvir and dasabuvir exposures increased in a dose proportional manner, paritaprevir and ritonavir exposures increased in a more than dose proportional manner. Accumulation is minimal for ombitasvir and dasabuvir and approximately 1.5- to 2-fold for ritonavir and paritaprevir. Pharmacokinetic steady state for the combination is achieved after approximately 12 days of dosing.

The absolute bioavailability of ombitasvir and paritaprevir when administered with ritonavir as 25/150/100 mg ombitasvir/paritaprevir/ritonavir was approximately 48% and 53%, respectively. The absolute bioavailability of dasabuvir when administered alone is estimated to be approximately 70%.

Effects of Food on Oral Absorption

Food increased the exposure (AUC) of ombitasvir, paritaprevir, ritonavir, and dasabuvir by up to 82, 211, 49, and 30% respectively relative to the fasting state. The increase in exposure was similar regardless of meal type (e.g., high-fat versus moderate-fat) or calorie content (approximately 600 Kcal versus approximately 1000 Kcal).

Distribution

Ombitasvir, paritaprevir, ritonavir and dasabuvir are highly bound to plasma proteins. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. The blood to plasma concentration ratios in humans were 0.49, 0.7, 0.6, and 0.7 for ombitasvir, paritaprevir, ritonavir and dasabuvir, indicating that preferential distribution in the plasma compartment of whole blood.

Ombitasvir

Ombitasvir was approximately 99.9% bound to human plasma proteins over a concentration range of 0.09 to 9 mcg per mL.

Paritaprevir

Paritaprevir was approximately 97 to 98.6% bound to human plasma proteins over a concentration range of 0.08 to 8 mcg per mL.

Ritonavir

Ritonavir was greater than 99% bound to human plasma proteins over a concentration range of 0.007 to 22 mcg per mL.

Dasabuvir

Dasabuvir was greater than 99.5% bound to human plasma proteins over a concentration range of 0.15 to 5 mcg per mL.

In animals, paritaprevir liver levels are significantly higher than plasma levels (e.g. liver: plasma ratio of greater than 300:1 in mouse). In vitro data indicate that paritaprevir is a substrate for the human hepatic uptake transporters, OATP1B1 and OATP1B3.

Metabolism

Ombitasvir

Ombitasvir is metabolized via amide hydrolysis followed by oxidative metabolism. Following a 25 mg single dose of ¹⁴C-ombitasvir given alone, unchanged parent drug accounted for 8.9% of total radioactivity in human plasma; a total of 13 metabolites were identified in human plasma. These metabolites are not expected to have antiviral activity or off-target pharmacologic activity. Paritaprevir

Paritaprevir is metabolized predominantly by CYP3A4 and to a lesser extent CYP3A5. Following administration of a single 200/100 mg oral dose of ¹⁴C-paritaprevir/ritonavir to humans, the parent drug was the major circulating component accounting for approximately 90% of the plasma radioactivity. At least 5 minor metabolites of paritaprevir have been identified in circulation that accounted for approximately 10% of plasma radioactivity. These metabolites are not expected to have antiviral activity.

Dasabuvir

Dasabuvir is predominantly metabolized by CYP2C8 and to a lesser extent by CYP3A. Following a 400 mg ¹⁴C-dasabuvir dose in humans, unchanged dasabuvir was the major component (approximately 60%) of drug related radioactivity in plasma; seven metabolites were identified in plasma. The most abundant plasma metabolite was M1, which represented 21% of drug-related radioactivity (AUC) in circulation and has similar activity (after correction for plasma protein binding) as the parent drug against genotype 1 in vitro.

Ritonavir

Ritonavir is predominantly metabolized by CYP3A and to a lesser extent, by CYP2D6. Nearly the entire plasma radioactivity after a single 600 mg dose of ¹⁴C-ritonavir oral solution in humans was attributed to unchanged ritonavir.

Excretion

Ombitasvir

Following dosing of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, mean plasma half-life of ombitasvir was approximately 21 to 25 hours. Following a 25 mg ¹⁴C-ombitasvir dose, approximately 90.2% of the radioactivity was recovered in feces with limited radioactivity (1.91%) in urine. Unchanged ombitasvir accounted for 87.8% of the radioactivity in the feces and 0.03% in the urine.

Paritaprevir

Following dosing of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, mean plasma half-life of paritaprevir was approximately 5.5 hours. Following a 200 mg ¹⁴C-paritaprevir dose with 100 mg ritonavir, approximately 88% of the radioactivity was recovered in feces with limited radioactivity (8.8%) in urine. Unchanged paritaprevir accounted for 1.1% of the radioactivity in the feces and 0.05% in the urine. Unchanged parent drug and M29, the product of fecal hydrolysis, accounted for 87.8% of total radioactivity recovered in feces, indicating that biliary excretion of parent drug is a major elimination pathway for paritaprevir. Dasabuvir

Following dosing of dasabuvir with ombitasvir/paritaprevir/ritonavir, mean plasma half-life of dasabuvir was approximately 5.5 to 6 hours. Following a 400 mg ¹⁴C-dasabuvir dose, approximately 94.4% of the radioactivity was recovered in feces with limited radioactivity (approximately 2%) in urine. Unchanged dasabuvir accounted for 26% of the radioactivity in the feces and 0.03% in the urine.

Ritonavir

Following dosing of paritaprevir/ritonavir/ombitasvir, mean plasma half-life of ritonavir was approximately 4 hours. Following a 600 mg dose of ¹⁴C-ritonavir oral solution, 86.4% of the radioactivity was recovered in the feces and 11.3% of the dose was excreted in the urine.

Special Populations and Conditions

Pediatrics

The pharmacokinetics of HOLKIRA PAK in pediatric patients has not been established (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics (< 18 years of age)).

Geriatrics (> 65 years of age)

Population pharmacokinetic analysis of data from Phase 3 clinical studies with HOLKIRA PAK showed that a 10 year increase or decrease in age from 54 years (median age in the Phase 3 studies) would result in approximately 10% change in ombitasvir exposures, ≤ 20% change in paritaprevir exposures and < 10% change in dasabuvir exposures. Age was not a significant predictor for ritonavir exposures. There is no pharmacokinetic information in patients > 75 years. Phase 3 studies of HOLKIRA PAK included 174 patients aged 65 and over. The response rates observed for patients ≥ 65 years of age (97%) were similar to those of patients < 65 years of age (96%), across treatment groups (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics (> 65 years of age).

Gender

Population pharmacokinetic analysis of data from Phase 3 clinical studies with HOLKIRA PAK showed that female patients would have approximately 55% higher ombitasvir exposures, 100% higher paritaprevir exposures, 15% higher ritonavir exposures and 14 to 30% higher dasabuvir exposures than male patients. The relationship between gender and HOLKIRA PAK exposures was not considered clinically relevant as high response rates (SVR > 90%) were achieved in male and female patients across the Phase 3 studies.

Race

patients of Black race compared to patients of

Population pharmacokinetic analysis of data from Phase 3 clinical studies with HOLKIRA PAK showed that Asian patients had 18 to 21% higher ombitasvir exposures, 37 to 39% higher paritaprevir exposures and 29 to 39% higher dasabuvir exposures than non-Asian patients. The ritonavir exposures were comparable between Asians and non-Asians. These differences in exposures were not clinically significant.

Hepatic Insufficiency

subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment.

In patients with mild hepatic impairment, ombitasvir, paritaprevir and ritonavir mean AUC values decreased by 8, 29 and 34%, respectively, and dasabuvir mean AUC values were 17% higher compared to patients with normal hepatic function. No dose adjustment for HOLKIRA PAK is recommended for HCV-infected patients with mild hepatic impairment.

patients with moderate hepatic impairment, ombitasvir and ritonavir mean AUC values

patients with normal hepatic function. HOLKIRA PAK is contraindicated in patients with moderate hepatic impairment (Child Pugh B) (see WARNINGS AND PRECAUTIONS and CONTRAINDICATIONS).

In patients with severe hepatic impairment, paritaprevir and dasabuvir mean AUC values

compared to patients with normal hepatic function. HOLKIRA PAK is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see CONTRAINDICATIONS).

Renal Insufficiency

Pharmacokinetics of the combination of ombitasvir 25 mg, paritaprevir 150 mg and ritonavir 100 mg, with or without dasabuvir 400 mg were evaluated in patients with mild (creatinine clearance [CrCl]: 60 to 89 mL per min), moderate (CrCl: 30 to 59 mL per min) and severe (CrCl: 15 to 29 mL per min) renal impairment.

patients with mild renal impairment, the mean AUC values of ombitasvir, paritaprevir,

tion.

In patients with moderate renal impairment, the mean AUC values of ombitasvir, paritaprevir,

normal renal function.

In patients with severe renal impairment, the mean AUC values of ombitasvir, paritaprevir,

function. Consult the ribavirin Product Monograph for patients with renal impairment.

STORAGE AND STABILITY

Store between 2 and 30°C. Protect from moisture.

SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions.

DOSAGE FORMS, COMPOSITION AND PACKAGING

HOLKIRA PAK (ombitasvir/paritaprevir/ritonavir and dasabuvir) is

ombitasvir/paritaprevir/ritonavir fixed dose combination tablets co-packaged with dasabuvir tablets.

• Ombitasvir/paritaprevir/ritonavir 12.5/75/50 mg tablets are pink-colored, film-coated, oblong biconvex shaped, debossed with “AV1” on one side.

• Dasabuvir 250 mg tablets are beige-colored, film-coated, oval-shaped, debossed with

  “AV2” on one side.

HOLKIRA PAK is dispensed in a convenient monthly carton for a total of 28 days of therapy. Each monthly carton contains four weekly cartons. Each weekly carton contains seven daily dose packs.

Each daily dose pack contains four tablets: two 12.5/75/50 mg ombitasvir/paritaprevir/ritonavir tablets and two 250 mg dasabuvir tablets, and indicates which tablets need to be taken in the morning and evening.

Listing of Non-Medicinal Ingredients

Each ombitasvir/paritaprevir/ritonavir fixed dose combination tablet contains 12.5 mg ombitasvir /75 mg paritaprevir/50 mg ritonavir with the following non-medicinal ingredients: colloidal silicon dioxide/anhydrous colloidal silica, copovidone, propylene glycol monolaurate, sodium

not contain gluten. Each dasabuvir immediate release tablet contains 250 mg dasabuvir (as dasabuvir sodium

not contain gluten. PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Ombitasvir Hydrate

Common name: ombitasvir

Chemical name: Dimethyl ([(2S,5S)-1-(4-tert-butylphenyl) pyrrolidine-2,5-diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate hydrate

Molecular formula

and molecular

mass:

C₅₀H₆₇N₇O₈•4.5H₂O (hydrate) 975.20 (hydrate)

Structural formula:

Physicochemical

properties:

Appearance

Solubility

Ombitasvir Hydrate is a white to light yellow to light pink powder.

Ombitasvir Hydrate is practically insoluble in aqueous buffers but is soluble in ethanol.

Paritaprevir Hydrate

Common name: paritaprevir

Chemical name: (2R,6S,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-{[(5-methylpyrazin-2-yl)carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-

tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]

diazacyclopentadecine-14a(5H)-carboxamide dihydrate

Molecular formula

and molecular

mass:

C₄₀H₄₃N₇O₇S•2H₂O (dihydrate) 801.91 (dihydrate)

Structural formula:

Physicochemical

properties:

Appearance

Solubility

Paritaprevir Hydrate is a white to off white powder.

Paritaprevir Hydrate has very low water solubility.

Ritonavir

Proper name: ritonavir

Chemical name: [5S-(5R*,8R*,10R*,11R*)]10-Hydroxy-2-methyl-5-(1-methyethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid,5-thiazolylmethyl ester

Molecular formula

and molecular

mass:

C₃₇H₄₈N₆O₅S₂ 720.95

Structural formula:

Physicochemical

properties:

Appearance

Solubility

Ritonavir is a white to off white to light tan powder.

Ritonavir is insoluble in water and freely soluble in methanol and ethanol.

Dasabuvir

Common name: dasabuvir sodium monohydrate

Chemical name: Sodium 3-(3-tert-butyl-4-methoxy-5-{6-

[(methylsulfonyl)amino]naphthalene-2-yl}phenyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ide hydrate (1:1:1)

Molecular formula

and molecular

mass:

C₂₆H₂₆N₃O₅S•Na•H₂O

(monosodium, monohydrate)

533.57 (monosodium, monohydrate)

493.57 (free acid, anhydrate)

Structural formula:

Physicochemical properties:

Appearance

Solubility

Dasabuvir is white to pale yellow to pink powder.

Dasabuvir is slightly soluble in water and very slightly soluble in methanol and isopropyl alcohol.

CLINICAL TRIALS

Trial Design

The efficacy and safety of HOLKIRA PAK was evaluated in seven Phase 3 clinical trials, including two trials exclusively in patients with cirrhosis (Child-Pugh A), in over 2,300 patients with genotype 1 chronic hepatitis C infection, as summarized in Table 12. HOLKIRA PAK was also evaluated in patients with HCV GT1 co-infected with HIV-1 and in HCV GT1-infected liver transplant recipients.

Table 12. Summary of Clinical Trial Designs in Treatment of Genotype 1 Chronic Hepatitis C

Infection

Study #

Dosage, Route of Administration and

Duration^b

Treatment-Naïve^c, without Cirrhosis

SAPPHIRE-I

(M11-646)

ombitasvir/paritaprevir/ritonavir tablet:

25/150/100 mg or placebo QD; dasabuvir tablet: 250 mg or placebo BID;

RBV tablet: 1,000 or 1,200 mg or placebo QD (divided BID);

Oral

12 weeks

PEARL-III (M13-961)

ombitasvir/paritaprevir/ritonavir tablet:

25/150/100 mg QD; dasabuvir tablet: 250 mg BID; RBV tablet: 1,000 to 1,200 mg or placebo QD (divided BID);

Oral

12 weeks

PEARL-IV (M14-002)

ombitasvir/paritaprevir/ritonavir tablet:

25/150/100 mg QD; dasabuvir tablet: 250 mg BID; RBV tablet: 1,000 to 1,200 mg or placebo QD (divided BID)

Oral

12 weeks

Study #

Dosage, Route of Administration and

Duration^b

Treatment-Experienced^d, without Cirrhosis

SAPPHIRE-II

(M13-098)

ombitasvir/paritaprevir/ritonavir tablet:

25/150/100 mg or placebo QD; dasabuvir tablet: 250 mg or placebo BID;

RBV tablet: 1,000 or 1,200 mg or placebo QD (divided BID)

Oral

12 weeks

PEARL-II (M13-389)

ombitasvir/paritaprevir/ritonavir tablet:

25/150/100 mg QD; dasabuvir tablet: 250 mg BID; RBV tablet: 1,000 or 1,200 mg QD

(divided BID)

Oral

12 weeks

Treatment-Naïve and Treatment-Experienced^d, with Cirrhosis

TURQUOISE-II

(M13-099)

ombitasvir/paritaprevir/ritonavir tablet:

25/150/100 mg QD; dasabuvir tablet: 250 mg BID; RBV tablet: 1,000 to 1,200 mg or placebo QD (divided BID)

Oral

12 or 24 weeks

TURQUOISE-

III

(M14-490)

ombitasvir/paritaprevir/ritonavir tablet:

25/150/100 mg QD; dasabuvir tablet: 250 mg BID;

Oral

12 weeks

Patients with HCV GT1 Infection-HIV-1 Co-infection

TURQUOISE-I

(M14-004)

ombitasvir/paritaprevir/ritonavir tablet:

25/150/100 mg QD; dasabuvir tablet: 250 mg BID; RBV tablet: 1,000 to 1,200 mg QD

(divided BID)

Oral

12 or 24 weeks

Study #

Dosage, Route of Administration and

Duration^b

Liver Transplant Recipients

CORAL-I

(M12-999)

ombitasvir/paritaprevir/ritonavir tablet:

25/150/100 mg QD; dasabuvir tablet: 250 mg BID; RBV tablet^e: 600 to 800 mg

Oral

24 weeks

BID = twice daily, QD = daily, pegIFN = pegylated interferon, RBV = ribavirin

a. Treated is defined as patients who were randomized and received at least one dose of HOLKIRA PAK. b. For patients who received ribavirin, the ribavirin dose was 1000 mg per day for patients weighing less than 75 kg or

1200 mg per day for patients weighing greater than or equal to 75 kg.

c. Treatment naïve was defined as not having received any prior therapy for HCV infection.

d. Treatment-experienced patients were defined as either: prior relapsers (patients with HCV RNA undetectable at or after the end of at least 36 weeks of pegIFN/RBV treatment, but HCV RNA was detectable within 52 weeks of treatment follow-up) or prior partial responders (received at least 20 weeks of pegIFN/RBV and achieved a greater than or equal to 2 log₁₀ IU/mL reduction in HCV RNA at week 12, but not achieving HCV RNA undetectable at end of treatment) or prior null-responders (received at least 12 weeks of pegIFN/RBV treatment and failed to achieve a 2 log₁₀ IU/mL reduction in HCV RNA at week 12 or, for SAPPHIRE-II and TURQUOISE-II, received at least 4 weeks of pegIFN/RBV treatment and achieved a < 1 log₁₀ IU/mL reduction in HCV RNA at week 4). TURQUOISE-III also enrolled less well characterized failures of pegIFN/RBV treatment.

e. Ribavirin dosing was managed at the discretion of the investigator with 600 to 800 mg per day being the most frequently selected starting doses.

Sustained virologic response (SVR) (virologic cure) was defined as unquantifiable or undetectable HCV RNA 12 weeks after the end of treatment (SVR12) in the Phase 3 trials. Treatment duration was fixed in each trial and was not guided by patients’ HCV RNA levels (no response guided algorithm). Plasma HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL.

Clinical Trials in Treatment-Naïve Adults

SAPPHIRE-I was a randomized, global, multicenter, double-blind, placebo-controlled trial conducted in 631 treatment-naïve adults with genotype 1 chronic hepatitis C virus infection without cirrhosis. HOLKIRA PAK was given for 12 weeks of treatment in combination with ribavirin (RBV). Patients randomized to the placebo arm received placebo for 12 weeks, after which they received open-label HOLKIRA PAK in combination with ribavirin for 12 weeks. PEARL-III and PEARL-IV were randomized, global, multicenter, double-blind, controlled trials conducted in 419 treatment-naïve adults with genotype 1b chronic hepatitis C virus infection without cirrhosis (PEARL-III) and 305 treatment-naïve adults with genotype 1a chronic hepatitis C virus infection without cirrhosis (PEARL-IV). Patients were randomized, in a 1:1 ratio (PEARL-III) or a 1:2 ratio (PEARL-IV), to receive HOLKIRA PAK with or without ribavirin for 12 weeks of treatment.

Demographic and baseline characteristics for treatment-naïve patients in SAPPHIRE-I, PEARL-III and PEARL-IV are provided in Table 13.

Table 13. Demographic and Baseline Characteristics of Treatment-Naïve Patients without Cirrhosis in

SAPPHIRE-I, PEARL-III and PEARL-IV

Characteristics

PEARL-IV

N=305

Age (years)

Median (range)

54 (19 – 70)

Gender, n (%)

Male

199 (65.2) Female

106 (34.8)

Race, n (%)

White

257 (84.3) Black or African American

36 (11.8) Asian

4 (1.3) Other

8 (2.6)

Ethnicity, n (%)

Hispanic or Latino

28 (9.2) None of the above

277 (90.8)

Body mass index, n (%)

< 30 kg/m²

245 (80.3) ≥ 30 kg/m²

60 (19.7)

HCV genotype, n (%)

1a

304 (99.7) 1b

1 (0.3)

Baseline HCV RNA

Mean ± SD (log₁₀ IU/mL)

6.57 ± 0.63 < 800000 IU/mL, n (%)

41 (13.4) ≥ 800000 IU/mL, n (%)

264 (86.6)

IL28B, n (%)

CC

94 (30.8) Non-CC

211 (69.2) Characteristics

PEARL-IV

N=305

Baseline fibrosis stage, n (%)

F0-F1

195 (63.9) F2

56 (18.4) ≥ F3

54 (17.7)

History of depression or bipolar disorder, n (%)

No

242 (79.3) Yes

63 (20.7) N/A = Not Applicable.

Study Results

Table 14 shows the SVR12 rates for genotype 1-infected, treatment-naïve patients receiving HOLKIRA PAK with or without ribavirin for 12 weeks in SAPPHIRE-I, PEARL-III and PEARL-IV. All treatment groups met the primary efficacy endpoint. In study PEARL-III, HOLKIRA PAK without ribavirin had similar SVR12 rates (100%) compared to HOLKIRA PAK with ribavirin (99.5%). In study PEARL-IV, HOLKIRA PAK without ribavirin did not meet the pre-specified criteria for non-inferiority to HOLKIRA PAK with ribavirin. Table 14. SVR12 for Genotype 1-Infected Treatment-Naïve Patients without Cirrhosis in

SAPPHIRE-I, PEARL-III and PEARL-IV

Treatment Outcome

PEARL-IV Genotype 1a

HOLKIRA

PAK

N=205 % (n/N)

Overall SVR12

90 (185/205) 95% CI

86.2 to 94.3

HCV genotype 1a

90 (184/204) HCV genotype 1b

Outcome for patients without SVR12

On-treatment VF^a

3 (6/205) Relapse^b

5 (10/194) Other^c

2 (4/205)

CI = confidence interval, VF = virologic failure, N/A = Not Applicable

* For patients with GT1b infection without cirrhosis, HOLKIRA PAK alone for 12 weeks is the recommended regimen. ** For patients with GT1a infection without cirrhosis, HOLKIRA PAK with RBV for 12 weeks is the recommended regimen. a. On-treatment VF was defined as confirmed HCV ≥ 25 IU/mL after HCV RNA < 25 IU/mL during treatment, confirmed 1 log₁₀ IU/mL increase in HCV RNA from nadir, or HCV RNA persistently ≥ 25 IU/mL with at least 6 weeks of treatment. b. Relapse was defined as confirmed HCV RNA ≥ 25 IU/mL post-treatment before or during SVR12 window among patients with HCV RNA < 25 IU/mL at last observation during at least 11 weeks of treatment.

c. Other includes patients not achieving SVR12 but not experiencing on-treatment VF or relapse (e.g. missing HCV RNA values in the SVR12 window).

d. No patients with HCV genotype 1b infection experienced on-treatment virologic failure and one patient with HCV genotype

1b infection experienced relapse.

Table 15 presents the SVR12 rates by selected subgroups for genotype 1-infected, treatment-naïve patients in studies SAPPHIRE-I, PEARL-III and PEARL-IV. Table 15. SVR12 rates for Selected Subgroups of Genotype 1-infected, Treatment-Naïve Patients without Cirrhosis in SAPPHIRE-I, PEARL-III and PEARL-IV

Treatment

Outcome

PEARL-IV Genotype 1a

HOLKIRA

PAK

N=205 % (n/N)

IL28B

CC

97 (61/63) Non-CC

87 (124/142)

Sex

Female

95 (72/76) Male

88 (113/129)

Age

< 65 years

90 (172/192) ≥ 65 years

100 (13/13)

Race

85 (23/27) Non-black

91 (162/178)

Ethnicity

Hispanic or Latino

89 (16/18)

None of the above

90 (169/187)

Body mass index

< 30 kg/m²

92 (153/166) ≥ 30 kg/m²

82 (32/39)

Baseline HCV RNA

< 800000 IU/mL

91 (30/33)

≥ 800000 IU/mL

90 (155/172)

Baseline fibrosis stage

F0-F1

92 (122/132) F2

83 (29/35) ≥ F3

89 (34/38) Treatment Outcome

PEARL-IV Genotype 1a

HOLKIRA

PAK

N=205 % (n/N)

History of

depression or bipolar disorder

No

89 (142/159) Yes

93 (43/46)

* For patients with GT1b infection without cirrhosis, HOLKIRA PAK alone for 12 weeks is the recommended regimen. ** For patients with GT1a infection without cirrhosis, HOLKIRA PAK with RBV for 12 weeks is the recommended regimen.

These baseline viral (genotype 1 subtype, baseline viral load) and host factors (gender, race, ethnicity, age, IL28B allele, baseline body mass index, history of depression or bipolar disorder, fibrosis stage) were not associated with lower SVR12 rates across subgroups.

In addition, patients who underwent ribavirin dose modifications did not have lower SVR12 rates.

Clinical Trials in Treatment-Experienced Adults

SAPPHIRE-II was a randomized, global multicenter, double-blind, placebo-controlled trial conducted in 394 patients with genotype 1 chronic hepatitis C virus infection without cirrhosis who did not achieve SVR with prior treatment with peginterferon and ribavirin (pegIFN/RBV). HOLKIRA PAK in combination with ribavirin was given for 12 weeks of treatment. Patients randomized to the placebo arm received placebo for 12 weeks, after which they received HOLKIRA PAK in combination with ribavirin for 12 weeks.

PEARL-II was a randomized, global, multicenter, open-label trial conducted in 179 adults with chronic genotype 1b hepatitis C virus infection without cirrhosis who did not achieve SVR with prior treatment with pegIFN/RBV. Patients were randomized, in a 1:1 ratio, to receive HOLKIRA PAK with or without ribavirin for 12 weeks of treatment.

Demographic and baseline characteristics for treatment-experienced patients in SAPPHIRE-II and PEARL-II are provided in Table 16.

Table 16. Demographic and Baseline Characteristics of Treatment-Experienced Patients without

Cirrhosis in SAPPHIRE-II and PEARL-II

Characteristics

SAPPHIRE-II

N=394

PEARL-II

N=179

Age (years)

Median (range) 54 (19 – 71) 57 (26 – 70)

Characteristics

SAPPHIRE-II

N=394

PEARL-II N=179

Gender, n (%)

Male 227 (57.6) 97 (54.2) Female 167 (42.4) 82 (45.8)

Race, n (%)

White 355 (90.1) 165 (92.2) Black or African American 32 (8.1) 7 (3.9) Asian 6 (1.5) 3 (1.7) Other 1 (0.3) 4 (2.3)

Ethnicity, n (%)

Hispanic or Latino 25 (6.3) 3 (1.7) None of the above 369 (93.7) 176 (98.3)

Body mass index, n (%)

< 30 kg/m² 316 (80.2) 140 (78.2) ≥ 30 kg/m² 78 (19.8) 39 (21.8)

HCV genotype, n (%)

1a 230 (58.4) N/A 1b 163 (41.4) 179 (100)

Baseline HCV RNA

Mean ± SD (log₁₀ IU/mL) 6.55 ± 0.52 6.51 ± 0.55 < 800000 IU/mL, n (%) 51 (12.9) 22 (12.3) ≥ 800000 IU/mL, n (%) 343 (87.1) 157 (87.7)

IL28B, n (%)

CC 41 (10.4) 17 (9.5) Non-CC 353 (89.6) 162 (90.5)

Type of response to previous pegIFN/RBV

treatment, n (%)

Null responder 193 (49.0) 63 (35.2)

Nonresponder/partial responder 86 (21,8) 51 (28.5)

Relapser 115 (29.2) 65 (36.3)

Baseline fibrosis stage, n (%)

F0-F1 267 (67.8) 122 (68.2) F2 70 (17.8) 32 (17.9) ≥ F3 57 (14.5) 25 (14.0)

History of depression or bipolar disorder, n (%)

No 313 (79.4) 156 (87.2) Yes 81 (20.6) 23 (12.8)

N/A = Not Applicable

Study Results

Table 17 shows the SVR12 rates for treatment-experienced patients with genotype 1-infection receiving HOLKIRA PAK in combination with ribavirin for 12 weeks in SAPPHIRE-II and PEARL-II and HOLKIRA PAK alone in PEARL-II. All the treatment groups met the primary efficacy endpoint.

Table 17. SVR12 for Genotype 1-Infected Treatment-Experienced Patients without Cirrhosis in

SAPPHIRE-II and PEARL-II

Treatment Outcome

PEARL-II Genotype 1b

HOLKIRA PAK*

N=91

% (n/N)

Overall SVR12

100 (91/91) 95% CI

95.9 to 100

HCV genotype 1a

N/A

Prior pegIFN/RBV null responder

N/A

Prior pegIFN/RBV partial responder

N/A

Prior pegIFN/RBV relapser

N/A

HCV genotype 1b

100 (91/91)

Prior pegIFN/RBV null responder

100 (32/32)

Prior pegIFN/RBV partial responder

100 (26/26)

Prior pegIFN/RBV relapser

100 (33/33)

Outcome for patients without SVR12

On-treatment VF^a 0 0 0 Relapse^b 2 (7/293) 0 0 Other^c 1 (4/297) 2 (2/88) 0

CI = confidence interval, VF = virologic failure, N/A = Not Applicable

* For patients with GT1b infection without cirrhosis, HOLKIRA PAK alone for 12 weeks is the recommended regimen. a. On-treatment VF was defined as confirmed HCV ≥ 25 IU/mL after HCV RNA < 25 IU/mL during treatment, confirmed 1 log₁₀ IU/mL increase in HCV RNA from nadir, or HCV RNA persistently ≥ 25 IU/mL with at least 6 weeks of treatment. b. Relapse was defined as confirmed HCV RNA ≥ 25 IU/mL post-treatment before or during SVR12 window among patients with HCV RNA < 25 IU/mL at last observation during at least 11 weeks of treatment.

c. Other includes patients not achieving SVR12 but not experiencing on-treatment VF or relapse (e.g. missing HCV RNA values in the SVR12 window).

Table 18 presents the SVR12 rates by selected subgroups for genotype 1-infected, treatment-experienced patients in studies SAPPHIRE-II and PEARL-II.

Table 18. SVR12 rates for Selected Subgroups of Genotype 1-infected, Treatment-Experienced

Patients without Cirrhosis in SAPPHIRE-II and PEARL-II

Treatment Outcome

PEARL-II Genotype 1b

HOLKIRA PAK*

N=91

% (n/N)

IL28B

CC

100 (7/7) Non-CC

100 (84/84)

Sex

Female

100 (37/37) Male

100 (54/54)

Age

< 65 years

100 (76/76) ≥ 65 years

100 (15/15)

Race

100 (5/5) Non-black

100 (86/86)

Ethnicity

Hispanic or Latino

100 (1/ 1) None of the above

100 (90/90)

Body mass index

< 30 kg/m²

100 (69/69) ≥ 30 kg/m²

100 (22/22)

Baseline HCV RNA

< 800000 IU/mL

100 (9/9) ≥ 800000 IU/mL

100 (82/82)

Baseline fibrosis stage

F0-F1

100 (59/59) F2

100 (19/19) ≥ F3

100 (13/13)

History of depression or bipolar disorder

No

100 (83/83) Yes

100 (8/8) Treatment Outcome

PEARL-II Genotype 1b

HOLKIRA PAK*

N=91

% (n/N)

* For patients with GT1b infection without cirrhosis, HOLKIRA PAK alone for 12 weeks is the recommended regimen.

These baseline viral (genotype 1 subtype, baseline viral load) and host factors (prior treatment response, sex, race, ethnicity, age, IL28B allele, baseline body mass index, history of depression or bipolar disorder, fibrosis stage) were not associated with lower SVR12 rates across subgroups.

In addition, patients who underwent ribavirin dose modifications did not have lower SVR12 rates.

Clinical Trials in Patients with Cirrhosis

TURQUOISE-II was a randomized, global multicenter, open-label trial conducted exclusively in 380 genotype 1-infected patients with cirrhosis (Child-Pugh A) who were either treatment-naïve or did not achieve SVR with prior treatment with pegIFN/RBV. HOLKIRA PAK in combination with ribavirin was administered for either 12 or 24 weeks of treatment.

TURQUOISE-III is a Phase 3b, open-label, single-arm, multicenter study evaluating the efficacy and safety of HOLKIRA PAK administered for 12 weeks in HCV genotype 1b-infected, treatment-naïve and previous pegIFN/RBV treatment-experienced adults with compensated cirrhosis.

Demographic and baseline characteristics for genotype 1-infected patients with cirrhosis in studies TURQUOISE-II and TURQUOISE-III are provided in Table 19.

Table 19. Demographic and Baseline Characteristics of Patients with Cirrhosis in TURQUOISE-II and TURQUOISE-III

Characteristics

TURQUOISE-II HOLKIRA PAK + RBV

N = 380

TURQUOISE-III HOLKIRA PAK

N = 60

Age (years)

Median (range) 58 (21 – 71) 60.5 (26 – 78)

Gender, n (%)

Male 267 (70.3) 37 (61.7) Female 113 (29.7) 23 (38.3)

Race, n (%)

White 360 (94.7) 52 (86.7) Black or African American 12 (3.2) 7 (11.7) Asian 8 (2.1) 0

Characteristics

TURQUOISE-II HOLKIRA PAK + RBV

N = 380

TURQUOISE-III HOLKIRA PAK

N = 60

Ethnicity

Hispanic or Latino 45 (11.8) 3 (5.0) None of the above 335 (88.2) 57 (95.0)

Body mass index

< 30 kg/m² 272 (71.6) 43 (71.7) ≥ 30 kg/m² 108 (28.4) 17 (28.3)

HCV genotype, n (%)

1a 261 (68.7) 0 1b 119 (31.3) 60 (100)

Baseline HCV RNA 6.57 (0.6)

Mean ± SD (log₁₀ IU/mL) 6.47 ± 0.58 5 (8.3) < 800000 IU/mL, n (%) 53 (13.9) 55 (91.7) ≥ 800000 IU/mL, n (%) 327 (86.1)

Prior HCV Therapy

Treatment-Naive 160 (42.1) 27 (45.0) Treatment-experienced with

pegIFN/RBV, n (%) 220 (57.9) 33 (55.0)

Null responder 137 (36.1) 7 (21.2) Partial responder 31 (8.2) 5 (15.2) Relapser 52 (13.7) 3 (9.1) Other pegIFN/RBV failures N/A 18 (54.5)⁺

IL28B, n (%)

CC 69 (18.2) 10 (16.7) CT 237 (62.4) 36 (60.0) TT 74 (19.5) 14 (23.3)

Baseline platelet count, n (%)

< 90 x10⁹/L 56 (14.7) 13 (21.7) ≥ 90 x10⁹/L 324 (85.3) 47 (78.3)

Baseline albumin, n (%)

< 35 g/L 43 (11.3) 10 (16.7) ≥ 35 g/L 337 (88.7) 50 (83.3)

History of depression or bipolar

disorder, n (%)

No 286 (75.3) 43 (71.7) Yes 94 (24.7) 17 (28.3)

N/A = Not Applicable.

⁺ Other types of pegIFN/RBV failure include less well documented non-response, relapse/breakthrough or other pegIFN failure. Study Results

Table 20 shows the SVR12 rates for genotype 1-infected patients with cirrhosis who were treatment-naïve or previously treated with pegIFN/RBV in studies TURQUOISE-II and TURQUOISE-III. All the treatment groups met the primary efficacy endpoint.

Table 20. SVR12 for Genotype 1-Infected Patients with Cirrhosis who were Treatment-Naïve or

Previously Treated with pegIFN/RBV in TURQUOISE-II and TURQUOISE-III

Treatment Outcome

TURQUOISE-III

HOLKIRA PAK

12 Weeks

% (n/N)

Overall SVR12

100 (60/60) 97.5% CI

N/A 95% CI

94.0 to 100.0

HCV genotype 1a

N/A Treatment naïve

N/A Prior pegIFN/RBV null responders

N/A

Prior pegIFN/RBV partial responders

N/A

Prior pegIFN/RBV prior relapsers

N/A

HCV genotype 1b

100 (60/60) Treatment naïve

100 (27/27) Prior pegIFN/RBV null responders

100 (7/7)

Prior pegIFN/RBV partial responders

100 (5/5)

Prior pegIFN/RBV prior relapsers

100 (3/3) Other pegIFN/RBV failures

100 (18/18)⁺ Treatment Outcome

TURQUOISE-III

HOLKIRA PAK

12 Weeks

% (n/N)

Outcome for patients without SVR12

On-treatment VF^a

0 Relapse^b

0 Other^c

0

CI = confidence interval, VF = virologic failure , N/A = Not Applicable

* 12 weeks of HOLKIRA PAK with RBV is the recommended regimen for all patients with cirrhosis,except those with genotype

1a infection and prior null response to pegIFN/RBV.

**24 weeks of HOLKIRA PAK + ribavirin is recommended for patients with genotype 1a-infection with cirrhosis who have had a previous null response to pegIFN/RBV.

⁺ Other types of pegIFN/RBV failure include less well documented non-response, relapse/breakthrough or other pegIFN failure. a. On-treatment VF was defined as confirmed HCV ≥ 25 IU/mL after HCV RNA < 25 IU/mL during treatment, confirmed

1 log₁₀ IU/mL increase in HCV RNA from nadir, or HCV RNA persistently ≥ 25 IU/mL with at least 6 weeks of treatment. b. Relapse was defined as confirmed HCV RNA ≥ 25 IU/mL post-treatment before or during SVR12 window among patients with HCV RNA < 25 IU/mL at last observation during at least 11 or 22 weeks of treatment, for patients assigned to 12 or 24 weeks of treatment, respectively.

c. Other includes patients not achieving SVR12 but not experiencing on-treatment VF or relapse (e.g. missing HCV RNA values in the SVR12 window).

Based on logistic regression, the difference between treatment arms was not statistically significant (p value = 0.089).

Table 21 presents the SVR12 rates by selected subgroups for genotype 1-infected patients with cirrhosis who were treatment-naïve or previously treated with pegIFN/RBV.

Table 21. SVR12 rates for Selected Subgroups of Genotype 1-infected Patients with Cirrhosis who were Treatment-Naïve or Previously Treated with pegIFN/RBV in TURQUOISE-II and TRUQUOISE-III

Subgroup

TURQUOISE-III

HOLKIRA PAK

12 Weeks N = 60

% (n/N)

IL28B

CC

100 (10/10) Non-CC

100 (50/50)

Sex

Female

100 (23/23) Male

100 (37/37) Subgroup

TURQUOISE-III

HOLKIRA PAK

12 Weeks N = 60

% (n/N)

Age

< 65 years

100 (45/45) ≥ 65 years

100 (15/15)

Race

100 (7/7) Nonblack

100 (53/53)

Ethnicity

Hispanic or Latino

100 (3/3) None of the above

100 (57/57)

Body mass index

< 30 kg/m²

100 (43/43) ≥ 30 kg/m²

100 (17/17)

Baseline HCV RNA

< 800000 IU/mL

100 (5/5) ≥ 800000 IU/mL

100 (55/55)

Baseline platelet count

< 90 x 10⁹/L

100 (13/13) ≥ 90 x 10⁹/L

100 (47/47)

Baseline albumin

< 35 g/L

100 (10/10) ≥ 35 g/L

100 (50/50)

History of depression or bipolar disorder

No

100 (43/43) Yes

100 (17/17)

Patients who underwent ribavirin dose modifications did not have lower SVR12 rates.

Pooled Analyses of Clinical Trials

Durability of Response

Overall, 660 patients in Phase 2 and 3 clinical trials had HCV RNA results for both the SVR12 and SVR24 time points. Among these patients, the positive predictive value of SVR12 on SVR24 was 99.8%.

Pooled Efficacy Analysis

In Phase 3 clinical trials, 1088 patients (including 194 with cirrhosis) received the recommended regimen for their HCV subtype, cirrhosis status and previous treatment. Table 22 shows SVR rates for these patients. Among patients who received the recommended regimen in Phase 3 clinical trials, 97% achieved SVR (95% with cirrhosis and 97% without cirrhosis), while 0.6% demonstrated virologic breakthrough and 1.5% experienced post-treatment relapse.

Table 22. SVR12 Rates for Recommended Treatment Regimens

Genotype 1b

With Cirrhosis HOLKIRA PAK

12 weeks

Treatment-naïve

100% (27/27) Treatment-experienced

100% (33/33)⁺ Prior

pegIFN/RBV relapser

100% (3/3)

Prior pegIFN/RBV partial responder

100% (5/5)

Prior pegIFN/RBV null responder

100% (7/7)

Other pegIFN/RBV failures

100 % (18/18)⁺ TOTAL

100% (60/60)

* All patients received 12 weeks of therapy except for genotype 1a infected prior null responders with cirrhosis who received

24 weeks of therapy.

⁺ Other types of pegIFN/RBV failure include less well documented non-response, relapse/breakthrough or other pegIFN failure.

Impact of Ribavirin Dose Adjustment on Probability of SVR

In Phase 3 clinical trials, 91.5% of patients did not require ribavirin dose adjustments during therapy. In the 8.5% of patients who had ribavirin dose adjustments during therapy, the SVR rate (98.5%) was comparable to patients who maintained their starting ribavirin dose throughout treatment.

Clinical Trial in Patients with HCV Genotype 1 Infection-HIV-1 Co-infection (TURQUOISE-I)

In an open-label clinical trial (TURQOISE-I) the safety and efficacy of 12 or 24 weeks of treatment with HOLKIRA PAK and ribavirin was evaluated in 63 patients with genotype 1 chronic hepatitis C co-infected with HIV-1. See DOSAGE AND ADMINISTRATION for dosing recommendations in HCV-HIV-1 co-infected patients. Patients were on a stable HIV-1 antiretroviral therapy (ART) regimen that included ritonavir-boosted atazanavir or raltegravir, co-administered with a backbone of tenofovir plus emtricitabine or lamivudine.

Treated patients (N = 63) had a median age of 51 years (range: 31 to 69); 24% of patients were Black; 81% of patients had IL28B non-CC genotype; 19% of patients had compensated cirrhosis; 67% of patients were HCV treatment-naïve; 33% of patients had failed prior treatment with pegIFN/RBV; 89% of patients had HCV genotype 1a infection.

Study Results

Table 23 shows the SVR12 rates for patients with HCV genotype 1 infection and HIV-1 co-infection in TURQUOISE-I.

Table 23. SVR12 for HIV-1 Co-infected Patients in TURQUOISE-I

Arm A

12 Weeks N = 31

Arm B 24 Weeks N = 32

SVR12, n/N (%)

95% CI

29/31 (93.5) 79.3, 98.2

29/32 (90.6) 75.8, 96.8

Outcome of patients not achieving SVR12

On-treatment virologic failure^a 0 1 Post-treatment relapse^b 1 2^c Other^d 1 0 a. On-treatment virologic failure was defined as confirmed HCV RNA ≥ 25 IU/mL after HCV RNA < 25 IU/mL during treatment, confirmed 1 log₁₀ IU/mL increase in HCV RNA from nadir, or HCV RNA persistently ≥ 25 IU/mL with at least 6 weeks treatment.

b. Relapse was defined as confirmed HCV RNA ≥ 25 IU/mL post-treatment before or during SVR12 window among patients with HCV RNA < 25 IU/mL at last observation during at least 11 weeks of treatment.

c. These virologic failures appear to have resulted from reinfection based on phylogenetic analyses of baseline and virologic failure samples.

d. Other includes patients not achieving SVR12 but not experiencing on-treatment virologic failure or relapse (e.g., missing

HCV RNA values in the SVR12 window).

In TURQUOISE-I, the SVR12 rates in HCV/HIV-1 co-infected patients were consistent with SVR12 rates in the Phase 3 trials of HCV mono-infected patients. Fifty-one of 56 (91.1%) patients with genotype 1a infection and 7 of 7 (100%) patients with genotype 1b infection achieved SVR12. Five of 6 (83.3%) patients with compensated cirrhosis in each arm achieved SVR12.

Clinical Trial in Liver Transplant Recipients (CORAL-I)

The safety and efficacy of HOLKIRA PAK with ribavirin was studied in 34 HCV genotype 1-infected liver transplant recipients who were at least 12 months post transplantation at enrollment. The primary objectives of this study were to assess the safety and the percentage of patients achieving SVR12 following 24 weeks of treatment with HOLKIRA PAK and ribavirin. The initial dose of ribavirin was left to the discretion of the investigator with 600 to 800 mg per day being the most frequently selected dose range at initiation of HOLKIRA PAK and at the end of treatment.

Study Results

Thirty-four patients (29 with HCV genotype 1a infection and 5 with HCV genotype 1b infection) who had not received treatment for HCV infection after transplantation and had a METAVIR fibrosis score of F2 or less were enrolled. Thirty-three out of the 34 patients (97.1%) achieved SVR12 (96.6% in patients with genotype 1a infection and 100% in patients with genotype 1b infection). One patient with HCV genotype 1a infection relapsed post-treatment.

MICROBIOLOGY

Mechanism of Action

HOLKIRA PAK combines three direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.

Ombitasvir

Ombitasvir is an inhibitor of HCV NS5A which is essential for viral replication. In replicon cell culture assays, ombitasvir has half maximal effective concentration (EC₅₀) values of 14.1 and 5.0 pM against HCV genotypes 1a and 1b, respectively.

Paritaprevir

Paritaprevir is an inhibitor of HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, paritaprevir inhibited the proteolytic activity of the recombinant HCV genotype 1a and 1b NS3/4A protease enzymes with half maximal inhibitory concentration (IC₅₀) values of 0.18 and 0.43 nM, respectively.

Dasabuvir

Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome. In a biochemical assay, dasabuvir inhibited the polymerase activity of the recombinant HCV genotype 1a and 1b HCV NS5B enzymes with IC₅₀ values of 2.8 and 10.7 nM, respectively.

Activity in Cell Culture and/or Biochemical Studies

Ombitasvir

The EC₅₀ of ombitasvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays was 14.1 and 5 pM, respectively. The activity of ombitasvir was attenuated 11- to 13-fold in the presence of 40% human plasma. The mean EC₅₀ of ombitasvir against replicons containing NS5A from a panel of treatment-naïve genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.66 pM (range 0.35 to 0.88 pM; n = 11) and 1.0 pM (range 0.74 to 1.5 pM; n = 11), respectively. Ombitasvir has EC₅₀ values of 12, 4.3, 19, 1.7, 0.38, 3.2, and 366 pM against replicon cell lines constructed with NS5A from single isolates representing genotypes 2a, 2b, 3a, 4a, 4d, 5a, and 6a, respectively.

Paritaprevir

The EC₅₀ of paritaprevir against genotype 1a-H77 and 1b-Con1 strains in the HCV replicon cell culture assay was 1.0 and 0.21 nM, respectively. The activity of paritaprevir was attenuated 24- to 27-fold in the presence of 40% human plasma. The mean EC₅₀ of paritaprevir against replicons containing NS3 from a panel of treatment-naïve genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.86 nM (range 0.43 to 1.87 nM; n = 11) and 0.06 nM (range 0.03 to 0.09 nM; n = 9), respectively. Paritaprevir had an EC₅₀ value of 5.3 nM against the 2a-JFH-1 replicon cell line, and EC₅₀ values of 19, 0.09, 0.015, and 0.68 nM against replicon cell lines containing NS3 from a single isolate each of genotype 3a, 4a, 4d, and 6a, respectively. In a biochemical assay, paritaprevir inhibited the activity of NS3/4A enzymes from single isolates of genotypes 2a, 2b, 3a, and 4a with IC₅₀ values of 2.4, 6.3, 14.5, and 0.16 nM, respectively. .

Dasabuvir

The EC₅₀ of dasabuvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays was 7.7 and 1.8 nM, respectively. The replicon activity of dasabuvir was attenuated 12- to 13-fold in the presence of 40% human plasma. The mean EC₅₀ of dasabuvir against replicons containing NS5B from a panel of treatment-naïve genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.77 nM (range 0.4 to 2.1 nM; n = 11) and 0.46 nM (range 0.2 to 2 nM; n = 10), respectively. In biochemical assays, dasabuvir inhibited a panel of genotype 1a and 1b polymerases with a mean IC₅₀ value of 4.2 nM (range 2.2 to 10.7 nM; n = 7).

Ritonavir

Ritonavir did not exhibit a direct antiviral effect on the replication of HCV subgenomic replicons, and the presence of ritonavir did not affect the in vitro antiviral activity of paritaprevir.

Combination Activity in vitro

All two-drug combinations of paritaprevir, ombitasvir, dasabuvir and ribavirin demonstrated additive to synergistic inhibition of HCV genotype 1 replicon at the majority of drug concentrations studied in short term cell culture assays. In long term replicon survival assays, the ability of drug-resistant cells to form colonies in the presence of a single drug or drugs in combination was evaluated. In pair-wise combinations of paritaprevir, ombitasvir, and dasabuvir at concentrations 10-fold over their respective EC₅₀, colony numbers were reduced by more than 100-fold by two drugs as compared to each drug alone. When all three drugs were combined at concentrations of 5-fold above their respective EC₅₀, no drug-resistant colonies survived.

Resistance in Cell Culture

Resistance to paritaprevir, ombitasvir, or dasabuvir conferred by variants in NS3, NS5A, or NS5B, respectively, selected in cell culture or identified in Phase 2b and 3 clinical trials were phenotypically characterized in the appropriate genotype 1a or 1b replicons.

In genotype 1a, substitutions F43L, R155K, A156T, and D168A/H/V/Y in HCV NS3 reduced susceptibility to paritaprevir. In the genotype 1a replicon, the activity of paritaprevir was reduced 20-, 37-, and 17-fold by the F43L, R155K and A156T substitutions, respectively. The activity of paritaprevir was reduced 96-fold by D168V, and 50- to 219-fold by each of the other D168 substitutions. The activity of paritaprevir in genotype 1a was not significantly affected (less than or equal to 3-fold) by single substitutions V36A/M, V55I, Y56H, Q80K or E357K. Double variants including combinations of V36M, Y56H, or E357K with R155K or with a D168 substitution reduced the activity of paritaprevir by an additional 2- to 3-fold relative to the single R155K or D168 substitution. In genotype 1b, substitutions R155Q, D168H, D168V, and Y56H in combination with D168V in HCV NS3 reduced susceptibility to paritaprevir. In the genotype 1b replicon, the activity of paritaprevir was reduced 76- and 159-fold by D168H and D168V, respectively. Y56H alone could not be evaluated due to poor replication capacity, however, the combination of Y56H and D168V reduced the activity of paritaprevir by 2472-fold.

In genotype 1a, substitutions M28T/V, Q30R, H58D, Y93C/H/N, and M28V + Q30R in HCV NS5A reduced susceptibility to ombitasvir. In the genotype 1a replicon, the activity of ombitasvir was reduced by 58- and 243-fold against the M28V and H58D substitutions, respectively, and 800- and 1675-fold by the Q30R and Y93C substitutions, respectively. Y93H, Y93N or M28V in combination with Q30R reduced the activity of ombitasvir by more than 40,000-fold. In genotype 1b, substitutions L31F/V, as well as Y93H alone or in combination with L28M, R30Q, L31F/M/V or P58S in HCV NS5A reduced susceptibility to ombitasvir. In the genotype 1b replicon, the activity of ombitasvir was reduced by less than 10-fold by variants at amino acid positions 30 and 31. The activity of ombitasvir was reduced by 77-, 284- and 142-fold against the genotype 1b substitutions Y93H, R30Q in combination with Y93H, and L31M in combination with Y93H, respectively. All other double substitutions of Y93H in combination with substitutions at positions 28, 31, or 58 reduced the activity of ombitasvir by more than 400-fold.

In genotype 1a, substitutions C316Y, M414T, Y448H, A553T, G554S, S556G/R, and Y561H in HCV NS5B reduced susceptibility to dasabuvir. In the genotype 1a replicon, the activity of dasabuvir was reduced 21- to 32-fold by the M414T, S556G or Y561H substitutions; 152- to 261-fold by the A553T, G554S or S556R substitutions; and 1472- and 975-fold by the C316Y and Y448H substitutions, respectively. G558R and D559G/N were observed as treatment-emergent substitutions but the activity of dasabuvir against these variants could not be evaluated due to poor replication capacity. In genotype 1b, substitutions C316N, C316Y, M414T, Y448H, and S556G in HCV NS5B reduced susceptibility to dasabuvir. The activity of dasabuvir was reduced by 5- and 11-fold by C316N and S556G, respectively; 46-fold by M414T or Y448H; and 1569-fold by the C316Y substitutions in the genotype 1b replicon. Dasabuvir retained full activity against replicons containing substitutions S282T in the nucleoside binding site, M423T in the lower thumb site, and P495A/S, P496S or V499A in the upper thumb site.

Effect of Baseline HCV Substitutions/Polymorphisms on Treatment Response

A pooled analysis of patients in the Phase 2b and 3 clinical trials treated with paritaprevir, ombitasvir, and dasabuvir with or without ribavirin was conducted to explore the association between the baseline NS3/4A, NS5A or NS5B substitutions/polymorphisms and treatment outcome in recommended regimens.

In the greater than 500 genotype 1a baseline samples in this analysis, the most frequently observed resistance-associated variants were M28V (7.4%) in NS5A and S556G (2.9%) in NS5B. Q80K, although a highly prevalent polymorphism in NS3 (41.2% of samples), confers minimal resistance to paritaprevir. Resistance-associated variants at amino acid positions R155 and D168 in NS3 were rarely observed (less than 1%) at baseline. In the greater than 200 genotype 1b baseline samples in this analysis, the most frequently observed resistance-associated variants observed were Y93H (7.5%) in NS5A, and C316N (17.0%) and S556G (15%) in NS5B. Given the low virologic failure rates observed with recommended treatment regimens for HCV genotype 1a- and 1b-infected patients, the presence of baseline variants appears to have little impact on the likelihood of achieving SVR.

Resistance in Clinical Studies

Of the 2,510 HCV genotype 1 infected patients in the Phase 2b and 3 clinical trials treated with regimens containing paritaprevir, ombitasvir, and dasabuvir with or without ribavirin (for 8, 12, or 24 weeks), a total of 74 patients (3%) experienced virologic failure (primarily post-treatment relapse). Treatment-emergent variants and their prevalence in these virologic failure populations are shown in Table 24. In the 67 genotype 1a infected patients, NS3 variants were observed in 50 patients, NS5A variants were observed in 46 patients, NS5B variants were observed in 37 patients, and treatment-emergent variants were seen in all 3 drug targets in 30 patients. In the 7 genotype 1b infected patients, treatment-emergent variants were observed in NS3 in 4 patients, in NS5A in 2 patients, and in both NS3 and NS5A in 1 patient. No genotype 1b infected patients had treatment-emergent variants in all 3 drug targets.

Table 24. Treatment-Emergent Amino Acid Substitutions in the Pooled Analysis of HOLKIRA PAK with and without Ribavirin Regimens in Phase 2b and Phase 3 Clinical Trials (N = 2510)

Target

Genotype 1b

N = 7

% (n)

NS3

-

42.9 (3)^d

-

-

-

42.9 (3)^d

-

• NS5A

-

-

-

28.6 (2)

• NS5B

-

-

• a. Observed in at least 2 patients of the same subtype.

b. N = 66 for the NS5B target.

c. Substitutions were observed in combination with other emergent substitutions at NS3 position R155 or D168. d. Observed in combination in genotype 1b-infected patients.

e. Observed in combination in 6% (4/67) of the patients.

Note: The following variants were selected in cell culture but were not treatment-emergent: NS3 variants A156T in genotype 1a, and R155Q and D168H in genotype 1b; NS5A variants Y93C/H in genotype 1a, and L31F/V or Y93H in combination with L28M, L31F/V or P58S in genotype 1b; and NS5B variants Y448H in genotype 1a, and M414T and Y448H in genotype 1b.

Persistence of Resistance-Associated Substitutions

The persistence of paritaprevir, ombitasvir, and dasabuvir resistance-associated amino acid substitutions in NS3, NS5A, and NS5B, respectively, was assessed in genotype 1a-infected patients in Phase 2b trials. Paritaprevir treatment-emergent variants V36A/M, R155K or D168V were observed in NS3 in 47 patients. Ombitasvir treatment-emergent variants M28T, M28V or Q30R in NS5A were observed in 32 patients. Dasabuvir treatment-emergent variants M414T, G554S, S556G, G558R or D559G/N in NS5B were observed in 34 patients.

NS3 variants V36A/M and R155K and NS5B variants M414T and S556G remained detectable at post-treatment Week 48, whereas NS3 variant D168V and all other NS5B variants were not observed at post-treatment Week 48. All treatment-emergent variants in NS5A remained detectable at post-treatment Week 48. Due to high SVR rates in genotype 1b, trends in persistence of treatment-emergent variants in this genotype could not be established.

The lack of detection of virus containing a resistance-associated substitution does not indicate that the resistant virus is no longer present at clinically significant levels. The long-term clinical impact of the emergence or persistence of virus containing HOLKIRA PAK-resistance-associated substitutions is unknown.

Cross-resistance

Cross-resistance is expected among NS5A inhibitors, NS3/4A protease inhibitors, and non-nucleoside NS5B inhibitors by class. The impact of prior ombitasvir, paritaprevir or dasabuvir treatment experience on the efficacy of other NS5A inhibitors, NS3/4A protease inhibitors, or NS5B inhibitors has not been studied.

NON-CLINICAL TOXICOLOGY

General Toxicity

Paritaprevir/ritonavir

Paritaprevir/ritonavir was well tolerated in repeated-dose oral toxicity studies in mice (up to 6-months duration), rats (up to 3-months) and dogs (up to 9-months). The safety margins for studies in the rat, mouse and dog were 15-, 60-, and 210-fold the exposure in human at the recommended dose.

Paritaprevir/ritonavir associated adverse effects were limited to the gallbladder in mice and dogs. In a 6 month mouse study, the adverse findings included focal erosion/ulceration, inflammation (both acute and chronic active), and epithelial hypertrophy/hyperplasia at paritaprevir exposures of 30-fold the exposure in humans at the recommended dose. Gallbladder findings in the dog were limited to minimal epithelial degeneration/necrosis. No evidence of disruption of the epithelial integrity was noted, despite achieving exposures of up to 210-fold the exposure in humans at the recommended dose. The severity and character of the gallbladder change in the dog did not progress from the 1-month to the 9 month toxicology study, despite achieving higher exposures in the 9-month study as compared to the 1-month study.

Ombitasvir

Ombitasvir was well tolerated without adverse effects in repeated-dose oral toxicity studies in mice (up to 6-months duration), rats (up to 3-months) and dogs (up to 6-months). Maximum achieved ombitasvir plasma exposures in the longest duration studies were at least 20-fold or higher as compared to human exposure at the recommended dose.

Both inactive, major, disproportionate human metabolites of ombitasvir (M29, M36) did not cause adverse effects in 1 month repeated-dose studies at AUC exposures that were ≥ 25-fold relative to anticipated human exposures.

Dasabuvir

Dasabuvir was well tolerated in repeated-dose oral toxicity studies in mice (up to 3-months duration), rats (up to 6-months), dogs (up to 9-months) and monkeys (up to 1-month). The safety margins were approximately 30-fold for the rodent (mouse and rat), 120-fold for the dog, and 15-fold for the monkey as compared to human exposure at the recommended dose.

Mutagenicity and Carcinogenicity

Ombitasvir

Ombitasvir and its major inactive human metabolites (M29, M36) were not genotoxic in bacterial mutagenicity, human lymphocyte chromosome aberration and in vivo mouse micronucleus assays.

Ombitasvir was not carcinogenic in a 6-month transgenic mouse study and a 2-year rat study up to AUC exposures approximately 26- and 16-fold the exposure in humans at the recommended dose.

Paritaprevir/ritonavir

Paritaprevir was positive for genotoxicity in an in vitro human chromosome aberration test but negative in a bacterial mutation assay, and in two in vivo genetic toxicology assays (rat bone marrow micronucleus and rat liver Comet tests).

Ritonavir was not genotoxic in bacterial mutation assay, mouse lymphoma assay, chromosomal aberration assay and in vivo mouse micronucleus test.

Paritaprevir/ritonavir was not carcinogenic in a 6-month transgenic mouse study up to AUC exposures approximately 38- and 4-fold the exposure in humans at the recommended dose. Similarly, paritaprevir/ritonavir was not carcinogenic in a 2-year rat study up to AUC exposures approximately 8- and 4-fold the exposure in humans at the recommended dose.

Dasabuvir

Dasabuvir was not genotoxic in bacterial mutagenicity, human lymphocyte chromosome aberration and in vivo rat micronucleus assays.

Dasabuvir was not carcinogenic in a 6-month transgenic mouse study and a 2-year rat study up to AUC exposures approximately 19-fold the exposure in humans at the recommended dose.

Use with Ribavirin

Ribavirin was shown to be genotoxic in several in vitro and in vivo assays. Ribavirin was not carcinogenic in a 6-month p53+/- transgenic mouse study or a 2-year rat study. See the Product Monograph for ribavirin for additional information.

Fertility

Ombitasvir

Ombitasvir had no effects on fertility when evaluated in mice up to AUC exposures approximately 25-fold the exposure in humans at the recommended clinical dose.

Paritaprevir/ritonavir

Paritaprevir/ritonavir had no effects on fertility when evaluated in rats up to AUC exposures approximately 8- and 2-fold higher than the exposure in humans at the recommended clinical dose.

Dasabuvir

Dasabuvir had no effects on fertility when evaluated in rats up to AUC exposures approximately 16-fold the exposure in humans at the recommended clinical dose.

Use with Ribavirin

In fertility studies in male animals, ribavirin induced reversible testicular toxicity. Refer to Product Monograph for ribavirin for additional information.

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