FDA Hepatitis Update -

"U.S. Food & Drug Administration (FDA)" <fda@xxxxxxxxxxxxxxxxxxxxxxx> · Fri, 19 Dec 2014 15:14:52 -0600

Title:     FDA Hepatitis Update -

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  On December  19, 2014, FDA approved VIEKIRA Pak (ombitasvir, paritaprevir, ritonavir fixed  dose combination tablets copackaged with dasabuvir tablets) for use with or  without ribavirin for the treatment of patients with genotype 1 chronic  hepatitis C virus (HCV) infection including those with compensated cirrhosis. (Also see FDA Press Release)
VIEKIRA PAK includes ombitasvir, a hepatitis C virus NS5A  inhibitor, paritaprevir, a hepatitis C virus NS3/4A protease inhibitor,  ritonavir, a CYP3A inhibitor and dasabuvir, a hepatitis C virus non-nucleoside  NS5B palm polymerase inhibitor.
VIEKIRA PAK  is not recommended for use in patients with decompensated liver disease.
VIEKIRA PAK’s  efficacy was evaluated in six clinical trials enrolling 2,308 participants with  chronic HCV infection with and without cirrhosis.
DOSAGE AND ADMINISTRATION
 Recommended Dosage in Adults 
 VIEKIRA PAK is ombitasvir, paritaprevir, ritonavir  fixed dose combination tablets copackaged with dasabuvir tablets.
 The recommended oral dosage of  VIEKIRA PAK is two ombitasvir, paritaprevir, ritonavir tablets once daily (in  the morning) and one dasabuvir tablet twice daily (morning and evening). Take  VIEKIRA PAK with a meal without regard to fat or calorie content  
 VIEKIRA  PAK is used in combination with ribavirin (RBV) in certain patient populations  (see Table 1).   When administered with VIEKIRA PAK, the recommended dosage of RBV is based on weight: 1000 mg for subjects ≤75 kg and 1200  mg/day for those >75 kg, divided and administered twice-daily  with food. For ribavirin dosage modifications, refer to the ribavirin  prescribing information. 
 For  patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table  1. Refer to Drug Interactions (7) for  dosage recommendations for concomitant HIV-1 antiviral drugs.
Monitor  liver chemistry tests before initiating and during therapy
Table 1 shows the recommended VIEKIRA PAK treatment  regimen and duration based on patient population.
Table  1. Treatment Regimen and Duration by Patient Population (Treatment-Naïve or  Interferon-Experienced)

 Patient    Population  
Treatment*

Duration

Genotype 1a,
 without cirrhosis

VIEKIRA    PAK + ribavirin

12 weeks

Genotype 1a,
 with cirrhosis

VIEKIRA    PAK + ribavirin

24 weeks**

Genotype 1b, 
 without cirrhosis

VIEKIRA    PAK

12 weeks

Genotype 1b, 
 with cirrhosis

VIEKIRA    PAK + ribavirin

12 weeks

*Note: Follow the genotype 1a    dosing recommendations in patients with an unknown genotype 1 subtype or with    mixed genotype 1 infection.
**VIEKIRA PAK administered with    ribavirin for 12 weeks may be considered for some patients based on prior    treatment history [see Clinical Studies    (14.3)].

2.2 Use in Liver Transplant  Recipients 
 In  liver transplant recipients with normal hepatic function and mild fibrosis  (Metavir fibrosis score 2 or lower), the recommended duration of VIEKIRA PAK  with ribavirin is 24 weeks, irrespective of HCV genotype 1 subtype. When VIEKIRA  PAK is administered with calcineurin inhibitors in liver transplant recipients,  dosage adjustment of calcineurin inhibitors is needed. 
 2.3 Hepatic Impairment    No dosage adjustment of VIEKIRA PAK  is required in patients with mild hepatic impairment (Child-Pugh A). VIEKIRA  PAK is not recommended in patients with moderate hepatic impairment (Child-Pugh  B). VIEKIRA PAK is contraindicated in patients with severe hepatic impairment  (Child-Pugh C).

CONTRAINDICATIONS

If VIEKIRA PAK is administered with  ribavirin, the contraindications to ribavirin also apply to this combination  regimen. Refer to the ribavirin prescribing information for a list of  contraindications for ribavirin.
VIEKIRA PAK is contraindicated in  patients with severe hepatic impairment due to risk of potential toxicity.  VIEKIRA PAK is contraindicated with: 

Drugs  that are highly dependent on CYP3A for clearance and for which elevated plasma  concentrations are associated with serious and/or life-threatening events.
Drugs  that are strong inducers of CYP3A and CYP2C8 and may lead to reduced efficacy  of VIEKIRA PAK.Drugs that are strong inhibitors of  CYP2C8 and may increase dasabuvir plasma concentrations and the risk of QT  prolongation.

Table 2 lists drugs that are  contraindicated with VIEKIRA PAK.
Table 2. Drugs that are Contraindicated with VIEKIRA PAK

 Drug Class  
Drug(s) within Class that are Contraindicated

Clinical Comments

Alpha1-adrenoreceptor antagonist

Alfuzosin HCL

Potential for hypotension.

Anticonvulsants

Carbamazepine, phenytoin, phenobarbital

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

Antihyperlipidemic agent

Gemfibrozil

Increase in dasabuvir exposures by 10-fold which may increase the    risk of QT prolongation.

Antimycobacterial

Rifampin

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

Ergot derivatives

Ergotamine, dihydroergotamine,
 ergonovine, methylergonovine

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

Ethinyl estradiol-containing products

Ethinyl    estradiol-containing medications such as combined oral contraceptives

Potential    for ALT elevations

Herbal Product

St. John’s Wort (Hypericum perforatum)

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

HMG-CoA Reductase Inhibitors

Lovastatin, simvastatin

Potential for myopathy including rhabdomyolysis.

Neuroleptics

Pimozide

Potential for cardiac arrhythmias.

Non-nucleoside reverse transcriptase    inhibitor

Efavirenz

Co-administration of efavirenz based regimens with paritaprevir,    ritonavir plus dasabuvir was poorly tolerated and resulted in liver enzyme    elevations.

Phosphodiesterase-5 (PDE5) inhibitor

Sildenafil when dosed as REVATIO for the treatment of pulmonary    arterial hypertension (PAH)

There is increased potential for sildenafil-associated adverse    events such as visual disturbances, hypotension, priapism, and syncope.

Sedatives/hypnotics

Triazolam
Orally administered midazolam

Triazolam and orally administered    midazolam are extensively metabolized by CYP3A4. Coadministration of    triazolam or orally administered midazolam with VIEKIRA PAK may cause large    increases in the concentration of these benzodiazepines. The potential exists    for serious and/or life threatening events such as prolonged or increased    sedation or respiratory depression.

VIEKIRA PAK is contraindicated in  patients with known hypersensitivity (e.g. toxic epidermal necrolysis (TEN) or  Stevens-Johnson syndrome) to ritonavir.
WARNINGS AND  PRECAUTIONS                                                                                                 
 Increased Risk of ALT Elevations
 During  clinical trials with VIEKIRA PAK with or without ribavirin, elevations of ALT to greater than 5 times the upper limit of  normal (ULN) occurred in approximately 1% of all.  ALT elevations were typically asymptomatic,  occurred during the first 4 weeks of treatment, and declined within two to  eight weeks of onset with continued dosing of VIEKIRA PAK with or without  ribavirin.
 These  ALT elevations were significantly more frequent in female subjects who were using  ethinyl estradiol-containing medications such as combined oral contraceptives,  contraceptive patches or contraceptive vaginal rings. Ethinyl  estradiol-containing medications must be discontinued prior to starting therapy  with VIEKIRA PAK. Alternative methods of contraception (e.g, progestin  only contraception or non-hormonal methods) are recommended during VIEKIRA PAK  therapy.  Ethinyl estradiol-containing  medications can be restarted approximately 2 weeks following completion of  treatment with VIEKIRA PAK.
 Women  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; however, due to the limited  number  of subjects taking these other  estrogens, caution is warranted for co-administration with VIEKIRA PAK. 
 Hepatic laboratory testing should be performed during  the first 4 weeks of starting treatment  and as clinically indicated thereafter. If ALT is found to be elevated  above baseline levels, it should be repeated and monitored closely:

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, jaundice or discolored feces. 
Consider       discontinuing VIEKIRA PAK if ALT levels remain persistently greater than 10 times the ULN. 
Discontinue VIEKIRA PAK if ALT elevation is       accompanied by signs or symptoms of liver inflammation or increasing       conjugated bilirubin, alkaline phosphatase, or INR.  

 Risks Associated With Ribavirin Combination Treatment 
 If  VIEKIRA PAK is administered with ribavirin, the warnings and precautions for  ribavirin, in particular the pregnancy avoidance warning, apply to this  combination regimen. Refer to the ribavirin prescribing information for a full  list of the warnings and precautions for ribavirin.
Risk of Adverse Reactions or Reduced  Therapeutic Effect Due to Drug Interactions
 The concomitant  use of VIEKIRA PAK and certain other drugs may result in known or potentially  significant drug interactions, some of which may lead to:

Loss of therapeutic effect of       VIEKIRA PAK and possible development of resistance
Possible clinically significant       adverse reactions from greater exposures of concomitant drugs or       components of VIEKIRA PAK

See Table 5 for steps to prevent or manage these possible  and known significant drug interactions, including dosing recommendations.  Consider the potential for drug interactions prior to and during VIEKIRA PAK  therapy; review concomitant medications during VIEKIRA PAK therapy; and monitor  for the adverse reactions associated with the concomitant drugs. 
Risk of HIV-1 Protease Inhibitor  Drug Resistance in HCV/HIV-1 Co-infected Patients
The ritonavir component of VIEKIRA 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 VIEKIRA PAK should also be on a  suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease  inhibitor drug resistance.

 ADVERSE  REACTIONS                                                                                                                  
 If VIEKIRA PAK is administered with ribavirin  (RBV), refer to the prescribing information for ribavirin for a list of  ribavirin-associated adverse reactions.
 The following adverse reaction is described below and elsewhere in the  labeling:

Increased Risk of ALT Elevations 

Clinical Trials Experience 
 Because clinical trials are  conducted under widely varying conditions, adverse reaction rates observed in  clinical trials of VIEKIRA PAK cannot be directly compared to rates in the  clinical trials of another drug and may not reflect the rates observed in  practice.
The  safety assessment was based on data from six Phase 3 clinical trials in more  than 2,000 subjects who received VIEKIRA PAK with or without ribavirin for 12  or 24 weeks.

 VIEKIRA  PAK with Ribavirin in Placebo-Controlled Trials                         
 The  safety of VIEKIRA PAK in combination with ribavirin was assessed in 770  subjects with chronic HCV infection in two placebo-controlled trials  (SAPPHIRE-I and -II). Adverse reactions that occurred more often in subjects  treated with VIEKIRA PAK in combination with ribavirin compared to placebo were  fatigue, nausea, pruritus, other skin reactions, insomnia, and asthenia (see  Table 3). The majority of the adverse reactions were mild in severity. Two  percent of subjects experienced a serious adverse event (SAE). The proportion  of subjects who permanently discontinued treatment due to adverse reactions was  less than 1%.

 Table  3. Adverse Reactions with ≥5% Greater Frequency Reported in Subjects with  Chronic HCV GT1 Infection Treated with VIEKIRA PAK in Combination with  Ribavirin Compared to Placebo for 12 Weeks

SAPPHIRE-I     and -II

VIEKIRA     PAK + RBV 
 12 Weeks
 N = 770 
 %

Placebo 
 12 Weeks
 N = 255 
 %

Fatigue

34

26

Nausea

22

15

Pruritus*

18

7

Skin reactions**

16

9

Insomnia

14

8

Asthenia

14

7

*Grouped term ‘pruritus’ included the    preferred terms pruritus and pruritus generalized.
 **Grouped terms:    rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash    papular, skin exfoliation, rash pruritic, rash erythematous,  rash generalized, dermatitis allergic,    dermatitis contact, exfoliative rash,     dermatitis, photosensitivity reaction, psoriasis, skin reaction, ulcer,  urticaria.

VIEKIRA  PAK with and without Ribavirin in Regimen-Controlled Trials 
 VIEKIRA  PAK with and without ribavirin was assessed in 401 and 509 subjects with  chronic HCV infection, respectively, in three clinical trials (PEARL-II,  PEARL-III and PEARL-IV). Pruritus, nausea, insomnia, and asthenia were  identified as adverse events occurring more often in subjects treated with  VIEKIRA PAK in combination with ribavirin (see Table 4). The majority of  adverse events were mild to moderate in severity. The proportion of subjects  who permanently discontinued treatment due to adverse events was less than 1%  for both VIEKIRA PAK in combination with ribavirin and VIEKIRA PAK alone.
Table 4. Adverse Events with ≥5% Greater Frequency Reported  in Subjects with Chronic HCV GT1 Infection Treated with VIEKIRA PAK in  Combination with Ribavirin Compared to VIEKIRA PAK for 12 Weeks

PEARL-II,     -III and -IV

VIEKIRA     PAK + RBV
 12 Weeks 
 N = 401 
 %

VIEKIRA     PAK
 12 Weeks 
 N = 509 
 %

Nausea

16

8

Pruritus*

13

7

Insomnia

12

5

Asthenia

9

4

*Grouped term ‘pruritus’ included the    preferred terms pruritus and pruritus generalized.

VIEKIRA  PAK with Ribavirin in Subjects with Compensated Cirrhosis 
 VIEKIRA  PAK with ribavirin was assessed in 380 subjects with compensated cirrhosis who  were treated for 12 (n=208) or 24 (n=172) weeks duration (TURQUOISE-II).The type and severity of adverse events  in subjects with compensated cirrhosis was comparable to non-cirrhotic subjects  in other phase 3 trials. Fatigue, skin reactions and dyspnea occurred at least  5% more often in subjects treated for 24 weeks. The majority of adverse events  occurred during the first 12 weeks of dosing in both treatment arms. Most of  the adverse events were mild to moderate in severity. The proportion of  subjects treated with VIEKIRA PAK for 12 and 24 weeks with SAEs was 6% and 5%,  respectively and 2% of subjects permanently discontinued treatment due to  adverse events in each treatment arm.

Skin Reactions

In  PEARL-II, -III and -IV, 7% of subjects receiving VIEKIRA PAK alone and 10% of  subjects receiving VIEKIRA PAK with ribavirin reported rash-related  events.  In SAPPHIRE-I and -II 16% of  subjects receiving VIEKIRA PAK with ribavirin and 9% of subjects receiving placebo  reported skin reactions.  In TURQUOISE-II,  18% and 24% of subjects receiving VIEKIRA PAK with ribavirin for 12 or 24 weeks  reported skin reactions. The majority of events were graded as mild in  severity. There were no serious events or severe cutaneous reactions, such as  Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), erythema  multiforme (EM) or drug rash with eosinophilia and systemic symptoms (DRESS). 
Laboratory  Abnormalities                                      
 Serum ALT Elevations                                                                                                                  
 Approximately  1% of subjects treated with VIEKIRA PAK experienced post-baseline serum ALT  levels greater than 5 times the upper limit of normal (ULN) after starting  treatment.  The incidence increased to  25% (4/16) among women taking a concomitant ethinyl estradiol containing  medication. The incidence of clinically relevant ALT elevations among women  using estrogens other than ethinyl estradiol, such as estradiol and conjugated  estrogens used in hormone replacement therapy was 3% (2/59).
ALT  elevations were typically asymptomatic, generally occurred during the first 4  weeks of treatment (mean time 20 days, range 8-57 days) and most resolved with  ongoing therapy. The majority of these ALT elevations were assessed as  drug-related liver injury. Elevations in ALT were generally not associated with  bilirubin elevations. Cirrhosis was not a risk factor for elevated ALT.
Serum Bilirubin Elevations 
 Post-baseline  elevations in bilirubin at least 2 x ULN were observed in 15% of subjects  receiving VIEKIRA PAK with ribavirin compared to 2% in those receiving VIEKIRA  PAK alone. These bilirubin increases were predominately indirect and 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 serum ALT elevations.
Anemia/Decreased Hemoglobin
 Across  all Phase 3 studies, the mean change from baseline in hemoglobin levels in  subjects treated with VIEKIRA PAK in combination with ribavirin was -2.4 g/dL  and the mean change in subjects treated with VIEKIRA PAK alone was -0.5 g/dL.  Decreases in hemoglobin levels occurred early in treatment (Week 1-2) with  further reductions through Week 3. Hemoglobin values remained low during the  remainder of treatment and returned towards baseline levels by post-treatment  Week 4. Less than 1% of subjects treated with VIEKIRA PAK with ribavirin had  hemoglobin levels decrease to less than 8.0 g/dL during treatment.  Seven percent of subjects treated with  VIEKIRA PAK in combination with ribavirin underwent a ribavirin dose reduction  due to a decrease in hemoglobin levels; three subjects received a blood  transfusion and five required erythropoietin.   One patient discontinued therapy due to anemia. No subjects treated with  VIEKIRA PAK alone had a hemoglobin level less than 10 g/dL.

VIEKIRA PAK in HCV/HIV-1 Co-infected  Subjects

VIEKIRA PAK with ribavirin was  assessed in 63 subjects with HCV/HIV-1 co-infection who were on stable  antiretroviral therapy. The most common adverse events occurring in at least  10% of subjects were fatigue (48%), insomnia (19%), nausea (17%), headache  (16%), pruritus (13%), cough (11%), irritability (10%), and ocular icterus  (10%).
Elevations in total bilirubin greater  than 2 x ULN (mostly indirect) occurred in 34 (54%) subjects.  Fifteen of these subjects were also receiving  atazanavir at the time of bilirubin elevation and nine also had adverse events  of ocular icterus, jaundice or hyperbilirubinemia. None of the subjects with  hyperbilirubinemia had concomitant elevations of aminotransferases. No subject experienced a grade 3 ALT elevation.
Seven subjects (11%) had at least  one post-baseline hemoglobin value of less than 10 g/dL, and six of these  subjects had a ribavirin dose modification; no subject in this small cohort  required a blood transfusion or erythropoietin.
Median declines in CD4+ T-cell  counts of 47 cells/mm3 and 62 cells/mm3 were observed at  the end of 12 and 24 weeks of treatment, respectively, and most returned to  baseline levels post-treatment. Two subjects had CD4+ T-cell counts decrease to  less than 200 cells/mm3 during treatment without a decrease in CD4%.  No subject experienced an AIDS-related opportunistic infection.

VIEKIRA PAK in Selected Liver Transplant  Recipients

VIEKIRA PAK with ribavirin was  assessed in 34 post-liver transplant subjects with recurrent HCV infection.  Adverse events occurring in more than 20% of subjects included fatigue 50%,  headache 44%, cough 32%, diarrhea 26%, insomnia 26%, asthenia 24%, nausea 24%,  muscle spasms 21% and rash 21%.  Ten  subjects (29%) had at least one post-baseline hemoglobin value of less than 10  g/dL. Ten subjects underwent a ribavirin dose  modification due to decrease in hemoglobin and 3% (1/34) had an interruption  of ribavirin. Five subjects received erythropoietin, all of whom initiated  ribavirin at the starting dose of 1000 to 1200 mg daily. No subject received a  blood transfusion .

DRUG INTERACTIONS
 Potential  for VIEKIRA PAK to Affect Other Drugs 
Ombitasvir, paritaprevir, and  dasabuvir are inhibitors of UGT1A1, and ritonavir is an inhibitor of CYP3A4.  Paritaprevir is an inhibitor of OATP1B1 and OATP1B3 and paritaprevir, ritonavir  and dasabuvir are inhibitors of BCRP. Co-administration of VIEKIRA PAK with  drugs that are substrates of CYP3A, UGT1A1, BCRP, OATP1B1 or OATP1B3 may result  in increased plasma concentrations of such drugs.

 Potential for Other Drugs to Affect One or More Components  of VIEKIRA PAK
 Paritaprevir and ritonavir are  primarily metabolized by CYP3A enzymes. Co-administration of VIEKIRA PAK with  strong inhibitors of CYP3A may increase paritaprevir and ritonavir  concentrations. Dasabuvir is primarily metabolized by CYP2C8 enzymes.  Co-administration of VIEKIRA PAK with drugs that inhibit CYP2C8 may increase  dasabuvir plasma concentrations. Ombitasvir is primarily metabolized via amide  hydrolysis while CYP enzymes play a minor role in its metabolism. Ombitasvir, paritaprevir, dasabuvir and ritonavir  are substrates of P-gp. Ombitasvir, paritaprevir and dasabuvir are substrates  of BCRP. Paritaprevir is a substrate of OATP1B1 and OATP1B3. Inhibition of  P-gp, BCRP, OATP1B1 or OATP1B3 may increase the plasma concentrations of the  various components of VIEKIRA PAK.
Established  and Other Potential Drug Interactions 
 If dose adjustments of concomitant  medications are made due to treatment with VIEKIRA PAK, doses should be  re-adjusted after administration of VIEKIRA PAK is completed. Dose adjustment  is not required for VIEKIRA PAK.
Table 5 provides the effect of co-administration of VIEKIRA PAK on  concentrations of concomitant drugs and the effect of concomitant drugs on the  various components of VIEKIRA PAK. See Contraindications for drugs that are contraindicated with VIEKIRA PAK. Refer to the ritonavir  prescribing information for other potentially significant drug interactions  with ritonavir.
Table  5. Established Drug Interactions Based on Drug Interaction Trials 

 Concomitant     Drug Class:
 Drug Name  
Effect on Concentration

Clinical Comments

ANTIARRHYTHMICS

amiodarone,
 bepridil,
 disopyramide,
 flecainide,
 lidocaine (systemic),
 mexiletine,
 propafenone,
 quinidine

↑ antiarrhythmics 

Caution is warranted and therapeutic concentration    monitoring (if available) is recommended for antiarrhythmics when    co-administered with VIEKIRA PAK.

ANTIFUNGALS

ketoconazole

↑ ketoconazole

When VIEKIRA PAK is co-administered with ketoconazole, the    maximum daily dose of ketoconazole should be limited to 200 mg per day.

voriconazole

↓ voriconazole

Co-administration of VIEKIRA PAK with voriconazole is not    recommended unless an assessment of the benefit-to-risk ratio justifies the    use of voriconazole.

CALCIUM CHANNEL BLOCKERS

amlodipine

↑ amlodipine

Consider dose reduction for amlodipine.  Clinical monitoring is recommended. 

CORTICOSTEROIDS (INHALED/NASAL)

fluticasone

↑ fluticasone

Concomitant use of VIEKIRA PAK with inhaled or nasal    fluticasone may reduce serum cortisol concentrations.  Alternative corticosteroids should be considered,    particularly for long term use. 

DIURETICS

furosemide

↑ furosemide (Cmax)

Clinical monitoring of patients is recommended and therapy    should be individualized based on patient’s response.

HIV-ANTIVIRAL AGENTS

atazanavir/ritonavir once daily

↑ paritaprevir

When coadministered with VIEKIRA PAK, atazanavir 300 mg    (without ritonavir) should only be given in the morning.

darunavir/ritonavir

↓ darunavir (Ctrough)

Co-administration of VIEKIRA PAK with darunavir/ritonavir    is not recommended.

lopinavir/ritonavir

↑ paritaprevir

Co-administration of VIEKIRA PAK with lopinavir/ritonavir    is not recommended.

rilpivirine

↑ rilpivirine

Co-administration of VIEKIRA PAK with rilpivirine once    daily is not recommended due to potential for QT interval prolongation with    higher concentrations of rilpivirine.

HMG CoA REDUCTASE INHIBITORS

rosuvastatin

↑ rosuvastatin

When VIEKIRA PAK is co-administered with rosuvastatin, the    dose of rosuvastatin should not exceed 10 mg per day.

pravastatin

↑ pravastatin

When VIEKIRA PAK is co-administered with pravastatin, the    dose of pravastatin should not exceed 40 mg per day.

IMMUNOSUPPRESSANTS

cyclosporine

tacrolimus

↑ cyclosporine

↑ tacrolimus

When initiating therapy with VIEKIRA PAK, reduce cyclosporine    dose to 1/5th of the patient’s current cyclosporine dose. Measure    cyclosporine blood concentrations to determine subsequent dose    modifications.  Upon completion of    VIEKIRA PAK therapy, the appropriate time to resume pre-VIEKIRA PAK dose of    cyclosporine should be guided by assessment of cyclosporine blood    concentrations. Frequent assessment of renal function and    cyclosporine-related side effects is recommended.
When initiating therapy with VIEKIRA PAK, the dose of    tacrolimus needs to be reduced.  Do not    administer tacrolimus on the day VIEKIRA PAK is initiated. Beginning the day    after VIEKIRA PAK is initiated; reinitiate tacrolimus at a reduced dose based    on tacrolimus blood concentrations.     Typical tacrolimus dosing is 0.5 mg every 7 days.
Measure tacrolimus blood concentrations and adjust dose or    dosing frequency to determine subsequent dose modifications.  Upon completion of VIEKIRA PAK therapy, the    appropriate time to resume pre-VIEKIRA PAK dose of tacrolimus should be    guided by assessment of tacrolimus blood concentrations. Frequent assessment    of renal function and tacrolimus related side effects is recommended.

LONG ACTING BETA-ADRENOCEPTOR AGONIST

salmeterol

↑ salmeterol

Concurrent administration of VIEKIRA PAK and salmeterol is not    recommended. The combination may result in increased risk of cardiovascular    adverse events associated with salmeterol, including QT prolongation,    palpitations and sinus tachycardia.

NARCOTIC ANALGESICS

buprenorphine/naloxone

↑ buprenorphine
 ↑ norbuprenorphine

No dose adjustment of buprenorphine/naloxone is required    upon co-administration with VIEKIRA PAK.     Patients should be closely monitored for sedation and cognitive    effects.  

PROTON PUMP INHIBITORS

omeprazole

↓ omeprazole

Monitor patients for decreased    efficacy of omeprazole.  Consider increasing the omeprazole dose in    patients whose symptoms are not well controlled; avoid use of more than 40 mg    per day of omeprazole.

SEDATIVES/HYPNOTICS

alprazolam

↑ alprazolam

Clinical monitoring of patients is recommended. A decrease    in alprazolam dose can be considered based on clinical response.

The direction of the arrow    indicates the direction of the change in exposures (Cmax and AUC)    (↑ = increase of more than 20%, ↓ = decrease of more than 20%, ↔ = no change or change less than 20%).

Drugs without Clinically Significant Interactions with VIEKIRA PAK 
 No  dose adjustments are recommended when VIEKIRA PAK is co-administered with the following medications:  digoxin, duloxetine, emtricitabine/tenofovir disoproxil fumarate, escitalopram,  methadone, progestin only contraceptives, raltegravir, warfarin and zolpidem.
CLINICAL  STUDIES
 Description of Clinical Trials 
 The  efficacy and safety of VIEKIRA PAK was evaluated in six randomized,  multicenter, clinical trials in 2,308 subjects with genotype 1 (GT1) chronic  hepatitis C virus (HCV) infection, including one trial exclusively in subjects  with cirrhosis with mild hepatic impairment (Child-Pugh A), as summarized in Table 9.
Table 9. Randomized, Multicenter  Trials Conducted with VIEKIRA PAK With or Without Ribavirin (RBV) in Subjects  with Chronic HCV GT1 Infection

 Trial  
Population

Study     Arms
 (Number     of Subjects Treated)

SAPPHIRE-I
 (double-blind)

GT1 (a and b)
 TNa without cirrhosis

VIEKIRA PAK + RBV (473)
Placebo   (158)

SAPPHIRE-II
 (double-blind)

GT1 (a and b)
 TEb without cirrhosis

VIEKIRA PAK + RBV (297)
Placebo (97)

PEARL-II
 (open-label)

GT1b
 TE without cirrhosis

VIEKIRA PAK + RBV (88) 
VIEKIRA PAK (91)

PEARL-III 
 (double-blind)

GT1b
 TN without cirrhosis

VIEKIRA PAK + RBV (210) 
VIEKIRA PAK (209)

PEARL-IV
 (double-blind)

GT1a
 TN without cirrhosis

VIEKIRA PAK + RBV (100) 
VIEKIRA PAK (205)

TURQUOISE-II
 (open-label)

GT1 (a and b)
 TN & TE with cirrhosis

VIEKIRA PAK + RBV (12 weeks) (208)
VIEKIRA PAK + RBV (24 weeks) (172)

TN,    treatment-naïve was defined as not having received any prior therapy for HCV    infection.
TE,    treatment-experienced subjects were defined as either: prior relapsers, prior    partial responders, or prior null responders to pegIFN/RBV treatment. 

In       SAPPHIRE-I and -II, subjects without cirrhosis were randomized to VIEKIRA       PAK in combination with ribavirin        for 12 weeks or to placebo. Subjects in the placebo arm received       placebo for 12 weeks, after which they received open-label VIEKIRA PAK in       combination with RBV for 12 weeks.  
In       PEARL-II, -III and -IV, subjects without cirrhosis were randomized to       receive VIEKIRA PAK with or without RBV for 12 weeks of treatment.
In       the open-label TURQUOISE-II trial, subjects with compensated cirrhosis       (Child-Pugh A) who were either treatment-naïve or pegylated interferon/RBV       (pegIFN/RBV) treatment-experienced were randomized to receive VIEKIRA PAK       in combination with RBV for either 12 or 24 weeks of treatment. Subjects       who previously failed therapy with a treatment regimen that included       VIEKIRA PAK or other direct-acting antiviral agents were excluded.

In  these six clinical trials, the ombitasvir, paritaprevir, ritonavir dose was  25/150/100 mg once daily and the dasabuvir dose was 250 mg twice daily. Doses  of drugs in VIEKIRA PAK were not adjusted. For subjects who received RBV, the  RBV dose was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg  per day for subjects weighing greater than or equal to 75 kg. RBV dose  adjustments were performed according to the RBV labeling.

 VIEKIRA  PAK with RBV was also evaluated in the following two studies:                  

HCV GT1-infected liver       transplant recipients (CORAL-I). 
Subjects with HCV GT1       co-infected with HIV-1 (TURQUOISE-I). 

In  all eight clinical studies, sustained virologic response was defined as HCV RNA  below the lower limit of quantification (<LLOQ) 12 weeks after the end of  treatment (SVR12). Plasma HCV RNA levels were measured using the COBAS TaqMan  HCV test (version 2.0), for use with the High Pure System, which has an LLOQ of  25 IU per mL.  Outcomes for subjects not  achieving an SVR12 were recorded as on-treatment virologic failure (VF),  post-treatment virologic relapse through post-treatment Week 12 or failure due  to other non-virologic reasons (e.g., premature discontinuation, adverse event,  lost to follow-up, consent withdrawn).
Clinical Trial Results in Adults with Chronic HCV Genotype  1a and 1b Infection without Cirrhosis
Subjects  with Chronic HCV GT1a Infection without Cirrhosis
 Subjects  with HCV GT1a infection without cirrhosis treated with VIEKIRA PAK with RBV for  12 weeks in SAPPHIRE-I and -II and in PEARL-IV had a median age of 53 years  (range: 18 to 70); 63% of the subjects were male; 90% were White; 7% were  Black/African American; 8% were Hispanic or Latino; 19% had a body mass index  of at least 30 kg per m2; 55% of patients were enrolled in US sites;  72% had IL28B non-CC genotype; 85% had baseline HCV RNA levels of at least  800,000 IU per mL.
Table  10 presents treatment outcomes for HCV GT1a treatment-naïve and  treatment-experienced subjects treated with VIEKIRA PAK with RBV for 12 weeks  in SAPPHIRE-I, PEARL-IV and SAPPHIRE-II.
Treatment-naïve,  HCV GT1a-infected subjects without cirrhosis treated with VIEKIRA PAK in  combination with RBV for 12 weeks in PEARL-IV had a significantly higher SVR12  rate than subjects treated with VIEKIRA PAK alone (97% and 90% respectively;  difference +7%  with 95% confidence  interval, +1% to +12%).  VIEKIRA PAK  alone was not studied in treatment-experienced subjects with GT1a infection.
In  SAPPHIRE-I and SAPPHIRE-II, no placebo subject achieved a HCV RNA <25 IU/mL  during treatment.
Table  10. SVR12 for HCV Genotype 1a-Infected Subjects without Cirrhosis Who Were Treatment-Naïve or Previously  Treated with PegIFN/RBV

VIEKIRA PAK with RBV 
 for    12 Weeks
 %    (n/N)

GT1a treatment-naïve

SAPPHIRE-I   SVR12
 Outcome    for subjects without SVR12
 On-treatment VF
 Relapse
 Other 

96%  (308/322)
<1%  (1/322)
 2%     (6/314)
 2%     (7/322)

PEARL-IV  SVR12
 Outcome    for subjects without SVR12
 On-treatment VF
 Relapse
 Other 

97%  (97/100)
1%     (1/100)
 1%     (1/98)
 1%     (1/100)

GT1a treatment-experienced 

SAPPHIRE-II    SVR12
 Outcome    for subjects without SVR12
 On-treatment VF
 Relapse
 Other 

96% (166/173)
0% (0/173)
 3% (5/172)
 1% (2/173)

SVR12 by Prior pegIFN Experience
 Null Responder
 Partial Responder
 Relapser

95% (83/87)
 100% (36/36)
 94% (47/50)

Subjects  with Chronic HCV GT1b Infection without Cirrhosis           
 Subjects  with HCV GT1b infection without cirrhosis were treated with VIEKIRA PAK with or  without RBV for 12 weeks in PEARL-II and -III. Subjects had a median age of 52  years (range: 22 to 70); 47% of the subjects were male; 93% were White; 5% were  Black/African American; 2% were Hispanic or Latino; 21% had a body mass index  of at least 30 kg per m2; 21% of patients were enrolled in US sites;  83% had IL28B non-CC genotype; 77% had baseline HCV RNA levels of at least  800,000 IU per mL.
The  SVR rate for HCV GT1b-infected subjects without cirrhosis treated with VIEKIRA  PAK without RBV for 12 weeks in PEARL-II (treatment-experienced: null  responder, n=32; partial responder, n=26; relapser, n=33) and PEARL-III  (treatment-naïve, n=209) was 100%.
Clinical Trial Results in Adults with Chronic HCV Genotype  1a and 1b Infection and Compensated Cirrhosis
 TURQUOISE-II  was an open-label trial that enrolled 380 HCV GT1a and 1b-infected subjects  with cirrhosis and mild hepatic impairment (Child-Pugh A) who were either  treatment-naïve or did not achieve SVR with prior treatment with pegIFN/RBV.  Subjects were randomized to receive VIEKIRA PAK in combination with RBV for  either 12 or 24 weeks of treatment.
Treated  subjects  had a median age of 58 years  (range: 21 to 71); 70% of the subjects were male; 95% were White; 3% were  Black/African American; 12% were Hispanic or Latino; 28% had a body mass index  of at least 30 kg per m2; 43% of patients were enrolled in US sites;  82% had IL28B non‑CC genotype; 86% had baseline HCV RNA levels of at least  800,000 IU per mL;  69% had HCV GT1a  infection, 31% had HCV GT1b infection; 42% were treatment-naïve, 36% were prior  pegIFN/RBV null responders; 8% were prior pegIFN/RBV partial responders, 14%  were prior pegIFN/RBV relapsers; 15% had platelet counts of less than 90 x 109  per L; 50% had albumin less than 4.0 mg per dL. 
 Table  11 presents treatment outcomes for GT1 treatment-naïve and treatment-experienced  subjects with cirrhosis treated with VIEKIRA PAK with RBV for 12 or 24 weeks in  TURQUOISE-II. In GT1a infected subjects, the overall SVR12 rate difference  between  24 and 12 weeks of treatment  with VIEKIRA PAK with RBV was +6% with 95% confidence interval, -0.1% to +13%  with differences varying by pretreatment history.
Table 11. TURQUOISE-II: SVR12 for Chronic HCV Genotype  1-Infected Subjects with Cirrhosis Who Were Treatment-Naïve or Previously  Treated with pegIFN/RBV

GT1a

GT1b

VIEKIRA    PAK with RBV for 24 Weeks
 %    (n/N)

VIEKIRA    PAK with RBV for 12 Weeks
 %    (n/N)

VIEKIRA    PAK with RBV for 12 Weeks
 %    (n/N) 

SVR12
 Outcome for subjects without SVR12
 On-treatment VF
 Relapse
 Other 

95% (115/121)
2% (3/121)
 1% (1/116)
 2% (2/121)

89% (124/140)
<1% (1/140)
 8%     (11/135)
 3% (4/140)

99% (67/68)
0% (0/68)
 1% (1/68)
 0% (0/68)

SVR12 for Naïve
SVR12 by Prior pegIFN Experience
 Null Responder
 Partial    Responder
 Relapser 

95% (53/56)

93%  (39/42)
 100% (10/10)
 100% (13/13)

92% (59/64)

80% (40/50)
 100% (11/11)
 93% (14/15)

100% (22/22)

100% (25/25)
 86% (6/7)
 100% (14/14)

Effect of Ribavirin Dose Reductions on SVR12
 Seven  percent of subjects (101/1551) treated with VIEKIRA PAK with RBV had a RBV dose  adjustment due to a decrease in hemoglobin level; of these, 98% (98/100)  achieved an SVR12.  
Clinical Trial of Selected Liver Transplant Recipients  (CORAL-I)
 VIEKIRA  PAK with RBV was administered for 24 weeks to 34 HCV GT1-infected liver  transplant recipients who were at least 12 months post transplantation at  enrollment with normal hepatic function and mild fibrosis (Metavir fibrosis  score F2 or lower). The initial dose of RBV 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 VIEKIRA PAK and at the end of treatment.
Of  the 34 subjects (29 with HCV GT1a infection and 5 with HCV GT1b infection)  enrolled, (97%) achieved SVR12 (97% in subjects with GT1a infection and 100% of  subjects with GT1b infection). One subject with HCV GT1a infection relapsed  post-treatment. 
Clinical Trial in Subjects with HCV/HIV-1 Co-infection (TURQUOISE-I)
 In  an open-label clinical trial 63 subjects with HCV GT1 infection co-infected  with HIV-1 were treated for 12 or 24 weeks with VIEKIRA PAK in combination with  RBV. Subjects were on a stable HIV-1 antiretroviral therapy (ART) regimen that  included tenofovir disoproxil fumarate plus emtricitabine or lamivudine,  administered with ritonavir boosted atazanavir or raltegravir.  Subjects on atazanavir stopped the ritonavir  component of their HIV-1 ART regimen upon initiating treatment with VIEKIRA PAK  in combination with RBV.  Atazanavir was taken with the morning dose of  VIEKIRA PAK. The ritonavir component of  the HIV-1 ART regimen was restarted after completion of treatment with VIEKIRA  PAK and RBV.
Treated subjects  had a median age of 51 years (range: 31 to 69); 24% of subjects were black; 81%  of subjects had IL28B non-CC genotype; 19% of subjects had compensated  cirrhosis; 67% of subjects were HCV treatment-naïve; 33% of subjects had failed  prior treatment with pegIFN/RBV; 89% of subjects had HCV genotype 1a infection. 
 The  SVR12 rates were 91% (51/56) for subjects with HCV GT1a infection and 100%  (7/7) for those with HCV GT1b infection.   Of the 5 subjects who were non-responders, 1 experienced virologic  breakthrough, 1 discontinued treatment, 1 experienced relapse and 2 subjects  had evidence of HCV re-infection post-treatment.
 One subject had confirmed HIV-1 RNA  >400 copies/mL during the post-treatment period. This subject had no  evidence of resistance to the ART regimen. No subjects switched their ART  regimen due to loss of plasma HIV-1 RNA suppression.
Durability of Response
 In an open-label clinical trial, 92% of subjects (526/571) who  received various combinations of the direct acting antivirals included in  VIEKIRA PAK with or without RBV achieved SVR12, and 99% of those who achieved  SVR12 maintained their response through 48 weeks post-treatment (SVR48).
Viekira Pak is marketed by AbbVie Inc., based in North Chicago,  Illinois. Olysio is marketed by Raritan, New Jersey-based Janssen  Pharmaceuticals. Sovaldi and Harvoni are marketed by Gilead Sciences,  based in Foster City, California.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration

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GT1a treatment-naïve
	VIEKIRA PAK with RBV for 12 Weeks % (n/N)
SAPPHIRE-I SVR12 Outcome for subjects without SVR12 On-treatment VF Relapse Other	96% (308/322) <1% (1/322) 2% (6/314) 2% (7/322)
PEARL-IV SVR12 Outcome for subjects without SVR12 On-treatment VF Relapse Other	97% (97/100) 1% (1/100) 1% (1/98) 1% (1/100)
GT1a treatment-experienced
SAPPHIRE-II SVR12 Outcome for subjects without SVR12 On-treatment VF Relapse Other	96% (166/173) 0% (0/173) 3% (5/172) 1% (2/173)
SVR12 by Prior pegIFN Experience Null Responder Partial Responder Relapser	95% (83/87) 100% (36/36) 94% (47/50)

Patient Population	Treatment*	Duration
Genotype 1a, without cirrhosis	VIEKIRA PAK + ribavirin	12 weeks
Genotype 1a, with cirrhosis	VIEKIRA PAK + ribavirin	24 weeks**
Genotype 1b, without cirrhosis	VIEKIRA PAK	12 weeks
Genotype 1b, with cirrhosis	VIEKIRA PAK + ribavirin	12 weeks
Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection. VIEKIRA PAK administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history [see Clinical Studies (14.3)]*.

Drug Class	Drug(s) within Class that are Contraindicated	Clinical Comments
Alpha1-adrenoreceptor antagonist	Alfuzosin HCL	Potential for hypotension.
Anticonvulsants	Carbamazepine, phenytoin, phenobarbital	Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of VIEKIRA PAK.
Antihyperlipidemic agent	Gemfibrozil	Increase in dasabuvir exposures by 10-fold which may increase the risk of QT prolongation.
Antimycobacterial	Rifampin	Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of VIEKIRA PAK.
Ergot derivatives	Ergotamine, dihydroergotamine, ergonovine, methylergonovine	Acute ergot toxicity characterized by vasospasm and tissue ischemia has been associated with co-administration of ritonavir and ergonovine, ergotamine, dihydroergotamine, or methylergonovine.
Ethinyl estradiol-containing products	Ethinyl estradiol-containing medications such as combined oral contraceptives	Potential for ALT elevations
Herbal Product	St. John’s Wort (Hypericum perforatum)	Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of VIEKIRA PAK.
HMG-CoA Reductase Inhibitors	Lovastatin, simvastatin	Potential for myopathy including rhabdomyolysis.
Neuroleptics	Pimozide	Potential for cardiac arrhythmias.
Non-nucleoside reverse transcriptase inhibitor	Efavirenz	Co-administration of efavirenz based regimens with paritaprevir, ritonavir plus dasabuvir was poorly tolerated and resulted in liver enzyme elevations.
Phosphodiesterase-5 (PDE5) inhibitor	Sildenafil when dosed as REVATIO for the treatment of pulmonary arterial hypertension (PAH)	There is increased potential for sildenafil-associated adverse events such as visual disturbances, hypotension, priapism, and syncope.
Sedatives/hypnotics	Triazolam Orally administered midazolam	Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with VIEKIRA PAK may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life threatening events such as prolonged or increased sedation or respiratory depression.

	SAPPHIRE-I and -II
	VIEKIRA PAK + RBV 12 Weeks N = 770 %	Placebo 12 Weeks N = 255 %
Fatigue	34	26
Nausea	22	15
Pruritus*	18	7
Skin reactions**	16	9
Insomnia	14	8
Asthenia	14	7
Grouped term ‘pruritus’ included the preferred terms pruritus and pruritus generalized. *Grouped terms: rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash papular, skin exfoliation, rash pruritic, rash erythematous, rash generalized, dermatitis allergic, dermatitis contact, exfoliative rash, dermatitis, photosensitivity reaction, psoriasis, skin reaction, ulcer, urticaria.

	PEARL-II, -III and -IV
	VIEKIRA PAK + RBV 12 Weeks N = 401 %	VIEKIRA PAK 12 Weeks N = 509 %
Nausea	16	8
Pruritus*	13	7
Insomnia	12	5
Asthenia	9	4
*Grouped term ‘pruritus’ included the preferred terms pruritus and pruritus generalized.

Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comments
ANTIARRHYTHMICS
amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with VIEKIRA PAK.
ANTIFUNGALS
ketoconazole	↑ ketoconazole	When VIEKIRA PAK is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day.
voriconazole	↓ voriconazole	Co-administration of VIEKIRA PAK with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole.
CALCIUM CHANNEL BLOCKERS
amlodipine	↑ amlodipine	Consider dose reduction for amlodipine. Clinical monitoring is recommended.
CORTICOSTEROIDS (INHALED/NASAL)
fluticasone	↑ fluticasone	Concomitant use of VIEKIRA PAK with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
DIURETICS
furosemide	↑ furosemide (Cmax)	Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response.
HIV-ANTIVIRAL AGENTS
atazanavir/ritonavir once daily	↑ paritaprevir	When coadministered with VIEKIRA PAK, atazanavir 300 mg (without ritonavir) should only be given in the morning.
darunavir/ritonavir	↓ darunavir (Ctrough)	Co-administration of VIEKIRA PAK with darunavir/ritonavir is not recommended.
lopinavir/ritonavir	↑ paritaprevir	Co-administration of VIEKIRA PAK with lopinavir/ritonavir is not recommended.
rilpivirine	↑ rilpivirine	Co-administration of VIEKIRA PAK with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine.
HMG CoA REDUCTASE INHIBITORS
rosuvastatin	↑ rosuvastatin	When VIEKIRA PAK is co-administered with rosuvastatin, the dose of rosuvastatin should not exceed 10 mg per day.
pravastatin	↑ pravastatin	When VIEKIRA PAK is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day.
IMMUNOSUPPRESSANTS
cyclosporine tacrolimus	↑ cyclosporine ↑ tacrolimus	When initiating therapy with VIEKIRA PAK, reduce cyclosporine dose to 1/5th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of VIEKIRA PAK therapy, the appropriate time to resume pre-VIEKIRA PAK dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended. When initiating therapy with VIEKIRA PAK, the dose of tacrolimus needs to be reduced. Do not administer tacrolimus on the day VIEKIRA PAK is initiated. Beginning the day after VIEKIRA PAK is initiated; reinitiate tacrolimus at a reduced dose based on tacrolimus blood concentrations. Typical tacrolimus dosing is 0.5 mg every 7 days. Measure tacrolimus blood concentrations and adjust dose or dosing frequency to determine subsequent dose modifications. Upon completion of VIEKIRA PAK therapy, the appropriate time to resume pre-VIEKIRA PAK dose of tacrolimus should be guided by assessment of tacrolimus blood concentrations. Frequent assessment of renal function and tacrolimus related side effects is recommended.
LONG ACTING BETA-ADRENOCEPTOR AGONIST
salmeterol	↑ salmeterol	Concurrent administration of VIEKIRA PAK and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
NARCOTIC ANALGESICS
buprenorphine/naloxone	↑ buprenorphine ↑ norbuprenorphine	No dose adjustment of buprenorphine/naloxone is required upon co-administration with VIEKIRA PAK. Patients should be closely monitored for sedation and cognitive effects.
PROTON PUMP INHIBITORS
omeprazole	↓ omeprazole	Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole.
SEDATIVES/HYPNOTICS
alprazolam	↑ alprazolam	Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response.
The direction of the arrow indicates the direction of the change in exposures (Cmax and AUC) (↑ = increase of more than 20%, ↓ = decrease of more than 20%, ↔ = no change or change less than 20%).

Trial	Population	Study Arms (Number of Subjects Treated)
SAPPHIRE-I (double-blind)	GT1 (a and b) TNa without cirrhosis	VIEKIRA PAK + RBV (473) Placebo (158)
SAPPHIRE-II (double-blind)	GT1 (a and b) TEb without cirrhosis	VIEKIRA PAK + RBV (297) Placebo (97)
PEARL-II (open-label)	GT1b TE without cirrhosis	VIEKIRA PAK + RBV (88) VIEKIRA PAK (91)
PEARL-III (double-blind)	GT1b TN without cirrhosis	VIEKIRA PAK + RBV (210) VIEKIRA PAK (209)
PEARL-IV (double-blind)	GT1a TN without cirrhosis	VIEKIRA PAK + RBV (100) VIEKIRA PAK (205)
TURQUOISE-II (open-label)	GT1 (a and b) TN & TE with cirrhosis	VIEKIRA PAK + RBV (12 weeks) (208) VIEKIRA PAK + RBV (24 weeks) (172)
TN, treatment-naïve was defined as not having received any prior therapy for HCV infection. TE, treatment-experienced subjects were defined as either: prior relapsers, prior partial responders, or prior null responders to pegIFN/RBV treatment.