Welcome to HCV Advocate’s hepatitis blog. The intent of this blog is to keep our website audience up-to-date on information about hepatitis and to answer some of our web site and training audience questions. People are encouraged to submit questions and post comments.

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Alan Franciscus
Editor-in-Chief
HCV Advocate
HBV Advocate

Drugs in Development / Clinical Trials—Updated December 2, 2014

Saturday, December 20, 2014

AbbVie Receives U.S. FDA Approval of VIEKIRA PAK™ (Ombitasvir/Paritaprevir/Ritonavir Tablets; Dasabuvir Tablets) for the Treatment of Chronic Genotype 1 Hepatitis C

  • In Phase 3 clinical trials, VIEKIRA PAK cured 95-100 percent of hepatitis C patients, with less than 2 percent of patients experiencing virological failure
  • Tolerability profile shows more than 98 percent of patients completed a full course of therapy 
  • All-oral interferon-free regimen also approved for HCV/HIV-1 co-infection and patients who have undergone a liver transplant

NORTH CHICAGO, Ill., Dec. 19, 2014 /PRNewswire/ -- The U.S. Food and Drug Administration (FDA) has approved AbbVie's (NYSE:ABBV) VIEKIRA PAK, an all-oral, interferon-free treatment, with or without ribavirin (RBV), for the treatment of patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection, including those with compensated cirrhosis. VIEKIRA PAK is the only FDA-approved regimen that contains three distinct mechanisms of action - NS5A inhibitor, NS3/4A protease inhibitor and a non-nucleoside NS5B polymerase inhibitor - that work together to attack the virus at three separate stages of the disease lifecycle to inhibit it from reproducing.

"We are proud of the work of our research and development organization to bring this important therapy, offering high cure rates, to patients with hepatitis C. We believe appropriate patients, regardless of their fibrosis stage, should have broad market access to VIEKIRA PAK, and we are committed to supporting access to this therapy," said Richard Gonzalez, Chairman of the Board and Chief Executive Officer, AbbVie. "This is the first of several potential new therapies that we are advancing to treat a multitude of serious disease states, and we anticipate bringing them to market in the coming years."

The approval of VIEKIRA PAK is supported by a robust clinical development program designed to study the safety and efficacy of the regimen in more than 2,300 enrolled patients across 25 countries. The program consisted of six pivotal Phase 3 studies, which demonstrated that VIEKIRA PAK cured 95-100 percent of GT1a and GT1b hepatitis C patients, including patients new and experienced to treatment, and patients with compensated cirrhosis, with less than 2 percent of patients experiencing virological failure. Additionally, more than 98 percent of patients in clinical trials completed a full course of therapy.

VIEKIRA PAK's approval is also based on the results from Phase 2 clinical trials, which showed that VIEKIRA PAK cured 97 percent of liver transplant recipients and 92 percent of patients co-infected with HCV/HIV-1. Patients who achieve a sustained virologic response (SVR12) are considered cured of HCV.

"AbbVie's clinical trial program includes landmark, placebo-controlled studies evaluating a wide variety of patients with hepatitis C," said Fred Poordad, M.D., vice president, academic and clinical affairs, the Texas Liver Institute and Professor of Medicine, University of Texas Health Science Center, San Antonio, and investigator for several VIEKIRA PAK trials. "The studies have shown that treatment with VIEKIRA PAK resulted in high cure rates, even in patients who have historically been challenging to treat, such as patients with cirrhosis, patients who have had liver transplants and patients co-infected with HIV."

HCV is the most common, blood-borne infection in the United States, affecting more than 3.2 million Americans, which is nearly three times as many people affected by the human immunodeficiency virus (HIV). More than 70 percent of all HCV patients have GT1 infection. It is estimated that more than 1 million people currently living with HCV will develop cirrhosis (scarring of the liver) by the year 2020, and with HCV-related liver transplants on the rise, it has become a critical public health issue. As the population ages and HCV progresses, it is projected that total annual direct medical costs of HCV in the U.S. will reach $85 billion over the next 20 years.

"Treating hepatitis C is complex because the virus mutates and replicates rapidly. With so many Americans affected by HCV, it is critical that patients have access to a regimen that, in clinical trials, produced high cure rates with low rates of treatment failures, even in the most difficult-to-treat patients," said Michael Severino, M.D., Executive Vice President, Research and Development and Chief Scientific Officer, AbbVie.

For people living with hepatitis C who face financial difficulties, the AbbVie Patient Assistance Program provides medication at no cost. A co-pay assistance program will be available for commercially-insured patients being treated with VIEKIRA PAK. Out-of-pocket costs for eligible patients could be as little as $5.00 per month. 

Additionally, AbbVie has launched a patient support program, called proCeed™, which is intended to provide a broad range of patient support options. The proCeed program can be accessed soon at www.viekira.com or by calling 1-844-2-PROCEED.

AbbVie also supports independent non-profit organizations that assist eligible patients enrolled in federal and private insurance plans with their out-of-pocket medication costs.

2015 OutlookAbbVie expects to provide earnings-per-share guidance for 2015 in early January. The company will provide detailed 2015 guidance, including product sales estimates and other financial metrics, on its fourth quarter earnings conference call, scheduled for January 30, 2015.

About VIEKIRA PAK™VIEKIRA PAK™ (ombitasvir/paritaprevir/ritonavir tablets; dasabuvir tablets) has been studied in a broad range of genotype 1 (GT1) patients with chronic hepatitis C virus (HCV) infection, ranging from treatment-naive to some of the most difficult to treat, such as patients with compensated (mild, Child-Pugh A) cirrhosis of the liver, HCV/HIV-1 co-infection, liver transplant recipients with normal hepatic function and mild fibrosis, and those who have failed previous treatment with pegylated interferon (pegIFN) and ribavirin (RBV). VIEKIRA PAK is not recommended in patients with moderate hepatic impairment (Child-Pugh B), and is contraindicated in patients with severe hepatic impairment (Child-Pugh C). VIEKIRA PAK consists of the fixed-dose combination of ombitasvir 25mg (an NS5A inhibitor), paritaprevir 150mg (an NS3/4A protease inhibitor), and ritonavir 100mg (an approved HIV-1 protease inhibitor), dosed once daily with a meal, and dasabuvir 250mg (a non-nucleoside NS5B palm polymerase inhibitor), dosed twice daily with a meal. VIEKIRA PAK is taken for 12 weeks, except in certain GT1a patients with cirrhosis, who should take it for 24 weeks. Ribavirin should be co-administered in GT1a patients, and in all patients who have cirrhosis or who have received a liver transplant.

Paritaprevir was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. Paritaprevir is being investigated by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.

VIEKIRA PAK was granted priority review and designated as a Breakthrough Therapy by the U.S. FDA, a status given to medicines or regimens that may offer substantial improvement over available therapies.

Full Prescribing Information, including the Medication Guide, can be found here.

Use and Important Safety Information
USE VIEKIRA PAK™ (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) is a prescription medicine used with or without ribavirin to treat adults with genotype 1 chronic (lasting a long time) hepatitis C virus (HCV) infection, including people who have a certain type of cirrhosis (compensated).

VIEKIRA PAK is not for people with advanced cirrhosis (decompensated). If people have cirrhosis, they should talk to a healthcare provider before taking VIEKIRA PAK.

IMPORTANT SAFETY INFORMATION
When taking VIEKIRA PAK in combination with ribavirin, people should also read the Medication Guide that comes with ribavirin, especially the important pregnancy information.
What is the most important information to know about VIEKIRA PAK?VIEKIRA PAK can cause increases in liver function blood test results, especially if people use ethinyl estradiol-containing medicines (such as some birth control products).
  • Ethinyl estradiol-containing medicines (combination birth control pills or patches, such as Lo Loestrin® FE, Norinyl®, Ortho Tri-Cyclen Lo®, Ortho Evra®; hormonal vaginal rings such as NuvaRing®; and the hormone replacement therapy medicine, Fem HRT®) must be stopped before starting treatment with VIEKIRA PAK. If these medicines are used as a method of birth control, another method must be used during treatment with VIEKIRA PAK, and for about 2 weeks after treatment with VIEKIRA PAK ends. A healthcare provider can provide instruction on when to begin taking ethinyl estradiol-containing medicines.
  • A healthcare provider should do blood tests to check liver function during the first 4 weeks of treatment and then as needed.
  • A healthcare provider may tell people to stop taking VIEKIRA PAK if signs or symptoms of liver problems develop. A healthcare provider must be notified right away if any of the following symptoms develop or if they worsen during treatment with VIEKIRA PAK: tiredness, weakness, loss of appetite, nausea, vomiting, yellowing of the skin or eyes, or color changes in stools.
VIEKIRA PAK must not be taken if people:
  • have severe liver problems
  • take any of the following medicines: alfuzosin hydrochloride (Uroxatral®) - carbamazepine (Carbatrol®, Epitol®, Equetro®, Tegretol®) - efavirenz (Sustiva®, Atripla®) - ergot containing medicines including ergotamine tartrate (Cafergot®, Migergot®, Ergomar®, Ergostat®, Medihaler®, Wigraine®, Wigrettes®), dihydroergotamine mesylate (D.H.E. 45®, Migranal®), methylergonovine (Ergotrate®, Methergine®) - ethinyl estradiol-containing medicines - gemfibrozil (Lopid®) - lovastatin (Advicor®, Altoprev®, Mevacor®) - midazolam (when taken by mouth) - phenytoin (Dilantin®, Phenytek®) - phenobarbital (Luminal®) - pimozide (Orap®) - rifampin (Rifadin®, Rifamate®, Rifater®, Rimactane®) - sildenafil citrate (Revatio®) when taken for pulmonary artery hypertension (PAH) - simvastatin (Zocor®, Vytorin®, Simcor®) - St. John's wort (Hypericum perforatum) or a product that contains St. John's wort - triazolam (Halcion®).
  • have had a severe skin rash after taking ritonavir (Norvir®).
What should people tell a healthcare provider before taking VIEKIRA PAK?
  • If they have: liver problems other than HCV infection, HIV infection, or any other medical conditions.
  • If they have had a liver transplant. If they take the medicines tacrolimus (Prograf®) or cyclosporine (Gengraf®, Neoral®, Sandimmune®), a healthcare provider should check blood levels, and, if needed, may change the dose of these medicines or how often they are taken, both during and after treatment with VIEKIRA PAK.
  • If they are pregnant or plan to become pregnant or if they are breastfeeding or plan to breastfeed. It is not known if VIEKIRA PAK will harm a person's unborn baby or pass into breast milk. A healthcare provider should be consulted about the best way to feed a baby if taking VIEKIRA PAK. For pregnant females that have both HCV and HIV infection, they should talk with a healthcare provider about enrolling in the antiretroviral pregnancy registry.
  • About all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with VIEKIRA PAK.
    • A new medicine must not be started without telling a healthcare provider. A healthcare provider will provide instruction on whether it is safe to take VIEKIRA PAK with other medicines.
    • When VIEKIRA PAK is finished, a healthcare provider should be consulted on what to do if one of the usual medicines taken was stopped or if the dose changed during VIEKIRA PAK treatment.
What are the common side effects of VIEKIRA PAK?
  • For VIEKIRA PAK used with ribavirin, side effects include tiredness, nausea, itching, skin reactions such as redness or rash, sleep problems, and feeling weak.
  • For VIEKIRA PAK used without ribavirin, side effects include nausea, itching, and sleep problems.
These are not all of the possible side effects of VIEKIRA PAK. A healthcare provider should be notified if there is any side effect that is bothersome or that does not go away.
This is the most important information to know about VIEKIRA. For more information, talk with a healthcare provider.

People are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

About AbbVieAbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. AbbVie employs approximately 25,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking StatementsSome statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2013 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.


SOURCE AbbVie
For further information: Media: David Freundel, +1 (847) 937-4522, david.freundel@abbvie.com, or Morry Smulevitz, +1 (847) 937-2152, morry.smulevitz@abbvie.com, or Investor Relations: Liz Shea, +1 (847) 935-2211, liz.shea@abbvie.com

VIEKERA PAK Easy C Fact Sheet Now Available from HCSP

Be sure to check out the new Easy C Facts fact sheet on Viekira Pak from the Hepatitis C Support Project


FDA Approves $11,000 Cheaper Hepatitis C Drug

On Friday, the U.S. Food and Drug Administration (FDA) approved AbbVie’s Viekira Pak, a new hepatitis C cure, that will challenge Gilead Sciences’ more expensive cure. Both FDA and Medicaid programs hoped that the new drug would bring some real competition in hepatitis C drug market.

However, there wasn’t much improvement, since AbbVie is going to sell a 12-week kit of the new drug for $83,319. Although it is about $11,000 cheaper than Gilead’s Harvoni, Viekira Pak is still pricey.

David Lassen, a Prime Therapeutics’ spokesperson, said that the wholesale price was higher than expected. But Morry Smulevitz, Abb Vie representative, said that the price reflected both “market dynamics” and the “value it brought to the health care system.” Additionally, some patients may need only an 8-week therapy for full recovery, thus lowering the price.

Read more...

Friday, December 19, 2014

U.S. FDA approves AbbVie hepatitis C drug, costs $83,319 for 12 weeks

Dec 19 (Reuters) - An AbbVie Inc spokeswoman on Friday said that the company's newly approved hepatitis C treatment will cost $83,319 for a 12-week course, coming in a bit below the price of competing treatments from Gilead Sciences Inc.

U.S. health regulators earlier on Friday approved AbbVie's all-oral treatment for hepatitis C, providing the first competition for Gilead. (Reporting by Caroline Humer)

Read more....

UPDATE 1-U.S. FDA approves AbbVie all-oral hepatitis C treatment

(Adds no price available yet, details on hepatitis c)

Dec 19 (Reuters) - U.S. health regulators on Friday approved AbbVie's all-oral treatment for hepatitis C, providing the first competition for Gilead Sciences huge selling and expensive medicine for the liver-destroying virus.

The AbbVie regimen consists of four different anti-viral drugs to be taken as three pills in the morning and one in the evening. The U.S. Food and Drug Administration approved the regimen, which will be sold under the brand name Viekira Pak, for patients with genotype 1 form of the virus, the most common type of hepatitis C and the most difficult to treat.

Gilead's Sovaldi, which was approved a year ago, had been selling at the rate of about $3 billion per quarter due to huge pent up demand. Sovaldi is now combined with another Gilead drug and sold as Harvoni, which is taken as one pill once a day for 12 weeks at a cost of about $94,500. Some patients can take it for just eight weeks, which costs about $63,000.

Read more...

Disability & Benefits: Medicaid —Jacques Chambers, CLU

When Congress enacted Medicare in 1965, they also added Title XIX, creating Medicaid. While Medicare was enacted to provide health coverage primarily for seniors with the disabled added later, the purpose of Medicaid was to provide health coverage to lower income individuals.

However, unlike Medicare, which is essentially the same coverage throughout the nation, the federal Medicaid law set out mandatory as well as optional guidelines that each state was to follow. Further, the cost of the Medicaid was split evenly between the federal government and the states. As if that was not a big enough bureaucracy, states set the requirements for their Medicaid program, but turned it over to counties and other regional entities to actually administer.

The federal government requires at a minimum that the following services must be provided to Medicaid beneficiaries without charge provided they are “medically necessary”:
  • Inpatient and outpatient hospital services
  • Physician services
  • Medical and surgical dental services, but not dental care
  • Nursing facility services for individuals aged 21 or older
  • Home health care for people eligible for nursing facility services
  • Family planning services and supplies
  • Clinic treatment
  • Laboratory and x-ray services
  • Pediatric and family nurse practitioner services
  • Nurse-midwife services, to the extent authorized under state law; and
  • Early and periodic screening, diagnosis, and treatment services for people under age 21
States may choose to offer additional, optional benefits such as dental care, vision, and prescription drug coverage.

Many states are now providing these benefits through a Managed Care program, usually Health Maintenance Organizations (HMOs). This means that to receive the benefit, patients must receive their treatment from doctors and hospitals that are in the HMO network.

While this article outlines Medicaid provisions as much as possible, there will be many details where you will need to do a browser search for “Medicaid in (your state)” to discover exactly how your Medicaid works. Also, some states have adopted names other than Medicaid for their program, such as TennCare in Tennessee or Medi-Cal in California.

There are several groups of people who can benefit from Medicaid coverage, including pregnant women and single parent households; however, this article focuses on the Medicaid programs that can primarily benefit or affect persons with HCV.
This includes:
  • Medicaid for the Aged & Disabled
  • Medicaid for the Medically Needy
  • Medicaid for the Working Disabled
  • Medicaid in those states which expanded Medicaid under the Affordable Care Act (Obamacare) and,
  • Estate Recovery and its possible effect on your heirs
First, however, I should mention that, because many Medicaid programs are based on a person’s income, eligibility for programs is determined by relating one’s income to the Federal Poverty Level (FPL). This is an annual table that is usually published between January and March of each year. Currently, Medicaid is using the 2014 FPL. Under that table an individual is at 100% of FPL if his or her income is $11,670 per year. For each additional person in the household, $4,060 should be added. Therefore a family of four is at 100% FPL if their earnings are $23,850 (11,670 + 4,060 X 3). Tables with higher numbers are used for people living in Alaska and Hawaii.

Aged & Disabled Medicaid
This program is for low-income persons who are either age 65 or over or are under age 65 and disabled. Disability is determined under the same definition as Social Security’s definition:
  • A person has a serious and documented medical condition which prevents the person from working and earning Substantial Gainful Activity ($1,090 per month in 2015), and
  • The condition has or is expected to last for at least twelve months or result in death.
To be eligible, a person must show they are low income and have little or no personal assets. While it can vary by state, a person’s income must usually be from below 100% to 133% of FPL.

There is also an asset test (usually $2,000 for a single individual or $3,000 for a couple). Assets include money in the bank, stocks and bonds, individual retirement accounts, and real property. However, they do not count one vehicle and they do not count the home an applicant occupies. It should be noted that this amount has not changed in at least twenty years.

You can get more information on eligibility and see if you might qualify in your state, and even apply for Medicaid by going to: www.healthcare.gov/medicaid-chip/eligibility/ In many states, if you are approved for Supplemental Security Income (SSI) by Social Security, you are automatically enrolled in Medicaid. In other states, if you get SSI, you are eligible for Medicaid, but you have to apply separately.

Medically Needy Program
Thirty-six (36) states plus the District of Columbia have added Medically Needy or Spend Down Medicaid to their programs. This program provides Medicaid benefits to people whose income exceeds the Aged & Disabled Program limits, but, because their medical bills are so high, they become eligible for Medicaid.

Medically Needy Medicaid provides the same benefits as Aged & Disabled EXCEPT the benefits sit behind a monthly deductible that must be paid before Medicaid pays any benefits. A person will have to spend down their income by paying medical bills until the deductible, also called a Share of Cost, is met after which Medicaid pays the remainder of medical bills for the rest of the month.

The deductible or Share of Cost is determined by the person’s monthly, countable income. Countable income is based on the IRS definition of Modified Adjusted Gross Income (MAGI) reduced by any health, dental, or vision insurance premiums he or she pays.

250% Federal Poverty Level Working Disabled Program
Not every state offers this program, but it can be very helpful to certain Medicaid beneficiaries.
A person is determined to be disabled according to the Social Security definition of disability. However, his or her income is high enough that the Share of Cost under the Medically Needy Program is several hundred dollars that must be paid by the beneficiary each month before Medicaid pays anything. This program is an excellent alternative to the Medically Needy Program for such a beneficiary. Their total income must remain less than 250% FPL ($29,175 per year for an individual in 2014). That person is also able to do some work.

Under this program such a person would receive full Medicaid without any spend-down or Share of Cost. They would be responsible for paying a premium for the Medicaid coverage, but the premium would be based on the beneficiary’s monthly income. Premiums usually range from $20 to $200 per month.

For people living in states that offer this program, it is excellent for someone whose disability income gives them a high spend-down amount. Medicaid does not have formal requirements about the type of job. I am aware of people collecting disability benefits that walk a neighbor’s dog or water their lawn for $10 - $15 per week. That is work which gets him or her into the Working Disabled Program, but is not enough work earnings to interfere with their Social Security Disability or private disability benefits.

However, the requirements for this program are set by each state and many are not as generous as the examples I just cited. Check with your state’s Medicaid program.

Expanded Medicaid under the Affordable Care Act
Twenty-seven states plus the District of Columbia, so far, have elected to expand their Medicaid Programs as allowed under the Affordable Care Act. They are: Arizona, Arkansas, California, Colorado, Connecticut, Delaware, District of Columbia, Hawaii, Illinois, Iowa, Kentucky, Maryland, Massachusetts, Michigan, Minnesota, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Dakota, Ohio, Oregon, Pennsylvania, Rhode Island, Vermont, Washington, and West Virginia.

Some states are still considering the expansion so be sure to check with your state for the most current information.

Under Expanded Medicaid, there is no longer an asset test nor is there a requirement that you be disabled. To qualify for expanded Medicaid, you simply need to have income that is at or below 138% FPL ($16,105 for an individual in 2014).

To apply for Expanded Medicaid, start with your state’s health exchange website. If you do not know it, go to www.healthcare.gov. You will be directed to your state’s exchange or Medicaid site.

Estate Recovery
Because Medicaid was originally created for low-income people, the federal government and the states seek reimbursement, when possible, for medical bills paid. To this end, they created the Estate Recovery Program.

For individuals age 55 and older, states are now required to seek reimbursement of money paid from a person’s estate for medical services rendered including hospital and nursing home services. There are exceptions to this rule when recovery of payments would cause undue hardship. States are further encouraged to seek additional reimbursement when possible beyond the mandate.

States also have the right to place a lien on a Medicaid beneficiary’s home if they are permanently residing in a nursing home or similar facility. However, there is an exception to this when the home is still occupied by a spouse, child under age 21, blind or disabled child of any age, or sibling who has an equity interest in the home.

This potential recovery using a person’s estate after death has caused many to reconsider obtaining Medicaid, especially persons under Expanded Medicaid, since it could reduce or eliminate assets to be passed on to the beneficiary’s heirs. There is a sense of unfairness since there is no such recovery from people who qualify for regular health insurance under the Affordable Care Act. There has been some discussion about amending this requirement under Expanded Medicaid, but no action is expected in the foreseeable future.


http://hcvadvocate.org/news/newsLetter/2014/advocate1214_mid.html#4

FDA Hepatitis Update: VIEKIRA Pak

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