FDA approved changes to the Olysio (simeprevir) package insert to include two new Warnings and Precautions

FDA approved changes to the Olysio (simeprevir) package insert to include two new Warnings and Precautions;

1. serious symptomatic bradycardia when co-administered with sofosbuvir and amiodarone
2. hepatic decompensation and hepatic failure.

Additional changes to the Indication and Usage, Dosage and Administration, Adverse Reactions, Drug Interactions, Use in Specific Populations and Pharmacokinetic sections of the label were made based on these Warnings and Precautions and are summarized below.

Summary of new WARNINGS AND PRECAUTIONS

5              WARNINGS AND PRECAUTIONS

5.1          Serious Symptomatic Bradycardia When Co-administered with Sofosbuvir and Amiodarone

Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is co administered with sofosbuvir in combination with another HCV direct acting antiviral, including OLYSIO. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with co administration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this bradycardia effect is unknown.

Co administration of amiodarone with OLYSIO in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative treatment options, and who will be co administered OLYSIO and sofosbuvir:

• Counsel patients about the risk of serious symptomatic bradycardia
• Cardiac monitoring in an in-patient setting for the first 48 hours of co administration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

Patients who are taking sofosbuvir in combination with OLYSIO who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above.

Due to amiodarone’s long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with OLYSIO should also undergo similar cardiac monitoring as outlined above.

Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems [see Adverse Reactions (6.2) and Drug Interactions (7.3)].

5.2          Hepatic Decompensation and Hepatic Failure

Hepatic decompensation and hepatic failure, including fatal cases, have been reported postmarketing in patients treated with OLYSIO in combination with peginterferon alfa and ribavirin or in combination with sofosbuvir. Most cases were reported in patients with advanced and/or decompensated cirrhosis who are at increased risk for hepatic decompensation or hepatic failure. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between treatment with OLYSIO and these events has not been established [see Adverse Reactions (6.2)].

OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Dosage and Administration (2.5) and Use in Specific Populations (8.8)].

In clinical trials of OLYSIO, modest increases in bilirubin levels were observed without impacting hepatic function [see Adverse Reactions (6.1)]. Postmarketing cases of hepatic decompensation with markedly elevated bilirubin levels have been reported. Monitor liver chemistry tests before and as clinically indicated during OLYSIO combination therapy. Patients who experience an increase in total bilirubin to greater than 2.5 times the upper limit of normal should be closely monitored:

• Patients should be instructed to contact their healthcare provider if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces.
• Discontinue OLYSIO if elevation in bilirubin is accompanied by liver transaminase increases or clinical signs and symptoms of hepatic decompensation.

Additional Changes

The Indications and Usage section was updated to state:

Limitations of Use:

• OLYSIO is not recommended in patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Adverse Reactions (6.1, 6.2), Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)].

The Dosage and Administration section was updated as follows:

2              DOSAGE AND ADMINISTRATION

2.1          OLYSIO Combination Treatment

Administer OLYSIO in combination with other antiviral drugs for the treatment of CHC infection. Monitor liver chemistry tests before and during OLYSIO combination therapy [see Warnings and Precautions (5.2)]. OLYSIO monotherapy is not recommended. For specific dosing recommendations for the antiviral drugs used in combination with OLYSIO, refer to their respective prescribing information.

2.5          Hepatic Impairment

OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Use in Specific Populations (8.8)]. There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO combination therapy [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Clinical Pharmacology (12.3)].

In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity [see Adverse Reactions (6.1)].

OLYSIO in combination with Peg IFN alfa and RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment) [see Peg IFN alfa prescribing information].

The Adverse Reactions section was updated as follows:

6              ADVERSE REACTIONS

Laboratory abnormalities

Elevations in bilirubin were predominately mild to moderate (Grade 1 or 2) in severity, and included elevation of both direct and indirect bilirubin. Elevations in bilirubin occurred early after treatment initiation, peaking by study Week 2, and were rapidly reversible upon cessation of OLYSIO. Bilirubin elevations were generally not associated with elevations in liver transaminases. The frequency of elevated bilirubin was higher in subjects with higher simeprevir exposures.

6.2          Postmarketing Experience

The following adverse reactions have been reported during post approval use of OLYSIO. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship between drug exposure and these adverse reactions.

Cardiac Disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with sofosbuvir in combination with another HCV direct acting antiviral, including OLYSIO [see Warnings and Precautions (5.1) and Drug Interactions (7.3)].

Hepatobiliary Ddisorders: hepatic decompensation, hepatic failure [see Warnings and Precautions (5.2)].

Section 7 Drug Interactions was updated to include revisions to the antiarrhythmic section.

Table 6:                Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class Drug Name	Effect on Concentration of Simeprevir or Concomitant Drug	Clinical Comment
Antiarrhythmics
Amiodarone	Effect on amiodarone, simeprevir, and sofosbuvir concentrations unknown	Co‑administration of amiodarone with OLYSIO in combination with sofosbuvir is not recommended because it may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. If co‑administration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.1), Adverse Reactions (6.2)].
	­ amiodarone	Caution is warranted and therapeutic drug monitoring of amiodarone, if available, is recommended for concomitant use of amiodarone with an OLYSIO-containing regimen that does not contain sofosbuvir. Concomitant use of OLYSIO with amiodarone when given orally may result in mild increases in amiodarone concentrations due to intestinal CYP3A4 inhibition by simeprevir.

Section 8 Use in Specific Populations was updated as follows:

8              USE IN SPECIFIC POPULATIONS

8.8          Hepatic Impairment

No dose adjustment of OLYSIO is required in patients with mild hepatic impairment (Child Pugh Class A) [see Clinical Pharmacology (12.3)].

The safety and efficacy of OLYSIO have not been established in HCV infected patients with moderate or severe hepatic impairment (Child Pugh Class B or C).

OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Dosage and Administration (2.5)]. There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO combination therapy [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Clinical Pharmacology (12.3)]. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity [see Adverse Reactions (6.1)].

Refer to the prescribing information for the antiviral drug(s) used in combination with OLYSIO regarding their use in patients with hepatic impairment. The combination of OLYSIO with Peg IFN alfa and RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment).

Section 12.3 Pharmacokinetics included the following updates:

12.3        Pharmacokinetics

Specific Populations

Hepatic Impairment

Simeprevir is primarily metabolized by the liver. Compared to HCV uninfected subjects with normal hepatic function, the mean steady state AUC of simeprevir was 2.4 fold higher in HCV uninfected subjects with moderate hepatic impairment (Child Pugh Class B) and 5.2 fold higher in HCV uninfected subjects with severe hepatic impairment (Child Pugh Class C).

No dose adjustment of OLYSIO is necessary in patients with mild hepatic impairment (Child Pugh Class A).

The safety and efficacy of OLYSIO have not been established in HCV infected patients with moderate or severe hepatic impairment (Child Pugh Class B or C).

OLYSIO is not recommended for use in patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Dosage and Administration (2.5), Warnings and Precautions (5.2) and Use in Specific Populations (8.8)].

In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity [see Adverse Reactions (6.1)].

Based on a population pharmacokinetic analysis of HCV infected subjects with mild hepatic impairment (Child-Pugh Class A) treated with OLYSIO, liver fibrosis stage did not have a clinically relevant effect on the pharmacokinetics of simeprevir.

Refer to the prescribing information for the antiviral drugs used in combination with OLYSIO regarding their use in patients with hepatic impairment.

Drug Interactions

[See also Warnings and Precautions (5.67) and Drug Interactions (7)]

In vitro studies indicated that simeprevir is a substrate and mild inhibitor of CYP3A. Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo. Simeprevir does not induce CYP1A2 or CYP3A4 in vitro. In vivo, simeprevir mildly inhibits the CYP1A2 activity and intestinal CYP3A4 activity, while it does not affect hepatic CYP3A4 activity. Simeprevir is not a clinically relevant inhibitor of cathepsin A enzyme activity.

In vitro, simeprevir is a substrate for P gp, MRP2, BCRP, OATP1B1/3 and OATP2B1; simeprevir inhibits the uptake transporters OATP1B1/3 and NTCP and the efflux transporters P gp/MDR1, MRP2 and BSEP. The inhibitory effects of simeprevir on the bilirubin transporters OATP1B1/3 and MRP2 likely contribute to clinical observations of elevated bilirubin [see Adverse Reactions (6.1)].

The updated product label will be available soon at DailyMed or at Drugs@FDA.

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration

Why You Should Care About Hep C

Hepatitis C may not be on your radar as a drug plan sponsor. But with the benefits—and costs—of new therapies, it will be.

Globally, there are 200 million people infected with hepatitis C.

There’s a high burden of illness in developing countries such as Africa due to “medical misadventure” such as using unsterilized needles, explained Dr. Jordan Feld, hepatologist, assistant professor, Toronto Western Hospital Liver Clinic, at a recent AbbVie Canada event on drug plan sustainability.

Read More...

Symptoms and Treatment of Hepatitis C

Hepatitis C is a disease affecting 170 million people worldwide!  Hepatitis C is an infection caused by the Hepatitis C virus. Celebrities from Pamela Anderson to Naomi Judd and Steven Tyler have announced they have been affected by this virus.

How do you get Hep C?  Using intravenous drugs is a major risk factor.  So is having a blood transfusion or organ transplant before 1992. Healthcare workers getting stuck with a needle also can get this infection.  Tattooing is associated with increased risk of hepatitis C. Sharing personal items like razors, toothbrushes, or nail clippers can lead to Hepatitis C.

Most people infected with the virus become chronically infected. Most people infected have no symptoms. Fatigue can be present in some patients.

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AbbVie's Investigational Chronic Hepatitis C Treatment Granted Priority Review in Japan

- AbbVie's investigational, interferon and ribavirin-free treatment in Japan consists of a 12-week, two direct-acting antiviral, fixed-dosed combination of paritaprevir/ritonavir with ombitasvir, dosed once daily

 - New Drug Application, based on the Phase 3 GIFT-I study results in Japanese patients with genotype 1b hepatitis C virus (HCV) infection, was submitted in February 2015

 - GIFT-I met its primary endpoint, achieving 95 percent sustained virologic response rate at 12 weeks post-treatment (SVR12); two patients (0.9 percent) discontinued treatment due to adverse events

 - Approximately 1.5 to 2 million people are living with hepatitis C in Japan(1); genotype 1 is most common, accounting for 60 to 70 percent of all patients infected with HCV(2)

NORTH CHICAGO, Ill., April 15, 2015 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has granted priority review for its investigational, two direct-acting antiviral treatment of ombitasvir/paritaprevir/ritonavir. This all-oral treatment is interferon (IFN) and ribavirin (RBV)-free and will be dosed once daily. The MHLW grants priority review to certain medicines on the basis of clinical usefulness and severity of the disease, including diseases like hepatitis C, which affects approximately 1.5 to 2 million people in Japan.¹ AbbVie's investigational hepatitis C treatment was submitted for marketing approval in Japan in February 2015. The New Drug Application is for the treatment of patients with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection and is supported by the Phase 3 GIFT-I study in Japanese genotype 1b (GT1b) HCV patients.

"AbbVie is pleased that the Japanese MHLW has granted priority review for our interferon and ribavirin-free, 12-week, two direct-acting antiviral treatment regimen. This marks another important advancement in our HCV clinical development program as we aim to provide our HCV treatment to patients across the world," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "If approved, AbbVie's HCV treatment holds the potential to be a promising new treatment option for patients living with this chronic infection in Japan."

AbbVie studied a two direct-acting antiviral treatment regimen without RBV in Japan due to patient and viral characteristics specific to the Japanese population, including high prevalence of GT1b. In Japan, GT1 is the most common HCV genotype and accounts for 60 to 70 percent of all patients infected with HCV.² Of those patients, about 95 percent are infected with the GT1b sub-type.²
Additional information about AbbVie's GIFT-I study can be found on www.clinicaltrials.gov.

About AbbVie's Investigational Two Direct-Acting Antiviral HCV TreatmentFor the treatment of genotype 1 chronic hepatitis C virus (HCV) infection in Japan, AbbVie's investigational, two direct-acting antiviral treatment consists of the fixed-dosed combination of paritaprevir/ritonavir (150/100 mg) with ombitasvir (25 mg), dosed once daily.

AbbVie's chronic HCV treatment combines two direct-acting antivirals, each with a distinct mechanism of action that targets and inhibits specific HCV proteins of the viral replication process.

About AbbVie's HCV Clinical Development Program in Japan AbbVie's HCV clinical development program in Japan focuses on its investigational, two direct-acting antiviral treatment and is designed to achieve high SVR rates in chronic HCV infected patients, including additional genotypes and patients with compensated cirrhosis.

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 has been developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.

Ombitasvir/paritaprevir/ritonavir is an investigational product and its safety and efficacy have not been established in Japan.

SOURCE:  AbbVie 

Hepatitis C in Japan

Be sure to check out this new fact sheet in our "Hepatitis C Around the World" series:

Hepatitis C in Japan

Click here to download

Snapshots —Alan Franciscus, Editor-in-Chief

Article:  Improvement of health-related quality of life and work productivity in chronic hepatitis C patients with early and advanced fibrosis treated with ledipasvir and sofosbuvir—ZM Younossi
  Source: J Hepatol.2015 Mar 17. pii: S0168-8278(15)00192-0. doi: 10.1016/j.jhep.2015.03.014. [Epub ahead of print]

The main goal of HCV treatment is viral eradication or being cured of hepatitis C. However, there are equally important reasons and objectives besides being cured—better overall mental and physical functioning and being able to increase work productivity (and being able to increase income). 

The aim of the current study was to examine what being cured of hepatitis C with sofosbuvir plus ledipasvir with or without ribavirin means with respect to improving health-related quality of life—mainly physical functioning and work productivity.  There were 1,005 patients in the current study that were drawn for the ION-1,2,3 clinical trials.  The patient’s fibrosis stage was determined pretreatment based on the Metavir fibrosis staging system:

• F0: 94 patients (pts);
• F1: 311 pts;
• F2: 301 pts ;
• F3: 197 pts;
• F4:102 pts

Four questionnaires [Chronic Liver Disease Questionnaire-HCV (CLDQ-HCV), Short Form-36 (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Work Productivity and Activity Index: Specific Health Problem (WPAI:SHP)] were administered at baseline, during, and after treatment.

The Bottom Line:  It is not surprising that patients with the most advanced fibrosis (F4) had the most impairment in health-related quality of life with respect to physical functioning compared to those who were stage F0. 

This continued during and post-treatment.  After being cured there was a significant improvement from baseline in most areas of health-related quality of life regardless of the level of fibrosis stage. 

After analysis, not surprisingly, advanced fibrosis was associated with impairment of health-related quality of life and work productivity. However, it was noted that health-related quality of life and work productivity after being cured was not related to the stage of fibrosis.

Editorial Comment: This is an important study because it proved that curing people of hepatitis C improved physical well-being and work productivity.  I am eager to see more of these types of studies because we all need more information about every aspect of being cured of hepatitis C—this helps people living with hepatitis C to make the treatment decision and it will further justify the expense and need to treat people with hepatitis C.

Abstract: Chronic hepatitis C virus infection and lymphoproliferative disorders: Mixed cryoglobulinemia syndrome, monoclonal gammopathy of undetermined significance, and B-cell non-Hodgkin lymphoma—GP Caviglia
  Source: J Gastroenterol Hepatol.2015 Apr;30(4):742-7. doi: 10.1111/jgh.12837.

The researchers reviewed a study of 1,313 HCV patients who had enrolled in previous studies from January 2006 and December 2013.  There was a total of 121 people with HCV and lymphoproliferative disorders (LPDs) and 130 without LPDs.  The two groups were evenly divided between age and gender.  In the groups with LPDs—25 had mixed cryoglobulinemia (MCS)*; 55 had monoclonal gammopathy of undetermined significance (MGUS)**; 41 had B-cell non-Hodgkin Lymphoma (B-HNL)***.  The patients with LPDs did not differ in age, severity of disease, HCV genotype, and response HCV therapy. 

The Bottom Line:  After analyzing the data, it was found that there was an association between MGUS and B-NHL and cirrhosis, but there was no association between MCS and cirrhosis. 

Editorial Comment:  It is interesting that there was a correlation between MGUS and cirrhosis.  However, both conditions typically take many years before serious disease progression occurs.  In regards to MCS it can occur earlier in the course of HCV infection.  Still, it is important that people living with hepatitis C understand this information and talk with their medical providers to be tested for these conditions and for medical providers to make sure they are tested.  If someone infected with hepatitis C does have these serious conditions they may be more likely to qualify for treatment.  It would be, however, best medical and patient practice to nip these and HCV in the bud by treating and curing hepatitis early before any disease or associated condition has a chance to occur. 

*Mixed cryoglobulinemia (MCS) is one of the most common disorders associated with hepatitis C.  Cryoglobulinemia (cryo for short) is a blood disorder caused by abnormal proteins in the blood called cryoglobulins that precipitate or clump together when blood is chilled and then dissolve when warmed.  Cryo can lead to many other disorders. 

**Monoclonal gammopathy of undetermined significance (MGUS) are abnormal proteins in the blood.   They can be associated with another disease (such as hepatitis C).  They rarely cause disease, but in some people with certain conditions, such as hepatitis C, MGUS’s can progress to other diseases. 

***B-cell non-Hodgkin Lymphomas (B-HNL) are cancers of the lymphoid tissues.  The cancers are typically uncommon and usually occur after many years of infection with hepatitis C. 

More detailed information can be found on our fact sheet page.

http://hcvadvocate.org/news/newsLetter/2015/advocate0415_mid.html#1

Warning: Pegasys plus Ribavirin Pediatric Use

Pegasys (peginterferon alfa-2a)

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
March 2015

WARNINGS AND PRECAUTIONS

Impact on Growth in Pediatric Patients

• During combination therapy for up to 48 weeks with PEGASYS plus ribavirin growth inhibition was observed in pediatric subjects 5 to 17 years of age. Decreases in weight for age z-score and height for age z-score up to 48 weeks of therapy compared with baseline were observed. At 2 years post-treatment, 16% of pediatric subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve.
• The available longer term data on subjects who were followed up to 6 years post-treatment is too limited to determine the risk of reduced adult height in some patients [see Clinical Trials Experience (6.1)].

Read more...