An Overview of the Liver

The liver is the largest internal organ. It is reddish-brown, weighs approximately three pounds (in the adult male) and is about the size of a football. It is located behind the ribcage on the upper right side of the abdomen. The liver has the unique ability to regenerate its own tissue—as much as three-quarters of the liver can be lost, and the organ can grow back or expand to its original size within several weeks. This allows people who need transplants to receive part of a living or deceased donor's liver.

Download

Updates: Herbal Supplement Crackdown—GNC Reforms, by Alan Franciscus, Editor-in-Chief

In the February 2015 Mid-Monthly Advocate issue, I wrote about the New York State Attorney General’s Office crackdown on four major chains (GNC, Target, Walmart, and Walgreens).  The stores were selling herbal supplements that contained very little of the stated ingredients listed on the labels and that included contaminants.  The testing occurred in the brand named stores throughout New York State.  

Good news—GNC Holding announced that it had restocked some of the herbal supplements to their stores in New York after they reached an agreement with the New York Attorney General and complied and corrected the problems.  Furthermore, GNC agreed that they would adopt testing standards in the 6,000 stores nationwide that would exceed requirements that the Food and Drug Administration requires—this is a first for a major herbal supplement chain in the United States. 
Additionally, GNC committed to the following best practices: 

• Authentication: Within 18 months GNC will implement DNA barcoding to confirm the plant's authenticity.
• Broad Testing for Contaminants:  GNC will test for the eight most common allergens before and after production.
• Consumer transparency:  GNC will prominently display signs in their stores and on their website with relevant information about the herbs and supplements including extracts, chemicals, and solvents used and explain the different processes.  GNC will list all ingredients on its product labels, per existing FDA rules.
• Reporting:  GNC will provide semiannual reports to the Attorney General’s Office, detailing the above information.

In related news, 13 state attorneys have asked the U.S. Congress to investigate the herbal supplement industry based on the NY General’s Office investigation.  The state attorneys are considering giving the Food and Drug Administration (FDA) more oversight over herbal supplements.   However, it has been previously reported that the FDA is considerably underfunded already.  The question of undertaking a massive job of regulating herbal supplements would need a large funding package attached to any herbal regulation bill.   

Comment:  Regarding GNC—this is excellent progress.  However, where are the agreements with Target, Walmart, and Walgreens? Hopefully, the other stores will soon agree to the same terms as GNC.  If you want to know the potential harm of these herbs, check out the original article—it will make you think twice before buying any herbs or supplements unless there is some type of comprehensive oversight.  

Source: http://www.ag.ny.gov/press-release/ag-schneiderman-announces-agreement-gnc-implement-landmark-reforms-herbal-supplements

http://hcvadvocate.org/news/newsLetter/2015/advocate0415_mid.html#3

Covered California weighs plan to reduce financial burden of expensive drugs for people with serious illnesses

Covered California, the state’s Obamacare health insurance exchange, could alter the way consumers pay for extremely expensive specialty drugs, but patient advocates say that medications for conditions such as rheumatoid arthritis and hepatitis C will still cost too much.

The exchange’s board of directors, which meets today, is scheduled to consider a proposal that would set a maximum monthly co-insurance cost of $200 to $500 per prescription.

Currently, consumers pay 10 percent to 30 percent of the drug costs, which can run into thousands of dollars and cause them to quickly reach their plan’s maximum annual out-of-pocket spending limits, which range from $2,250 to $6,250.

Read more...

Resurgence of hepatitis C in Mass.

The opioid epidemic that is killing hundreds of intravenous drug users who overdosed this year in the state has resulted in a Hepatitis C epidemic, according to state health officials.

Most of those drug users, they note, are people younger than 30 who probably used contaminated syringes.

Read more...

The Five: Coffee —Alan Franciscus, Editor-in-Chief

For some people that morning cup of Joe is the perfect way to start the day.   Surprisingly, there are many published studies that show that caffeinated coffee can improve the health of the liver and provide other health benefits.  There are some caveats to these health claims that I will discuss at the end of this article.  First let’s talk about the good news—the possible health benefits:

1. Liver Fibrosis / HCV Disease Progression: 
In a review of 177 patients—121 patients with HCV who drank about 2 ¼ cups of coffee a day were found to have reduced levels of liver fibrosis.  The results were only found in those who drank caffeinated coffee.  

In another review, 766 participants in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial found more good news.  Those who had hepatitis C-related bridging fibrosis or cirrhosis on a liver biopsy and who failed to achieve a cure after being treated with pegylated interferon and ribavirin therapy also yielded some surprising results.  Those with advanced liver disease who regularly consumed coffee were found to have lower rates of HCV disease progression.

2. Liver Cancer:
A small study found that people who drank one to three cups of coffee a day had a 29% lower risk of developing liver cancer compared to those who drank 6 cups or less a week. 

Another study which reviewed 16 different studies involving over 3,200 patients found that drinking more than 3 cups of coffee a day might cut the risk of liver cancer by up to 50%. 

3. Other Conditions: 
There are many studies that show a link between the reduction or prevention of certain types of cancers and drinking caffeinated coffee (skin, breast, colon, prostate, uterine, oral).  There are also studies that show that caffeinated coffee can lower the risk of diabetes and death. 

4. The Downside:
Now, I am going to burst the bubble!  Coffee, specifically caffeine, is a drug (a stimulant).  Moreover, with any drug you can have withdrawal: It can take more than eight weeks to withdraw entirely from caffeine—although, caffeine withdrawal is usually just an annoying headache and some light fatigue. 

Drinking or consuming caffeine can raise blood pressure, lead to heart arrhythmia (irregular heartbeats), can cause cramps, diarrhea and other gastrointestinal health issues.  If you drink it too close to bedtime, it can cause insomnia.  Too much caffeine can cause depression, anxiety and other types of nervous behaviors.    Although rare there have been serious health consequences from people drinking energy drinks and shots. 

Examples of the typical amount of caffeine:*

• Coffee – 100 mg per cup
• Tea – 14 mg to 60 mg per cup
• Chocolate – 45 mg in 1.5 oz bar
• Most colas (unless they are labeled “caffeine-free”) – 45 mg in 12 oz. drink
• Candies, energy drinks, snacks, gum – 40-100 mg per serving

*http://www.nlm.nih.gov/medlineplus/ ency/article/002445.htm

There are many other side effects of caffeine, but I will stop here.  However, for most people caffeine in moderation is safe and well-tolerated!

5. Final Thoughts: 
What does all of this mean?   It is hard to draw concrete conclusions from these studies because you cannot measure what people drink, how it is made and what chemicals are in the coffee.  However, there must be something in caffeinated coffee that is contributing to all of these positive outcomes.  There are over 1,000 natural chemicals in coffee, and some of these chemicals may be contributing to the caffeine and providing these benefits.  Scientists are studying the various chemicals, and we may soon have more concrete information that may lead the way to more potent medications to treat many conditions.  In the meantime, it could not hurt to have a cup of Joe—that is if your health allows it. 

http://hcvadvocate.org/news/newsLetter/2015/advocate0415_mid.html#2

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...