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What Is Harvoni?(ledipasvir/sofosbuvir)

Harvoni contains a combination of ledipasvir and sofosbuvir. Ledipasvir and sofosbuvir are antiviral medications that prevent hepatitis C virus (HCV) from multiplying in your body. Harvoni is used to treat hepatitis C genotypes 1, 4, 5, or 6. This medicine is for use in adults and children who are at least 12 years old or who weigh at least 77 pounds (35 kilograms).

This medication is a combination of two drugs in a single form. Each tablet contains ledipasvir and sofosbuvir. It’s important to know about all the drugs in the combination because each drug may affect you in a different way.

Ledipasvir/sofosbuvir, sold under the trade name Harvoni among others, is a medication used to treat hepatitis C. It is a combination of ledipasvir and sofosbuvir. Cure rates are 94% to 99% in people infected with hepatitis C virus (HCV) genotype 1.Some evidence also supports use in HCV genotype 3 and 4. It is taken daily by mouth for 8–24 weeks.

It is generally well tolerated. Common side effects include muscle pains, headache, nausea, rash, and cough. It is unclear if use in pregnancy is safe for the baby. Ledipasvir works by decreasing the activity of NS5A and sofosbuvir works by decreasing the activity of NS5B polymerase.

Ledipasvir/sofosbuvir was approved for medical use in the United States in 2014. It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.The wholesale cost in the United States is about US$91,589.40 for 12 weeks as of 2016. In Bangladesh this amount costs US$1,092.00. Some people travel to India to get access to lower cost medication.

Harvoni is sometimes given in combination with another medicine called ribavirin.

Qualitative and quantitative composition

Each film-coated tablet contains 90 mg ledipasvir and 400 mg sofosbuvir.

Excipients with known effect:

Each film-coated tablet contains 156.8 mg of lactose (as monohydrate) and 261 micrograms of sunset yellow FCF aluminium lake.

Important information

You should not use Harvoni if you are also taking sofosbuvir tablets (Sovaldi).

If you have ever had hepatitis B, Harvoni can cause this condition to come back or get worse. You will need frequent blood tests to check your liver function.

Medical Uses

This drug is used to treat chronic hepatitis C virus infection.

Cure rates are 94% to 99% in people infected with genotype 1. It has also been evaluated for the treatment of infection with other hepatitis C genotypes, and has shown promising results in genotypes 3 and 4.

It should not be used with amiodarone or other drugs that lower heart rate; there is a serious risk of the heart slowing or stopping when ledipasvir/sofosbuvir is used with such drugs.

How it works

Ledipasvir and sofosbuvir are antiviral medications. They work together to inhibit enzymes and prevent the hepatitis C virus from making copies of itself. This stops the virus from spreading and may cure your infection.

Harvoni Side Effects

Along with its needed effects, ledipasvir / sofosbuvir may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking ledipasvir / sofosbuvir:

Incidence not known

  • Chest pain or discomfort
  • lightheadedness, dizziness, or fainting
  • slow or irregular heartbeat
  • trouble breathing
  • unusual tiredness

Some side effects of ledipasvir / sofosbuvir may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

  • Cough
  • diarrhea
  • headache
  • irritability
  • lack or loss of strength
  • muscle pain
  • nausea
  • trouble sleeping

Less common

  • Discouragement
  • dizziness
  • feeling sad or empty
  • lack of appetite
  • loss of interest or pleasure
  • trouble concentrating

More Side Effects

If you experience any of these serious side effects, call your doctor right away. If your symptoms are potentially life threatening, or if you think you’re experiencing a medical emergency, call 9-1-1

  • severe slowing of your heart rate. If you take amiodarone for your heart, ledipasvir/sofosbuvir can slow down your heart rate to a very low level and be fatal. Symptoms may include:
    • fainting or feeling like you may faint
    • lightheadedness
    • a general feeling of weakness
    • tiredness
    • trouble breathing
    • chest pain
    • confusion
    • trouble with your memory

Warnings and Precautions 

Harvoni should not be administered concomitantly with other medicinal products containing sofosbuvir.

Genotype-specific activity

Concerning recommended regimens with different HCV genotypes, see section 4.2. Concerning genotype-specific virological and clinical activity, see section 5.1.

The clinical data to support the use of Harvoni in adults infected with HCV genotype 3 are limited (see section 5.1). The relative efficacy of a 12-week regimen consisting of ledipasvir/sofosbuvir + ribavirin, compared to a 24-week regimen of sofosbuvir + ribavirin has not been investigated. A conservative 24 weeks of therapy is advised in all treatment-experienced genotype 3 patients and those treatment-naïve genotype 3 patients with cirrhosis (see section 4.2). In genotype 3-infection, the use of Harvoni (always in combination with ribavirin) should only be considered for patients who are deemed at high risk for clinical disease progression and who do not have alternative treatment options.

The clinical data to support the use of Harvoni in adults infected with HCV genotype 2 and 6 are limited (see section 5.1).

Severe bradycardia and heart block

Cases of severe bradycardia and heart block have been observed when Harvoni is used with concomitant amiodarone with or without other drugs that lower heart rate. The mechanism is not established.

The concomitant use of amiodarone was limited through the clinical development of sofosbuvir plus direct-acting antivirals (DAAs). Cases are potentially life threatening, therefore amiodarone should only be used in patients on Harvoni when other alternative anti-arrhythmic treatments are not tolerated or are contraindicated.

Should concomitant use of amiodarone be considered necessary it is recommended that patients are closely monitored when initiating Harvoni. Patients who are identified as being high risk of bradyarrhythmia should be continuously monitored for 48 hours in an appropriate clinical setting.

Due to the long half-life of amiodarone, appropriate monitoring should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on Harvoni.

All patients receiving Harvoni in combination with amiodarone with or without other drugs that lower heart rate should also be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them.

Treatment of patients with prior exposure to HCV direct-acting antivirals

In patients who fail treatment with ledipasvir/sofosbuvir, selection of NS5A resistance mutations that substantially reduce the susceptibility to ledipasvir is seen in the majority of cases (see section 5.1). Limited data indicate that such NS5A mutations do not revert on long-term follow-up. There are presently no data to support the effectiveness of retreatment of patients who have failed ledipasvir/sofosbuvir with a subsequent regimen that contains an NS5A inhibitor. Similarly, there are presently no data to support the effectiveness of NS3/4A protease inhibitors in patients who previously failed prior therapy that included an NS3/4A protease inhibitor. Such patients may therefore be dependent on other drug classes for clearance of HCV infection. Consequently, consideration should be given to longer treatment for patients with uncertain subsequent retreatment options.

Renal impairment

No dose adjustment of Harvoni is required for patients with mild or moderate renal impairment. The safety of Harvoni has not been assessed in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) or end stage renal disease (ESRD) requiring haemodialysis. When Harvoni is used in combination with ribavirin refer also to the Summary of Product Characteristics for ribavirin for patients with creatinine clearance (CrCl) < 50 mL/min (see section 5.2).

Adults with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant

The efficacy of ledipasvir/sofosbuvir in genotype 5 and genotype 6 HCV-infected patients with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant has not been investigated. Treatment with Harvoni should be guided by an assessment of the potential benefits and risks for the individual patient.

Use with moderate P-gp inducers

Medicinal products that are moderate P-gp inducers in the intestine (e.g. oxcarbazepine) may decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of Harvoni. Co-administration of such medicinal products is not recommended with Harvoni (see section 4.5).

Use with certain HIV antiretroviral regimens

Harvoni has been shown to increase tenofovir exposure, especially when used together with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of Harvoni with the fixed-dose combination tablet containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at increased risk of renal dysfunction.

Patients receiving Harvoni concomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for tenofovir-associated adverse reactions. Refer to tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate Summary of Product Characteristics for recommendations on renal monitoring.

Use with HMG-CoA reductase inhibitors

Co-administration of Harvoni and HMG-CoA reductase inhibitors (statins) can significantly increase the concentration of the statin, which increases the risk of myopathy and rhabdomyolysis (see section 4.5).

HCV/HBV (hepatitis B virus) co-infection

Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines.

Paediatric population

Harvoni is not recommended for use in paediatric patients aged < 12 years because the safety and efficacy have not been established in this population.

Excipients

Harvoni contains the azo colouring agent sunset yellow FCF aluminium lake (E110), which may cause allergic reactions. It also contains lactose. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Drug warnings

People with hepatitis B virus

If you have ever had hepatitis B virus infection, the hepatitis B virus could become active again during or after treatment with Harvoni. This could cause liver damage, liver failure, or death. Your doctor will check your blood for hepatitis B virus before you start taking this drug.

People with heart conditions who take amiodarone

If you’re taking the drug amiodarone for your heart, don’t take this drug. This combination can slow down your heart rate to a low level and be fatal.

Call your doctor right away if you have these symptoms:

  • fainting or feeling like you may faint
  • lightheadedness
  • a general feeling of weakness
  • tiredness
  • trouble breathing
  • chest pain
  • confusion
  • trouble with your memory

Pregnant women

There aren’t enough studies done in pregnant women to show that the drug poses a risk to a pregnancy. Tell your doctor if you’re pregnant or plan to become pregnant. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant women and their male partners should not take the combination of Harvoni and ribavirin, a treatment sometimes used for hepatitis C, because of risk to the fetus with ribavirin.

Women who are breast-feeding

It isn’t known if this drug passes through breast milk or whether it may cause side effects in a breastfeeding child.

You and your doctor may need to decide if you’ll take this drug or breastfeed.

For children

The safety and effectiveness of this drug haven’t been established in people under the age of 18 years.

Keep this drug and all medicines out of the reach of children.

When to call the doctor

  • If your symptoms don’t get better or if they get worse, talk to your doctor.
  • Talk to your doctor before starting any new drug, including prescription drugs, OTC products, vitamins, supplements, or other natural products while you’re taking this drug.

Allergies

This drug can cause a severe allergic reaction. Symptoms may include:

  • trouble breathing
  • swelling of your throat or tongue
  • hives

Don’t take this drug again if you’ve ever had an allergic reaction to it. Taking it again could be fatal.

Interaction

Ledipasvir-Sofosbuvir May Interact with Other Medications

Oral Tablet

Ledipasvir/sofosbuvir can interact with other medications, herbs, or vitamins you might be taking. That’s why your doctor should manage all of your medications carefully. If you’re curious about how this drug might interact with something else you’re taking, talk to your doctor or pharmacist.

Note: You can reduce your chances of drug interactions by having all of your prescriptions filled at the same pharmacy. That way, a pharmacist can check for possible drug interactions.

Medications That Might Interact with This Drug

Stomach acid reducing drugs

Examples are:

  • antacids
  • famotidine
  • cimetidine
  • omeprazole

These drugs can make ledipasvir/sofosbuvir less effective.

Your doctor may recommend that you take ledipasvir/sofosbuvir and these drugs at different times of the day.

Heart medications

  • amiodarone. You shouldn’t take this drug with ledipasvir/sofosbuvir. The combination can slow down your heart rate to dangerously low levels. This can be fatal.
  • digoxin. Ledipasvir/sofosbuvir can increase levels of digoxin in your body. This may cause serious side effects. Your doctor will monitor how much digoxin is in your body if you take these drugs together.

Anti-seizure medications

Examples are:

  • phenytoin
  • carbamazepine
  • phenobarbital
  • oxcarbazepine

These drugs can make ledipasvir/sofosbuvir less effective. Don’t combine ledipasvir/sofosbuvir with any of these drugs.

Tuberculosis drugs

Examples are:

  • rifabutin
  • rifampin
  • rifapentine

These drugs can make ledipasvir/sofosbuvir less effective. They shouldn’t be taken together.

Human immunodeficiency virus (HIV) medications

Examples are:

  • tenofovir or combination drugs that contain tenofovir

Ledipasvir/sofosbuvir can affect the levels of some HIV drugs. This may increase the side effects of those medications.

Hepatitis C virus drug

  • simeprevir

You shouldn’t take this drug with ledipasvir/sofosbuvir. It can increase the level of ledipasvir in your body.

Herbal supplement

  • St. John’s wort

Don’t take this supplement while taking ledipasvir/sofosbuvir. It can decrease the effectiveness of ledipasvir/sofosbuvir.

As Harvoni contains ledipasvir and sofosbuvir, any interactions that have been identified with these active substances individually may occur with Harvoni.

Potential for Harvoni to affect other medicinal products

Ledipasvir is an in vitro inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of co-administered substrates for these transporters. In vitro data indicate that ledipasvir may be a weak inducer of metabolising enzymes such as CYP3A4, CYP2C and UGT1A1.

Compounds that are substrates of these enzymes may have decreased plasma concentrations when co-administered with ledipasvir/sofosbuvir. In vitro ledipasvir inhibits intestinal CYP3A4 and UGT1A1. Medicinal products that have a narrow therapeutic range and which are metabolised by these isoenzymes should be used with caution and carefully monitored.

Potential for other medicinal products to affect Harvoni

Ledipasvir and sofosbuvir are substrates of drug transporter P-gp and BCRP while GS-331007 is not.

Medicinal products that are potent P-gp inducers (rifampicin, rifabutin, St. John’s wort, carbamazepine, phenobarbital and phenytoin) may significantly decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of ledipasvir/sofosbuvir and thus are contraindicated with Harvoni (see section 4.3). Medicinal products that are moderate P-gp inducers in the intestine (e.g. oxcarbazepine) may decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of Harvoni.

Co-administration with such medicinal products is not recommended with Harvoni (see section 4.4). Co-administration with medicinal products that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; Harvoni may be co-administered with P-gp and/or BCRP inhibitors. Clinically significant medicinal product interactions with ledipasvir/sofosbuvir mediated by CYP450s or UGT1A1 enzymes are not expected.

Patients treated with vitamin K antagonists

As liver function may change during treatment with Harvoni, a close monitoring of International Normalised Ratio (INR) values is recommended.

Interactions between Harvoni and other medicinal products

Table 5 provides a listing of established or potentially clinically significant medicinal product interactions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratio were within “↔”, extended above “↑”, or extended below “↓” the predetermined equivalence boundaries). The medicinal product interactions described are based on studies conducted with either ledipasvir/sofosbuvir or ledipasvir and sofosbuvir as individual agents, or are predicted medicinal product interactions that may occur with ledipasvir/sofosbuvir. The table is not all-inclusive.

Treatment

HARVONI gives you what you need

HARVONI transformed Hep C treatment as the first cure that’s one pill, once a day for the majority of patients.

Cure means the Hep C virus is not detected in the blood when measured 3 months after treatment is completed.

For specific patients, such as those who have had a liver transplant or are experiencing advanced cirrhosis,* it is recommended that ribavirin be added to their HARVONI regimen. If you take HARVONI with ribavirin, you should also read the ribavirin Medication Guide for important pregnancy-related information. Your Hep C Specialist will determine the regimen that’s right for you.

Length of treatment with HARVONI

Most patient types are recommended to receive 12 weeks of treatment, although 8 or 24 weeks may also be prescribed. Your Hep C Specialist will determine your treatment regimen and length based on your individual case.

Genotype 1 Adults Without Cirrhosis (GT1)

This information does not apply to patients with advanced cirrhosis (decompensated) or those who have had a liver transplant. Please see “Advanced Cirrhosis/Liver Transplant” tab for HARVONI treatment recommendations for these patients.

*HARVONI plus ribavirin for 12 weeks can be considered in previously treated genotype 1 patients with compensated cirrhosis who are eligible for ribavirin. If you take HARVONI with ribavirin, you should also read the ribavirin Medication Guide for important pregnancy-related information.

Adults With Genotype 4,5, or 6 With or Without Compensated Cirrhosis  (GT 4,5,or 6)

This information does not apply to patients with advanced cirrhosis (decompensated)* or those who have had a liver transplant. Please see “Advanced Cirrhosis/Liver Transplant” tab for HARVONI treatment recommendations for these patients.

Hep C & HIV-1

For patients with both Hep C and HIV-1, the recommended HARVONI treatment regimen and length is the same as that for someone without HIV-1. Please refer to the charts on tabs 1 and 2 for treatment information for your specific genotype.

It is important to talk with your healthcare provider about your HIV antiretroviral medicine(s) to understand potential interactions with HARVONI.

Advanced Cirrhosis or Liver Transplant

For patients with advanced cirrhosis (decompensated)* and Hep C genotype 1,HARVONI plus ribavirin provides an all-oral treatment option with just 12 weeks of therapy.

For patients who have had a liver transplant, don’t have advanced cirrhosis, and have Hep C genotype 1 or 4, HARVONI plus ribavirin provides an all-oral treatment option with just 12 weeks of therapy.

It’s important to talk to your Hep C Specialist about your individual situation to find out if this treatment regimen is right for you.

If you take HARVONI with ribavirin, you should also read the ribavirin Medication Guide for important pregnancy-related information.

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