Harvoni

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

WARNING

• There is an increased risk of low heart rate (bradycardia) when Harvoni is combined with amiodarone (Cordarone).
• Harvoni should not be combined with Sovaldi (sofosbuvir) or other drugs containing sofosbuvir.

• Hep C: Preparing for Treatment Success
• What Hep C Treatment Looks Like
• How to Treat Cold Sores

• 13 Best Quit-Smoking Tips Ever
• What Stress Does to Your Mouth
• Healthy Home: To Buy or Not to Buy Organic?

• Frequent Constipation?
• Greater Food Accessibility

• Gilead Sciences, Inc.

Before taking Harvoni, tell your healthcare provider if you:

• have liver problems other than hepatitis C infection
• if you have a history of hepatitis B infection
• have severe kidney problems or you are on dialysis
• have any other medical condition
• are pregnant or plan to become pregnant. It is not known if Harvoni will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if Harvoni passes into your breast milk.

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Harvoni may affect the way other medicines work, and other medicines may affect how Harvoni works.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

If you also take a heart medication called amiodarone, call your doctor at once if you have:

• extreme tiredness;

• unusual weakness, general ill feeling;

• confusion or memory problems;

• a light-headed feeling, like you might pass out;

• slowed breathing, feeling short of breath; or

• chest pain, slow heartbeats, weak pulse.

Common side effects may include:

• weakness;

• headache; or

• tired feeling.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Chronic HCV Infection

Treatment of chronic HCV genotype 1, 4, 5, or 6 infection in treatment-naive (previously untreated) or previously treated adults, including those with cirrhosis (compensated or decompensated), liver transplant recipients, and those with HIV coinfection.1 2 3 4 9 10 119

Used alone or in conjunction with ribavirin, depending on HCV genotype and certain patient factors (e.g., presence of compensated or decompensated cirrhosis, liver transplantation).1 2 3 4 9 10 119

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at .119

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• If ledipasvir/sofosbuvir used in conjunction with ribavirin, the contraindications to ribavirin also apply.1 (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Rash, sometimes with blisters or angioedema-like swelling, reported during postmarketing experience.1

Cardiovascular Effects

Postmarketing reports of symptomatic bradycardia, including cases requiring pacemaker intervention, in patients receiving amiodarone concomitantly with ledipasvir/sofosbuvir.1 23 Fatal cardiac arrest reported in one patient.1

In most reported cases, bradycardia occurred within hours to days after HCV treatment initiated in patients receiving amiodarone (also has been observed up to 2 weeks after initiation of HCV treatment) and resolved after HCV treatment discontinued.1 Mechanism for this adverse cardiovascular effect unknown.1

Patients who may be at increased risk for symptomatic bradycardia if amiodarone used concomitantly with ledipasvir/sofosbuvir include those also receiving a β-adrenergic blocking agent, those with underlying cardiac comorbidities, and/or those with advanced liver disease.1

Concomitant use of amiodarone with ledipasvir/sofosbuvir not recommended.1

If there are no alternative HCV treatment options and regimen of ledipasvir/sofosbuvir must be used in a patient receiving amiodarone, advise patient about the risk of serious bradycardia before initiating HCV treatment.1 Perform cardiac monitoring in an inpatient setting during first 48 hours of concomitant use of amiodarone and ledipasvir/sofosbuvir;1 heart rate monitoring should then be performed daily (outpatient or self-monitoring) through at least the first 2 weeks of concomitant use.1 Similar cardiac monitoring recommended in patients who discontinued amiodarone just prior to initiation of ledipasvir/sofosbuvir or if there are no other treatment options and amiodarone must be initiated in a patient already receiving ledipasvir/sofosbuvir.1

Advise patients receiving amiodarone concomitantly with ledipasvir/sofosbuvir to immediately contact a clinician if signs or symptoms of bradycardia (e.g., near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems) develop.1

Interactions

Concomitant use of ledipasvir/sofosbuvir and inducers of the P-glycoprotein (P-gp) transport system (e.g., rifampin, St. John's wort) not recommended.1 (See Interactions.)

Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens

Consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination.1 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both ledipasvir and sofosbuvir.1

Do not use ledipasvir/sofosbuvir concomitantly with any other preparation containing sofosbuvir.1

When used in conjunction with ribavirin, consider that ribavirin may cause fetal toxicity and/or death.349 377 Extreme care must be taken to avoid pregnancy in female patients and female partners of male patients receiving a ribavirin-containing regimen.349 377 Obtain a negative pregnancy test for female patients of childbearing potential immediately prior to initiating ribavirin;349 377 perform pregnancy tests monthly during and for 6 months after ribavirin treatment is completed.349 377 Women of childbearing potential (and their male partners) and male patients (and their female partners) must use at least 2 forms of effective contraception during and for 6 months after ribavirin treatment is completed.349 377

Specific Populations

Adequate data regarding use of ledipasvir/sofosbuvir in pregnant women not available.1 In animal studies, neither ledipasvir nor sofosbuvir affected fetal development at dosages tested.1

When used in conjunction with ribavirin, consider that ribavirin is contraindicated in pregnant women and male partners of pregnant women.1 349 377 (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Not known whether ledipasvir/sofosbuvir and metabolites distributed into human milk.1

Predominant metabolite of sofosbuvir (GS-331007) distributed into milk in rats;1 ledipasvir detected in plasma of suckling rat pups.1 No apparent effects on the nursing pups.1

Consider benefits of breast-feeding and importance of the drug to the woman;1 also consider potential adverse effects on the breast-fed child from the drug or underlying maternal condition.1

When used in conjunction with ribavirin,1 consider potential for adverse reactions to ribavirin in nursing infants and discontinue nursing or the ribavirin-containing regimen.349 377 (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Safety and efficacy not established in pediatric patients <18 years of age.1

No overall differences in safety and efficacy in patients ≥65 years of age compared with younger adults,1 but increased sensitivity in some older individuals cannot be ruled out.1

Severe hepatic impairment (Child-Pugh class C) without HCV infection: Ledipasvir exposure similar to exposure in individuals similar to exposure in individuals with normal hepatic function.1

HCV-infected individuals with moderate or severe hepatic impairment (Child-Pugh class B or C): Increased sofosbuvir and GS-331007 exposures compared with exposures in individuals with normal hepatic function.1

When ledipasvir/sofosbuvir is used in conjunction with ribavirin in patients with decompensated cirrhosis (Child-Pugh class B or C), clinical and hepatic laboratory monitoring is recommended as clinically indicated.1

Severe renal impairment (estimated GFR <30 mL/minute per 1.73 m2) or ESRD requiring hemodialysis: Safety and efficacy not established.1

Severe renal impairment without HCV infection: Ledipasvir exposure similar to exposure in healthy individuals;1 substantially increased sofosbuvir and GS-331007 exposures compared with exposures in individuals with normal renal function.1

Safety profile of ledipasvir/sofosbuvir in individuals with HCV genotype 1 or genotype 4 infection and HIV-1 coinfection generally comparable to that reported in HCV-infected individuals without HIV-1 coinfection.1

Common Adverse Effects

Ledipasvir/sofosbuvir: Fatigue,1 2 3 4 9 10 headache,1 2 3 4 9 10 nausea,1 2 3 4 9 diarrhea,1 2 3 4 9 10 abdominal pain,10 insomnia or sleep disorder,1 2 3 4 9 irritability,1 2 9 rash,2 4 pruritus,2 dry skin,9 arthralgia,3 4 9 10 myalgia,1 9 10 back pain,9 asthenia,2 9 10 cough,1 2 4 9 10 upper respiratory tract infection,4 9 10 dizziness.1 4 10

Ledipasvir/sofosbuvir in conjunction with ribavirin: Fatigue,9 headache,1 9 nausea,9 diarrhea,9 insomnia,9 asthenia,1 9 cough,1 9 bronchitis,9 dyspnea,1 irritability,1 9 pruritus,9 dry skin,9 myalgia,9 decreased hemoglobin.1

Storage

Oral

Room temperature <30ºC.1

Dispense only in original container.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of ledipasvir and sofosbuvir combination in children younger than 12 years of age and weighing less than 35 kg. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of ledipasvir and sofosbuvir combination in the elderly.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aluminum Carbonate, Basic
• Aluminum Hydroxide
• Aluminum Phosphate
• Amiodarone
• Calcium Carbonate
• Carbamazepine
• Cimetidine
• Dexlansoprazole
• Digoxin
• Dihydroxyaluminum Aminoacetate
• Dihydroxyaluminum Sodium Carbonate
• Esomeprazole
• Famotidine
• Fosphenytoin
• Lansoprazole
• Magaldrate
• Magnesium Carbonate
• Magnesium Hydroxide
• Magnesium Oxide
• Magnesium Trisilicate
• Nizatidine
• Omeprazole
• Oxcarbazepine
• Pantoprazole
• Phenobarbital
• Phenytoin
• Rabeprazole
• Ranitidine
• Rifabutin
• Rifampin
• Rifapentine
• Rosuvastatin
• Simeprevir
• Sodium Bicarbonate
• St John's Wort
• Tenofovir Disoproxil Fumarate
• Tipranavir
• Topotecan

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Hepatitis B, history of—Use with caution. May cause this condition to become active again.

• Liver problems or
• Liver transplant, history of—Use with caution. May make these conditions worse.

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine should come with a patient information leaflet. Read and follow the information carefully. Ask your doctor if you have any questions.

You may take this medicine with or without food.

To help clear up your infection completely, ledipasvir and sofosbuvir combination must be taken for the full time of treatment, even if you begin to feel better after a few days. Also, it is important to keep the amount of medicine in your body at a steady level. To help keep the amount constant, this medicine must be used on a regular schedule.

If you are taking an antacid containing aluminum or magnesium hydroxide, take it 4 hours before or after taking ledipasvir and sofosbuvir combination.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For hepatitis C virus infection:
    • Adults—1 tablet once a day, taken for 12 or 24 weeks. Each tablet contains ledipasvir 90 milligrams (mg) and sofosbuvir 400 mg.
    • Children 12 years of age and older or weighing at least 35 kilograms (kg)—Dose is based on body weight and must be determined by your doctor. The dose is usually 1 tablet once a day, taken for 12 weeks.
    • Children younger than 12 years of age or weighing less than 35 kg—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Do not take more than 1 tablet per day.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Keep the medicine in the original bottle that you were given at the pharmacy.

Potential for Drug Interaction

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

After oral administration of Harvoni, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction. In clinical pharmacology studies, both sofosbuvir and the inactive metabolite GS-331007 were monitored for purposes of pharmacokinetic analyses.

Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters.

Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin or St. John's wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of Harvoni, and the use with P-gp inducers is not recommended with Harvoni [see Warnings and Precautions (5.3)].

Established and Potentially Significant Drug Interactions

Table 5 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either Harvoni, the components of Harvoni (ledipasvir and sofosbuvir) as individual agents, or are predicted drug interactions that may occur with Harvoni [see Warnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].

Drugs without Clinically Significant Interactions with Harvoni

Based on drug interaction studies conducted with the components of Harvoni (ledipasvir or sofosbuvir) or Harvoni, no clinically significant drug interactions have been either observed or are expected when Harvoni is used with the following drugs [see Clinical Pharmacology (12.3)]: abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, dolutegravir, efavirenz, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, lamivudine, methadone, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, or verapamil. See Table 5 for use of Harvoni with certain HIV antiretroviral regimens [see Drug Interactions (7.2)].

You should not use Harvoni if you are allergic to ledipasvir or sofosbuvir, or if you are also taking sofosbuvir tablets (Sovaldi).

To make sure Harvoni is safe for you, tell your doctor if you have:

• a history of hepatitis B;

• liver problems other than hepatitis;

• a history of liver transplant;

• kidney disease (or if you are on dialysis);

• HIV or AIDS; or

• a heart rhythm problem for which you take a medicine called amiodarone (Cordarone, Pacerone).

You should not use Harvoni with ribavirin if you have:

• severe kidney disease;

• a hemoglobin blood cell disorder such as sickle-cell anemia or thalassemia; or

• if you are pregnant, or if you are a man and your sexual partner is pregnant.

Harvoni is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

Harvoni is sometimes used together with another medicine called ribavirin. Ribavirin can cause birth defects or death in an unborn baby. You may need to have a negative pregnancy test before taking ribavirin and every month during your treatment.

• If you are a woman, do not take ribavirin if you are pregnant. If you are a man, do not take ribavirin if your sexual partner is pregnant. An unborn baby could also be harmed if a man fathers the child while he is taking ribavirin.

• Use at least 2 effective forms of birth control to prevent pregnancy while either sexual partner is taking ribavirin. Keep using 2 forms of birth control for at least 6 months after treatment ends.

• Tell your doctor right away if a pregnancy occurs while either the mother or the father is taking ribavirin.

It is not known whether ledipasvir and sofosbuvir passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Harvoni is not approved for use by anyone younger than 12 years old or weighing less than 77 pounds.

Many drugs can interact with ledipasvir and sofosbuvir. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

• amiodarone;

• digoxin (digitalis);

• other drugs to treat hepatitis C, such as simeprevir (Olysio) or sofosbuvir (Sovaldi);

• rosuvastatin (Crestor);

• St. John's wort;

• HIV or AIDS medications - atazanavir, cobicistat, darunavir, elvitegravir, emtricitabine, lopinavir, ritonavir, tenofovir, tipranavir;

• seizure medicine - carbamazepine, oxcarbazepine, phenobarbital, phenytoin;

• stomach acid reducers - cimetidine (Tagamet), esomeprazole (Nexium), famotidine (Pepcid) lansoprazole (Prevacid), nizatidine (Axid), omeprazole (Prilosec), pantoprazole (Protonix), ranitidine (Zantac), and others; or

• tuberculosis medicine - rifabutin, rifampin, rifapentine.

This list is not complete and many other drugs can interact with ledipasvir and sofosbuvir. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.