Approved Drug Label (PDF)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(Newly added information)
Hepatitis C Virus Transmission
Inform patients that the effect of treatment of hepatitis C
infection on transmission is not
known, and that appropriate precautions to prevent
transmission of the hepatitis C virus
during treatment or in the event of treatment failure should
be taken.
For HARVONI oral pellets, advise patients or caregivers to
read and follow the
Instructions for Use for preparing the correct dose.
Patient Information
(Newly added information)
See the detailed Instructions for Use for information about how to give or take a dose of HARVONI oral
pellets.
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
(additions
underlined)
…
Adverse
Reactions in Adults with Severe Renal Impairment, Including those on Dialysis
In
an open-label trial (Trial 0154) in which adults with HCV with compensated
liver disease (with or without cirrhosis) and severe renal impairment received
HARVONI for 12 weeks (N=18), the most common adverse reaction was fatigue (17%)
.
In
an open-label clinical trial, Trial 4063, a total of 95 adults with HCV with
compensated liver disease (with or without cirrhosis) and ESRD requiring
dialysis received HARVONI for 8 (n=45), 12 (n=31), or 24 (n=19) weeks. The most
common adverse reactions were insomnia and headache (each reported in 4% of
subjects overall).
…
7
Drug Interactions
7.3 Drugs without Clinically Significant Interactions with HARVONI
(addition
underlined)
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: abacavir,
atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, dolutegravir,
efavirenz, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide,
emtricitabine, lamivudine, methadone, midazolam, oral contraceptives,
pravastatin, raltegravir, rilpivirine, tacrolimus, or verapamil. See Table 6
for use of HARVONI with certain HIV antiretroviral regimens.
8
Use in Specific Populations
8.4 Pediatric Use
(additions
underlined)
…
In
patients with severe renal impairment, including those requiring dialysis,
exposures of GS-331007, the inactive metabolite of sofosbuvir, are increased . No data are available regarding the
safety of HARVONI in pediatric patients with renal impairment.
…
8.6 Renal Impairment
(additions
underlined)
No
dosage adjustment of HARVONI is recommended for patients with mild, moderate,
or severe renal impairment, including ESRD requiring dialysis. No safety data
are available in subjects with both decompensated cirrhosis and severe renal
impairment, including those on dialysis.
Additionally,
no safety data are available in pediatric patients with renal impairment.
Refer to ribavirin tablet prescribing information regarding use in patients
with renal impairment.
Approved Drug Label (PDF)
7
Drug Interactions
7.2 Established and Potentially Significant Drug Interactions
(additions
underlined)
Clearance
of HCV infection with direct acting antivirals may lead to changes in hepatic
function, which may impact the safe and effective use of concomitant
medications. For example, altered blood glucose control resulting in serious
symptomatic hypoglycemia has been reported in diabetic patients in
postmarketing case reports and published epidemiological studies. Management of
hypoglycemia in these cases required either discontinuation or dose modification
of concomitant medications used for diabetes treatment.
Frequent
monitoring of relevant laboratory parameters (e.g. International Normalized
Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic
patients) or drug concentrations of concomitant medications such as cytochrome
P450 substrates with a narrow therapeutic index (e.g. certain
immunosuppressants) is recommended to ensure safe and effective use. Dose
adjustments of concomitant medications may be necessary.
Table
6 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.
(please
refer to label to view Table 6)
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
(tables are
re-numbered)
(additions/revisions
are underlined)
Adverse
Reactions in Pediatric
Subjects 3 Years of Age and Older
The safety assessment of HARVONI in pediatric subjects 3 years of age and older is based on data from a Phase 2,
open-label clinical trial (Study
1116). In total,
226 subjects were enrolled,
which included 223 subjects
without cirrhosis or with compensated cirrhosis who
were treated with HARVONI for 12 weeks; one genotype 1 treatment-experienced subject with
cirrhosis who was treated with HARVONI for 24 weeks;
and two genotype 3 subjects who were treated with HARVONI
+ ribavirin for 24 weeks. The adverse reactions observed were consistent
with those observed in clinical studies
of HARVONI in adults. Limited safety data
are available in pediatric subjects receiving HARVONI for
24 weeks.
No Grade 3 or 4
adverse reactions or discontinuation due
to an adverse reaction was observed in those pediatric subjects receiving HARVONI
for 24 weeks.
7
Drug Interactions
7.2 Established and Potentially Significant Drug Interactions
(additions/revisions
are underlined)
Table
6 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.
Table 6 Potentially
Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
7.3 Drugs without Clinically Significant Interactions with HARVONI
(additions/revisions
are underlined)
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: 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 6 for
use of HARVONI with certain
HIV antiretroviral regimens.
8
Use in Specific Populations
8.4 Pediatric Use
(additions/revisions
are underlined)
The safety, pharmacokinetics, and efficacy of HARVONI
for treatment of HCV genotype
1 and 4 infection in treatment-naïve and treatment-experienced pediatric patients
3 years of age
and older without cirrhosis
or with
compensated cirrhosis have been
established in an
open-label, multicenter clinical
trial (Study 1116, N=226; 186 treatment-naïve, 40
treatment-experienced) and are
comparable to that observed in adults.
The safety and efficacy of HARVONI for treatment
of HCV genotypes 5 or 6 infection in pediatric patients 3
years of age and older
without cirrhosis or with compensated cirrhosis is supported
by comparable
ledipasvir, sofosbuvir, and GS-331007
exposures between adults and pediatric patients
with HCV genotype 1 and
4, and similar efficacy
and exposures across HCV genotypes 1, 4, 5, and 6
in adults. Similar rationale
is used
to support dosing recommendations for pediatric patients with HCV genotype 1 infection who have decompensated
cirrhosis (Child-Pugh B or C) and
for pediatric patients with
HCV genotype 1 and 4 infection who are liver transplant
recipients without cirrhosis or with compensated cirrhosis.
The
safety and efficacy of HARVONI have not been
established in pediatric patients
less than 3 years of
age.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(additions/revisions
are underlined)
Administration
Advise patients to
take HARVONI every day at
the regularly scheduled time with or without
food. Inform patients that it is important not to miss or
skip doses and to take HARVONI
for the duration that is recommended by the physician.
Manufactured and distributed by: Gilead Sciences, Inc.
Foster City, CA 94404
HARVONI, ATRIPLA, COMPLERA,
TRUVADA and VIREAD are trademarks of Gilead
Sciences, Inc., or its related
companies. All other trademarks referenced herein are
the property of their respective
owners.
PATIENT INFORMATION
(additions/revisions
are underlined)
What is HARVONI?
HARVONI is a prescription medicine used to treat
adults and children 3 years of age and older with chronic (lasting
a long time) hepatitis C virus (HCV):
genotype 1, 4, 5, or 6
infection without cirrhosis or
with compensated cirrhosis
genotype 1
infection with advanced cirrhosis (decompensated) in combination
with ribavirin
genotype
1 or 4 infection without cirrhosis or with compensated cirrhosis who have had a liver transplant, in
combination with ribavirin
It is not known if HARVONI is safe and effective in children with HCV under 3 years of age,
with advanced cirrhosis
(decompensated), or who have had a liver transplant.
…
How should I take
HARVONI?
Take HARVONI
exactly as your healthcare provider tells
you to take it. Do
not change your dose unless
your healthcare provider tells
you
to.
Do not stop taking HARVONI without first talking with your healthcare provider.
Take HARVONI
tablets or oral pellets by mouth, with or without food.
It is important that you do not miss or skip
doses of HARVONI during treatment.
For adults the usual
dose of HARVONI is one 90/400 mg tablet
each day.
For children
3 years of age and
older your healthcare provider
will prescribe the right dose of HARVONI tablets or oral pellets based on your child’s body weight.
Tell your
healthcare provider if your child has
problems with swallowing tablets.
If your healthcare provider prescribes HARVONI
pellets for your child, see “How
should I give HARVONI oral pellets to my child.”
Do not miss a dose of HARVONI. Missing a dose lowers the amount
of medicine in your blood. Refill your HARVONI prescription before you run
out of medicine.
If you take
too much HARVONI,
call your healthcare provider or go to the nearest hospital emergency room
right away.
How should I give HARVONI oral pellets to my child?
Administer HARVONI oral pellets exactly as instructed
by your healthcare provider.
Do not open the packet until ready to use.
Hold the HARVONI
pellets packet with the cut line on top.
Shake the HARVONI
pellets packet gently to settle the pellets.
Tear or cut the
HARVONI packet along the cut line.
HARVONI oral pellets can be
taken right in the
mouth without chewing, or with food.
If HARVONI pellets
are taken with food, sprinkle the pellets
on one or more spoonfuls of non-acidic soft food at or below room
temperature. Examples of non-acidic foods include pudding, chocolate syrup,
mashed potato, and ice cream. Take HARVONI pellets
within 30 minutes of gently mixing with food and swallow
the entire contents without chewing to
avoid a bitter taste.
Do not store any leftover HARVONI mixture
(oral pellets mixed with food) for use at a
later time. Throw away any unused portion.
…
How should I store HARVONI?
Store HARVONI tablets or pellets below 86°F (30°C).
Keep HARVONI tablets in the original container.
Do not use HARVONI tablets if the seal over the bottle opening is broken or missing.
Do not use HARVONI pellets if the carton tamper-evident seal, or the pellets packet
seal, is broken or damaged.
Keep HARVONI and all medicines out of
the reach of children.
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions are underlined)
If HARVONI is
administered with ribavirin to adults, refer to the prescribing
information for ribavirin for a description of ribavirin-associated adverse
reactions.
Clinical Trials
in Adult Subjects
…Table 3
lists adverse reactions (adverse events assessed as causally related by the
investigator, all grades) observed in at least 5% of subjects receiving 8, 12,
or 24 weeks treatment with HARVONI in clinical trials. The majority of adverse
reactions presented in Table 3 occurred at severity of grade 1…
Table 3 Adverse Reactions (All Grades) Reported in
Greater than or Equal to 5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with HARVONI
Adverse
Reactions in Subjects with Cirrhosis
…Table 4
presents the adverse reactions, as defined above, that occurred with at
least 5% greater frequency in subjects treated with 24 weeks of HARVONI or
12 weeks of HARVONI + ribavirin, compared to those reported for 12 weeks of
placebo. The majority of the adverse reactions presented in Table 4 were
Grade 1 or 2 in severity.
Table 4 Adverse Reactions with Greater than or Equal to
5% Greater Frequency Reported in Treatment-Experienced Subjects with Cirrhosis
Receiving HARVONI for 24 Weeks or HARVONI + RBV for 12 Weeks Compared to
Placebo for 12 weeks
Adverse
Reactions in Pediatric Subjects 12 Years of Age and Older
The safety
assessment of HARVONI in pediatric subjects 12 years of age and older is based
on data from a Phase 2, open-label clinical trial (Study 1116) that enrolled
100 subjects without cirrhosis or with compensated cirrhosis who were treated
with HARVONI for 12 weeks. The adverse reactions observed were consistent with
those observed in clinical studies of HARVONI in adults. Limited safety data
are available in pediatric subjects receiving HARVONI for 24 weeks. No Grade 3
or 4 adverse reactions or discontinuation due to an adverse reaction was
observed in those pediatric subjects receiving HARVONI for 24 weeks.
6.2 Postmarketing Experience
(Additions and/or revisions are underlined)
Skin and
Subcutaneous Tissue Disorders
Skin rashes,
sometimes with blisters or angioedema-like swelling
Angioedema
7
Drug Interactions
7.2 Established and Potentially Significant Drug Interactions
(Additions and/or revisions are underlined)
Table 5 provides a listing of established or potentially
clinically significant drug interactions…
![]()
Table 5 Potentially
Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended
Based on Drug Interaction Studies or Predicted Interaction (superscript a)
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or revisions are underlined)
Risk Summary
If HARVONI is
administered with ribavirin, the combination regimen is contraindicated in pregnant
women and in men whose female partners are pregnant. Refer to the ribavirin
prescribing information for more information on ribavirin-associated risks
of use during pregnancy.
8.4 Pediatric Use
(Additions and/or revisions are underlined)
The safety,
pharmacokinetics, and efficacy of HARVONI for treatment of HCV genotype 1
infection in treatment-naïve and treatment-experienced pediatric patients 12 years of age
and older without cirrhosis or with compensated cirrhosis have been established
in an open-label, multicenter clinical trial (Study 1116, N=100; 80 treatment-
naïve, 20 treatment-experienced) and are comparable to that observed in adults.
The safety and
efficacy of HARVONI for treatment of HCV genotypes 4, 5, or 6 infection in
pediatric patients 12 years of age and older or weighing at least 35 kg without
cirrhosis or with compensated cirrhosis is supported by comparable ledipasvir,
sofosbuvir, and GS-331007 exposures between adults and adolescents with HCV
genotype 1 and similar efficacy and exposures across HCV genotypes 1, 4, 5, and
6 in adults.
The safety and
efficacy of HARVONI have
not been established in pediatric patients less than 12 years of age and
weighing less than 35 kg, in pediatric patients with decompensated cirrhosis,
or in pediatric liver transplant recipients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information
(Additions and/or revisions are underlined)
What is HARVONI?
HARVONI is a
prescription medicine used to treat adults with chronic (lasting a long time)
hepatitis C virus (HCV):
- genotype 1, 4, 5, or 6 infection without cirrhosis or with
compensated cirrhosis
- genotype 1 infection with advanced cirrhosis (decompensated) in
combination with ribavirin
- genotype 1 or 4 infection without cirrhosis or with compensated
cirrhosis who have had a liver transplant, in combination with ribavirin
HARVONI is used
to treat children 12 years of age and older or weighing at least 77 pounds (at
least 35 kg) with chronic HCV genotype 1, 4, 5, or 6 without cirrhosis or with
compensated cirrhosis.
It is not known
if HARVONI is safe and effective in children with HCV under 12 years of age and
weighing less than 77 pounds (less than 35 kg), with advanced cirrhosis
(decompensated), or who have had a liver transplant.
Before taking
HARVONI, tell your healthcare provider about all of your medical conditions,
including if you:
- are breastfeeding or plan to breastfeed. It is not known if
HARVONI passes into your breast milk.
- Talk to your healthcare provider about the best way to feed your
baby during treatment with HARVONI.
Approved Drug Label (PDF)
Boxed Warning
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV
(Newly added
section)
Test all patients for evidence of current or prior hepatitis
B virus (HBV) infection before initiating treatment with HARVONI. HBV
reactivation has been reported in HCV/HBV coinfected patients who were
undergoing or had completed treatment with HCV direct acting antivirals and
were not receiving HBV antiviral therapy. Some cases have resulted in fulminant
hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for
hepatitis flare or HBV reactivation during HCV treatment and post-treatment
follow-up. Initiate appropriate patient management for HBV infection as
clinically indicated.
5
Warnings and Precautions
5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
(Newly added subsection)
Hepatitis B virus (HBV) reactivation has been
reported in HCV/HBV coinfected patients who were undergoing or had completed
treatment with HCV direct acting antivirals, and who were not receiving HBV
antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic
failure, and death. Cases have been reported in patients who are HBsAg positive
and also in patients with serologic evidence of resolved HBV infection (i.e.,
HBsAg negative and anti-HBc positive). HBV reactivation has also been reported
in patients receiving certain immunosuppressants or chemotherapeutic agents;
the risk of HBV reactivation associated with treatment with HCV direct-acting
antivirals may be increased in these patients.
HBV reactivation is characterized as an abrupt
increase in HBV replication manifesting as a rapid increase in serum HBV DNA
level. In patients with resolved HBV infection, reappearance of HBsAg can
occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e.,
increases in aminotransferase levels and, in severe cases, increases in
bilirubin levels, liver failure, and death can occur.
Test all patients for evidence of current or prior
HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment
with HARVONI. In patients with serologic evidence of HBV infection, monitor for
clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV
treatment with HARVONI and during post-treatment follow-up. Initiate
appropriate patient management for HBV infection as clinically indicated.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions
and/or revisions are underlined)
Risk of Hepatitis B Virus Reactivation in Patients
Coinfected with HCV and HBV
Inform patients that
HBV reactivation can occur in patients coinfected with HBV during or after treatment
of HCV infection. Advise patients to tell their healthcare provider if they
have a history of HBV infection.
Patient Information HARVONI® (har-VOE-nee) (ledipasvir and sofosbuvir) tablets
(Additions
and/or revisions are underlined)
What is the most important information I should know about
HARVONI?
HARVONI can cause serious side effects, including,
Hepatitis B virus reactivation: Before
starting treatment with HARVONI, your healthcare provider will do blood tests
to check for hepatitis B virus infection. If you have ever had hepatitis B
virus infection, the hepatitis B virus could become active again during or
after treatment of hepatitis C virus with HARVONI. Hepatitis B virus becoming
active again (called reactivation) may cause serious liver problems including
liver failure and death. Your healthcare provider will monitor you if you are
at risk for hepatitis B virus reactivation during treatment and after you stop
taking HARVONI.
For more information about side effects, see the section
“What are the possible side effects of HARVONI?”
Hepatitis B virus reactivation.
See “What is the most important information I should know about HARVONI?”
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