Gilead Sciences, Inc. (Nasdaq:GILD) today announced that the
U.S. Food and Drug Administration (FDA) has approved Complera™
(emtricitabine/rilpivirine/tenofovir disoproxil fumarate), a
complete single-tablet regimen for the treatment of HIV-1 infection
in treatment-naïve adults. Complera combines three antiretroviral
medications in one daily tablet – Gilead’s Truvada®, which is a
fixed-dose combination of the two nucleoside reverse transcriptase
inhibitors emtricitabine and tenofovir disoproxil fumarate, and
Tibotec Pharmaceuticals’ non-nucleoside reverse transcriptase
inhibitor, rilpivirine (marketed as Edurant™ in the United States
by Janssen Therapeutics, Division of Janssen Products, LP). Truvada
and rilpivirine were approved by the FDA in August 2004 and May
2011, respectively, for use as part of HIV combination therapy.
“In the 30 years since the first AIDS cases were reported, we’ve
made incredible strides in the treatment of this disease,” said
Tony Mills, MD, Director of Medical Research, Anthony Mills MD,
Inc. and a participating investigator in ongoing Complera studies.
“The concept of a single-tablet regimen has become a goal in HIV
drug development, and the standard of care in medical practice in
the United States. However, no one therapy is appropriate for all
patients. Given its efficacy, safety and convenience, the
availability of Complera represents an exciting milestone in
addressing the individual needs of patients new to HIV
therapy.”
The approval of Complera is supported by 48-week data from two
Phase 3 double-blind, active controlled, randomized studies (ECHO
and THRIVE) conducted by Tibotec that evaluated the safety and
efficacy of rilpivirine compared to efavirenz among treatment-naïve
HIV-1 infected adults. Both arms of the study were administered
with a background regimen, in which the majority of patients in the
rilpivirine arm received Truvada. A bioequivalence study, conducted
by Gilead, demonstrated that the co-formulated single-tablet
regimen achieved the same levels of medication in the blood as
emtricitabine plus rilpivirine plus tenofovir disoproxil
fumarate.
“Complera is the second complete single-tablet regimen that
Gilead has introduced, and it represents a collaboration between
two organizations that share a vision of simplifying HIV therapy
for patients,” said John C. Martin, PhD, Chairman and Chief
Executive Officer, Gilead Sciences. “Tremendous progress has been
made in the field of HIV, but we recognize new therapies are still
needed, and we continue to work to advance options that address the
needs of patients.”
Complera is the second complete antiretroviral treatment regimen
for HIV-1 available to treatment-naïve patients in a single
once-daily pill. The first, Atripla® (efavirenz 600
mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg), is
marketed by Gilead and Bristol-Myers Squibb. Complera does not cure
HIV-1 infection or help prevent the transmission of HIV to others.
Complera has Boxed Warnings including lactic acidosis/severe
hepatomegaly with steatosis and post treatment acute exacerbation
of hepatitis B; see below for additional important safety
information. The following points should be considered when
initiating therapy with Complera:
- More rilpivirine-treated subjects with
HIV-1 RNA greater than 100,000 copies/mL at the start of therapy
experienced virologic failure compared to subjects with HIV-1 RNA
less than 100,000 copies/mL at the start of therapy.
- The observed virologic failure rate in
rilpivirine-treated subjects conferred a higher rate of overall
treatment resistance and cross-resistance to the NNRTI class
compared to efavirenz.
- More subjects treated with rilpivirine
developed lamivudine/emtricitabine associated resistance compared
to efavirenz.
- Complera is not recommended for
patients less than 18 years of age.
Gilead first entered into a license and collaboration agreement
with Tibotec for the development and commercialization of Complera
in July 2009. Under the terms of the agreement, Gilead will assume
the lead role in the manufacturing, registration, distribution and
commercialization of Complera in the United States, Canada, Brazil,
the European Union, Australia and New Zealand. Tibotec will be
responsible for the commercialization of rilpivirine as a
stand-alone product and will hold rights to co-detail Complera in
these territories. A marketing application for the
emtricitabine/rilpivirine/tenofovir disoproxil fumarate
single-tablet regimen is currently pending in the European
Union.
The companies also have finalized an agreement for the
development and commercialization of the single-tablet regimen for
the rest of world, including the developing world. Gilead will be
responsible for the registration, distribution and
commercialization of the single-tablet regimen in certain European
countries, Latin America and the Caribbean. Tibotec will be
responsible for all countries outside of the Gilead territories,
the most significant of which include Asia Pacific, including
Japan, the Middle East, Eastern Europe and all of Africa.
Important Product Safety Information
About Complera, Including Boxed Warnings
BOXED WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH
STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS
B
Lactic acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported with the use of
nucleoside analogs, including tenofovir disoproxil fumarate, a
component of Complera, in combination with other
antiretrovirals.
Complera is not approved for the treatment of chronic
hepatitis B virus (HBV) infection and the safety and efficacy of
Complera have not been established in patients coinfected with HBV
and HIV-1. Severe acute exacerbations of hepatitis B have
been reported in patients who are coinfected with HBV and HIV-1 and
have discontinued Emtriva or Viread, which are components of
Complera. Hepatic function should be monitored closely with
both clinical and laboratory follow-up for at least several months
in patients who are coinfected with HIV-1 and HBV and discontinue
Complera. If appropriate, initiation of anti-hepatitis B
therapy may be warranted.
CONTRAINDICATIONS
Complera should not be co-administered with the following drugs,
as significant decreases in rilpivirine plasma concentrations may
occur due to CYP3A enzyme induction or gastric pH increase, which
may result in loss of virologic response and possible resistance to
Complera or to the class of NNRTIs:
- the anticonvulsants carbamazepine,
oxcarbazepine, phenobarbital, phenytoin
- the antimycobacterials rifabutin,
rifampin, rifapentine
- proton pump inhibitors, such as
esomeprazole, lansoprazole, omeprazole, pantoprazole,
rabeprazole
- the glucocorticoid systemic
dexamethasone (more than a single dose)
- St John’s wort (Hypericum
perforatum)
WARNINGS AND PRECAUTIONS
- New onset or worsening renal
impairmentRenal impairment, including cases of acute renal
failure and Fanconi syndrome (renal tubular injury with severe
hypophosphatemia), has been reported with the use of tenofovir
disoproxil fumarate. Assess creatinine clearance (CrCl) before
initiating treatment with Complera. Monitor CrCl and serum
phosphorus in patients at risk for renal impairment, including
patients who have previously experienced renal events while
receiving Hepsera® (adefovir dipivoxil). Avoid administering
Complera with concurrent or recent use of nephrotoxic drugs.
Patients with CrCl below 50 mL per minute should not receive
Complera.
- Drug InteractionsComplera should
be used with caution when given with drugs that may reduce the
exposure of rilpivirine.Complera should be used with caution when
co-administered with a drug with a known risk of Torsade de
Pointes.
- Depressive DisordersThe adverse
reaction depressive disorders (depressed mood, depression,
dysphoria, major depression, mood altered, negative thoughts,
suicide attempt, suicidal ideation) has been reported with
rilpivirine. During the Phase 3 trials (N = 1,368), the incidence
of depressive disorders (regardless of causality, severity)
reported among rilpivirine (N = 686) or efavirenz (N = 682) was 8%
and 6%, respectively. Most events were mild or moderate in
severity. The incidence of Grade 3 and 4 depressive disorders
(regardless of causality) was 1% for both rilpivirine and
efavirenz. The incidence of discontinuation due to depressive
disorders among rilpivirine or efavirenz was 1% in each arm.
Suicide attempt was reported in 2 subjects in the rilpivirine arm
while suicide ideation was reported in 1 subject in the rilpivirine
arm and in 3 subjects in the efavirenz arm. Patients with severe
depressive symptoms should seek immediate medical evaluation to
assess the possibility that the symptoms are related to Complera,
and if so, to determine whether the risks of continued therapy
outweigh the benefits.
- Decreases in bone mineral
densityBone mineral density (BMD) monitoring should be
considered for patients who have a history of pathologic bone
fracture or other risk factors for osteoporosis or bone loss. Cases
of osteomalacia (associated with proximal renal tubulopathy and
which may contribute to fractures) have been reported in
association with the use of tenofovir disoproxil fumarate.
- Co-administration with other
productsComplera should not be administered concurrently with
other medicinal products containing any of the same active
components, emtricitabine, rilpivirine, or tenofovir disoproxil
fumarate (Emtriva, Edurant, Viread, Truvada, Atripla), with
medicinal products containing lamivudine (Epivir, Epivir-HBV,
Epzicom, Combivir, Trizivir), or with adefovir dipivoxil
(Hepsera).
- Fat
redistributionRedistribution/accumulation of body fat has been
observed in patients receiving antiretroviral therapy.
- Immune reconstitution
syndromeImmune reconstitution syndrome has been reported in
patients treated with combination antiretroviral therapy, including
the components of Complera. Further evaluation and treatment may be
necessary.
ADVERSE REACTIONS
The most common adverse drug reactions to rilpivirine (incidence
greater than or equal to 2%, Grades 2-4) were insomnia and
headache.
The most common adverse drug reactions to emtricitabine and
tenofovir disoproxil fumarate (incidence ≥ 10%) were diarrhea,
nausea, fatigue, headache, dizziness, depression, insomnia,
abnormal dreams, and rash.
DRUG INTERACTIONS
- Complera should not be used with drugs
where significant decreases in rilpivirine plasma concentrations
may occur (See CONTRAINDICATIONS).
- Complera is a complete regimen for the
treatment of HIV-1 infection; therefore Complera should not be
administered with other antiretroviral medications for the
treatment of HIV-1 infection.
- Drugs inducing or inhibiting CYP3A
enzymes: Rilpivirine is primarily metabolized by cytochrome
P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus
affect the clearance of rilpivirine. Coadministration of
rilpivirine and drugs that induce CYP3A may result in decreased
plasma concentrations of rilpivirine and loss of virologic response
and possible resistance to rilpivirine or to the class of NNRTIs.
Coadministration of rilpivirine and drugs that inhibit CYP3A may
result in increased plasma concentrations of rilpivirine.
- Drugs increasing gastric PH:
Coadministration of rilpivirine with drugs that increase gastric pH
may decrease plasma concentrations of rilpivirine and loss of
virologic response and possible resistance to rilpivirine or to the
class of NNRTIs.
- Drugs affecting renal function:
Since emtricitabine and tenofovir are primarily eliminated by the
kidneys, coadministration of Complera with drugs that reduce renal
function or compete for active tubular secretion may increase serum
concentrations of emtricitabine, tenofovir, and/or other renally
eliminated drugs. Some examples include, but are not limited to,
acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir
and valganciclovir.
- QT prolonging drugs: There is
limited information available on the potential for a
pharmacodynamic interaction between rilpivirine and drugs that
prolong the QTc interval of the electrocardiogram. In a study of
healthy subjects, supratherapeutic doses of rilpivirine (75 mg once
daily and 300 mg once daily) have been shown to prolong the QTc
interval of the electrocardiogram. Complera should be used with
caution when coadministered with a drug with a known risk of
Torsade de Pointes.
DOSAGE AND ADMINISTRATION
Adults: The recommended dose of Complera is one tablet taken
orally once daily with a meal.
Renal Impairment: Because Complera is a fixed-dose combination,
it should not be prescribed for patients requiring dose adjustment
such as those with moderate or severe renal impairment (creatinine
clearance below 50 mL per minute).
Important Safety Product Information
About Truvada, Including Boxed Warnings
Truvada, a combination of Emtriva (emtricitabine) and Viread
(tenofovir disoproxil fumarate [DF]), is indicated in combination
with other antiretroviral agents (such as non nucleoside reverse
transcriptase inhibitors or protease inhibitors) for the treatment
of HIV-1 infection.
The following points should be considered when initiating
therapy with Truvada for the treatment of HIV-1 infection:
- It is not recommended that Truvada be
used as a component of a triple nucleoside regimen.
- Truvada should not be coadministered
with Atripla (efavirenz/emtricitabine/tenofovir DF), Emtriva,
Viread, or lamivudine-containing products.
- In treatment-experienced patients, the
use of Truvada should be guided by laboratory testing and treatment
history.
WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS
and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B
Lactic acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported with the use of
nucleoside analogs, including Viread, a component of Truvada, in
combination with other antiretrovirals.
Truvada is not approved for the treatment of chronic
hepatitis B virus (HBV) infection, and the safety and efficacy of
Truvada have not been established in patients coinfected with HBV
and HIV-1. Severe acute exacerbations of hepatitis B have been
reported in patients who are coinfected with HBV and HIV-1 and have
discontinued Truvada. Hepatic function should be monitored closely
with both clinical and laboratory follow-up for at least several
months in patients who are coinfected with HIV-1 and HBV and
discontinue Truvada. If appropriate, initiation of anti-hepatitis B
therapy may be warranted.
WARNINGS AND PRECAUTIONS
New Onset or Worsening Renal Impairment
- Emtricitabine and tenofovir are
principally eliminated by the kidney. Renal impairment, including
acute renal failure and Fanconi syndrome (renal tubular injury with
severe hypophosphatemia), has been reported with the use of
tenofovir DF.
- Assess CrCl before initiating treatment
with Truvada. Routinely monitor CrCl and serum phosphorus in
patients at risk for renal impairment, including patients who have
previously experienced renal events while receiving Hepsera
(adefovir dipivoxil).
- Dosing interval adjustment of Truvada
and close monitoring of renal function are recommended in all
patients with CrCl 30–49 mL/min. No safety or efficacy data are
available in patients with renal impairment who received Truvada
using these dosing guidelines, so the potential benefit of Truvada
therapy should be assessed against the potential risk of renal
toxicity. Truvada should not be administered in patients with CrCl
60 kg. Data are not available to recommend a dose adjustment of ddI
for patients weighing
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