BMY News Bristol-Myers Squibb, Gilead Sciences and Merck & Co. Submit Marketing Authorisation Application for ATRIPLA(TM) (efavirenz 600 mg/ emtricitabine 200 mg/ tenofovir disoproxil fumarate 300 mg) to European Medicines Agency
PRINCETON, N.J. & FOSTER CITY, Calif. & WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY), Gilead Sciences, Inc.
(Nasdaq:GILD) and Merck & Co., Inc. (NYSE:MRK) today announced the
submission of a Marketing Authorisation Application (MAA) for ATRIPLATM
(efavirenz 600 mg/ emtricitabine 200 mg/ tenofovir disoproxil fumarate
300 mg) in the European Union to the European Medicines Agency (EMEA).
The MAA will be reviewed by the Committee for Medicinal Products for
Human Use (CHMP), subject to validation by the EMEA.
The MAA for ATRIPLA in the European Union was filed jointly by the three
companies through a newly established three-way joint venture based in
Ireland, Bristol-Myers Squibb Gilead Sciences And Merck Sharp & Dohme
Limited. Review of the MAA will be conducted by the EMEA under the
centralized licensing procedure, which, when finalized, provides one
marketing authorization in all member states of the European Union.
Discussions among the three companies regarding agreements for
manufacturing, commercialization and distribution of ATRIPLA in the
European Union are ongoing.
ATRIPLA is a once-daily single tablet regimen approved in the United
States for the treatment of HIV-1 infection in adults for use either as
stand-alone therapy or in combination with other antiretroviral agents.
The product contains 600 mg of efavirenz, a non-nucleoside reverse
transcriptase inhibitor (NNRTI), 200 mg of emtricitabine and 300 mg of
tenofovir disoproxil fumarate, both nucleoside reverse transcriptase
inhibitors (NRTIs). Efavirenz is marketed by Bristol-Myers Squibb under
the tradename SUSTIVA®
in the United States, Canada and six European countries (France,
Republic of Ireland, Germany, Italy, Spain and the United Kingdom). In
other territories, including all other countries of the European Union,
efavirenz is commercialized by Merck & Co., Inc., (also known as MSD
outside of the United States and Canada) and is marketed in most of
these countries under the tradename Stocrin®.
Emtricitabine and tenofovir disoproxil fumarate are commercialized by
Gilead Sciences under the tradenames Emtriva®
and Viread®,
respectively. The compounds are commonly prescribed together as a
once-daily, fixed-dose tablet, marketed under the tradename Truvada®
for use as part of combination therapy.
ATRIPLA was approved by the U.S. Food and Drug Administration (FDA) on
July 12, 2006. In the United States, the product is commercialized by
Bristol-Myers Squibb and Gilead Sciences through a joint venture. The
FDA also granted approval of an alternate tradedress of ATRIPLA for
developing countries, where ATRIPLA will be made available as a
white-colored tablet to distinguish it from the salmon-colored version
currently available in the United States. Gilead and Merck established a
separate agreement in August 2006 for distribution of the product in
developing countries.
“Bristol-Myers Squibb is committed to
delivering effective HIV therapies to patients worldwide and is pleased
to work with Gilead and Merck to realize this goal with ATRIPLA,”
said Lamberto Andreotti, president, Worldwide Pharmaceuticals,
Bristol-Myers Squibb. “With the filing of
ATRIPLA in Europe, we are one step closer to making available another
effective treatment option for European adult patients living with
HIV/AIDS.”
“As the first and only once-daily single
tablet regimen, ATRIPLA may help to simplify therapy for many
HIV-infected adults. Gilead is pleased to have established this
partnership with Bristol-Myers Squibb and Merck, and we look forward to
working with colleagues at both companies to make this product available
to people living with HIV in Europe as quickly as possible,”
said Kevin Young, Executive Vice President, Commercial Operations,
Gilead Sciences.
“ATRIPLA has the potential to offer an
important new tool to patients and physicians in Europe for treating HIV
infection in adults,” said Stefan J.
Oschmann, President, Europe, Middle East, Africa, Canada, Merck & Co.,
Inc. “This new single tablet regimen
exemplifies our commitment to putting patients first. We look forward to
collaborating with BMS, Gilead and national health authorities to
deliver ATRIPLA to those who need it as soon as possible.”
Important Safety Information About
ATRIPLA, Truvada, Viread and Emtriva
Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues alone or
in combination with other antiretrovirals. ATRIPLA, Truvada, Viread and
Emtriva are not indicated for the treatment of chronic hepatitis B virus
(HBV) infection and the safety and efficacy of these drugs have not been
established in patients co-infected with HBV and HIV. Severe acute
exacerbations of hepatitis B have been reported in patients who have
discontinued Emtriva or Viread (components of ATRIPLA and Truvada).
Hepatic function should be monitored closely with both clinical and
laboratory follow-up for at least several months in patients who
discontinue ATRIPLA, Truvada, Emtriva or Viread and are co-infected with
HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may
be warranted.
Antiretroviral therapies do not cure HIV infection or AIDS and have not
been proven to prevent the risk of transmission of HIV to others through
sexual contact or blood contamination.
Additional Important Information About
ATRIPLA in the United States
In the United States, ATRIPLA is indicated for use alone as a complete
regimen or in combination with other antiretroviral agents for the
treatment of HIV-1 infection in adults.
Coadministration of ATRIPLA with astemizole, cisapride, midazolam,
triazolam, ergot derivatives, or voriconazole is contraindicated.
Concomitant use of ATRIPLA with St. John’s
wort (Hypericum perforatum) or St. John’s
wort-containing products is not recommended. Since ATRIPLA contains
efavirenz, emtricitabine, and tenofovir disoproxil fumarate, ATRIPLA
should not be coadministered with SUSTIVA, EMTRIVA, VIREAD, or TRUVADA.
Due to similarities between emtricitabine and lamivudine, ATRIPLA should
not be coadministered with drugs containing lamivudine, including
Combivir®, Epivir®,
Epivir-HBV®, Epzicom™,
or Trizivir®.
Serious psychiatric adverse experiences, including severe depression
(2.4%), suicidal ideation (0.7%), nonfatal suicide attempts (0.5%),
aggressive behavior (0.4%), paranoid reactions (0.4%), and manic
reactions (0.2%) have been reported in patients receiving efavirenz. In
addition to efavirenz, factors identified in a clinical study that were
associated with an increase in psychiatric symptoms included a history
of injection drug use, psychiatric history, and use of psychiatric
medication. There have been occasional reports of suicide, delusions,
and psychosis-like behavior, but it could not be determined if efavirenz
was the cause. Patients with serious psychiatric adverse experiences
should be evaluated immediately to determine whether the risks of
continued therapy outweigh the benefits. Fifty-three percent of patients
reported central nervous system (CNS) symptoms including dizziness
(28.1%), insomnia (16.3%), impaired concentration (8.3%), somnolence
(7.0%), abnormal dreams (6.2%), and hallucinations (1.2%) when taking
efavirenz compared to 25% of patients receiving control regimens. These
symptoms usually begin during the first two days of therapy and
generally resolve after the first two to four weeks of therapy; they
were severe in 2.0% of patients and 2.1% of patients discontinued
therapy. After four weeks of therapy, the prevalence of CNS symptoms of
at least moderate severity ranged from 5% to 9% in patients treated with
regimens containing efavirenz. Nervous system symptoms are not
predictive of the less frequent psychiatric symptoms.
ATRIPLA should not be given to patients with creatinine clearance less
than 50 mL/min. Renal impairment, including cases of acute renal failure
and Fanconi syndrome (renal tubular injury with severe
hypophosphatemia), has been reported in association with the use of
tenofovir disoproxil fumarate. Renal impairment occurred most often in
patients with underlying systemic or renal disease, or in patients
taking concomitant nephrotoxic agents. Some cases have occurred in
patients with no identified risk factors. ATRIPLA should be avoided with
concurrent or recent use of a nephrotoxic agent.
ATRIPLA may cause fetal harm when administered during the first
trimester to a pregnant woman. Women should not become pregnant or
breastfeed while taking ATRIPLA. Barrier contraception must always be
used in combination with other methods of contraception (e.g., oral or
other hormonal contraceptives). If the patient becomes pregnant while
taking ATRIPLA, she should be apprised of the potential harm to the
fetus.
Mild to moderate rash is a common side effect of efavirenz. In
controlled clinical trials, 26% of patients treated with efavirenz
experienced new-onset skin rash compared with 17% of patients treated in
control groups. Skin discoloration, associated with emtricitabine, may
also occur. ATRIPLA should be discontinued in patients developing severe
rash associated with blistering, desquamation, mucosal involvement, or
fever. Liver enzymes should be monitored in patients with known or
suspected hepatitis B or C and when ATRIPLA is administered with
ritonavir or other medications associated with liver toxicity. Decreases
in bone mineral density (BMD) have been seen with tenofovir disoproxil
fumarate. Use ATRIPLA with caution in patients with a history of
seizures. Convulsions have been observed in patients receiving
efavirenz, generally in the presence of known medical history of
seizures. Redistribution/accumulation of body fat has been observed in
patients receiving antiretroviral therapy. Immune reconstitution
syndrome has been reported in patients treated with combination
antiretroviral therapy, including the components of ATRIPLA.
Coadministration with ATRIPLA and atazanavir is not recommended due to
concerns regarding decreased atazanavir concentrations. Atazanavir and
lopinavir/ritonavir have been shown to increase tenofovir
concentrations. Patients on atazanavir or lopinavir/ritonavir plus
ATRIPLA should be monitored for tenofovir-associated adverse events.
ATRIPLA should be discontinued in patients who develop
tenofovir-associated adverse events. Coadministration of ATRIPLA with
didanosine should be undertaken with caution. Patients receiving this
combination should be monitored closely for didanosine-associated
adverse events. See Full Prescribing Information for complete list of
drug-drug interactions.
In Study 934, the most frequently reported grades two to four adverse
events through 48 weeks in patients receiving efavirenz, emtricitabine
and tenofovir disoproxil fumarate were dizziness (8%), nausea (8%),
diarrhea (7%), fatigue (7%), headache (5%), rash (5%), sinusitis (4%),
depression (4%), insomnia (4%), and abnormal dreams (4%).
The dose of ATRIPLA is one tablet (containing 600 mg of efavirenz, 200
mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate) once
daily taken orally on an empty stomach. Dosing at bedtime may improve
the tolerability of nervous system symptoms. ATRIPLA is not recommended
for use in patients younger than 18 years of age.
Important Information About Efavirenz
Efavirenz in combination with other antiretroviral agents is indicated
for the treatment of HIV-1 infection. This indication is based on two
clinical trials of at least one year duration that demonstrated
prolonged suppression of HIV RNA.
Coadministration with astemizole, cisapride, midazolam, triazolam, ergot
derivatives, or voriconazole is contraindicated. Concomitant use of
efavirenz and St. John’s wort (Hypericum
perforatum) or St. John’s wort-containing
products is not recommended. This list of medications is not complete.
Serious psychiatric adverse experiences, including severe depression
(2.4%), suicidal ideation (0.7%), nonfatal suicide attempts (0.5%),
aggressive behavior (0.4%), paranoid reactions (0.4%) and manic
reactions (0.2%) have been reported in patients treated with efavirenz.
In addition to efavirenz, factors identified in a clinical study that
were associated with an increase in psychiatric symptoms included
history of injection drug use, psychiatric history, and use of
psychiatric medication. There have been occasional reports of suicide,
delusions, and psychosis-like behavior, but it could not be determined
if efavirenz was the cause. Patients with serious psychiatric adverse
experiences should be evaluated immediately to determine whether the
risks of continued therapy outweigh the benefits. Fifty-three percent of
patients reported central nervous system symptoms including dizziness
(28.1%), insomnia (16.3%), impaired concentration (8.3%), somnolence
(7.0%), abnormal dreams (6.2%) and hallucinations (1.2%) when taking
efavirenz compared to 25% of patients receiving control regimens. These
symptoms usually begin during Days 1-2 of therapy and generally resolve
after the first 2-4 weeks of therapy. After four weeks of therapy, the
prevalence of central nervous system symptoms of at least moderate
severity ranged from 5% to 9% in patients treated with regimens
containing efavirenz. Nervous system symptoms are not predictive of the
less frequent serious psychiatric symptoms.
Efavirenz may cause fetal harm when administered during the first
trimester to a pregnant woman. Women should not become pregnant or
breastfeed while taking efavirenz. Barrier contraception must always be
used in combination with other methods of contraception (e.g. oral or
other hormonal contraceptives). If the patient becomes pregnant while
taking efavirenz, she should be apprised of the potential harm to the
fetus.
Mild to moderate rash is a common side effect of efavirenz. In
controlled clinical trials, 26% of patients treated with efavirenz
experienced new-onset skin rash compared with 17% of patients treated in
control groups. Efavirenz should be discontinued in patients developing
severe rash associated with blistering, desquamation, mucosal
involvement, or fever. Rash is more common and often more severe in
pediatric patients.
Liver enzymes should be monitored in patients with known or suspected
hepatitis B or C, in patients treated with other medications associated
with liver toxicity, and when efavirenz is administered with ritonavir.
Use efavirenz with caution in patients with a history of seizures.
Convulsions have been observed in patients receiving efavirenz,
generally in the presence of known medical history of seizures.
Redistribution and/or accumulation of body fat have been seen in
patients receiving antiretroviral therapy. A causal relationship has not
been established. Immune reconstitution syndrome has been reported in
patients treated with combination antiretroviral therapy, including
efavirenz.
It is recommended that efavirenz be taken on an empty stomach,
preferably at bedtime. The increased concentrations following
administration of efavirenz with food may lead to an increase in
frequency of adverse events. Dosing at bedtime may improve the
tolerability of nervous system symptoms.
Additional Important Information About
Truvada
Truvada is a fixed-dose combination product that combines 200 mg of
Emtriva®
(emtricitabine) and 300 mg of Viread®
(tenofovir disoproxil fumarate)in one tablet, taken once a day.
In the United States and the European Union, Truvada 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 in adults. Truvada should not be
coadministered with Emtriva, Viread or lamivudine-containing products
and it is not recommended that Truvada be used as a component of a
triple nucleoside regimen. In treatment-experienced patients, the use of
Truvada should be guided by laboratory testing and treatment history.
Clinical Study 934 supports the use of Truvada tablets for the treatment
of HIV-1 infection. Additional data in support of the use of Truvada are
derived from Study 903, in which Viread and lamivudine were used in
combination in treatment-naïve adults, and
clinical Study 303, in which Emtriva and lamivudine demonstrated
comparable efficacy, safety and resistance patterns as part of multidrug
regimens.
No drug interaction studies have been conducted using Truvada. Drug
interactions have been observed when didanosine, atazanavir, or
lopinavir/ritonavir is co-administered with Viread, a component of
Truvada, and dose adjustments may be necessary. Data are not available
to recommend a dose adjustment of didanosine for patients weighing less
than 60 kg. In the European Union, the co-administration of tenofovir
disoproxil fumarate and didanosine is not recommended unless judged
strictly necessary. Patients on atazanavir or lopinavir/ritonavir plus
Truvada should be monitored for Truvada-associated adverse events that
may require discontinuation. When co-administered with Truvada, it is
recommended that atazanavir 300 mg be given with ritonavir 100 mg.
Atazanavir without ritonavir should not be co-administered with Truvada.
Four-hundred and forty-seven HIV-1 infected patients have received
combination therapy with Emtriva and Viread with either a non-nucleoside
reverse transcriptase inhibitor (Study 934) or protease inhibitor for 48
weeks in clinical studies. Adverse events observed in Study 934 were
generally consistent with those seen in other studies in
treatment-experienced or treatment-naïve
patients receiving Viread and/or Emtriva. Adverse events observed in
more than 5% of patients in the Viread/Emtriva group in Study 934
include diarrhea, nausea, fatigue, headache, dizziness and rash.
Renal impairment, including cases of acute renal failure and Fanconi
syndrome (renal tubular injury with severe hypophosphatemia), has been
reported among patients taking Viread, a component of Truvada
(emtricitabine and tenofovir disoproxil fumarate). Renal impairment
occurred most often in patients with underlying systemic or renal
disease or in patients taking concomitant nephrotoxic agents, though
some cases have appeared in patients without identified risk factors.
Decreases in bone mineral density (BMD) at the lumbar spine and hip have
been seen with the use of Viread. The effects of Viread-associated
changes in BMD and biochemical markers on long-term bone health and
future risk fracture are unknown. Redistribution and/or accumulation of
body fat have been observed in patients receiving combination
antiretroviral therapy. The cause and long term health effect of these
conditions are unknown. Immune reconstitution syndrome has been reported
in patients treated with combination antiretroviral therapy including
Truvada, Viread and Emtriva.
Skin discoloration, manifested by hyperpigmentation on the palms and/or
soles, has been reported with the use of Emtriva, a component of
Truvada. Skin discoloration was generally mild and asymptomatic and its
mechanism and clinical significance are unknown.
The parent compound of Viread was discovered through a collaborative
research effort between Dr. Antonin Holy, Institute for Organic
Chemistry and Biochemistry, Academy of Sciences of the Czech Republic
(IOCB) in Prague and Dr. Erik DeClercq, Rega Institute for Medical
Research, Katholic University in Leuven, Belgium.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global pharmaceutical and related healthcare
products company. Visit Bristol-Myers Squibb on the World Wide Web at www.bms.com.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops
and commercializes innovative therapeutics in areas of unmet medical
need. The company's mission is to advance the care of patients suffering
from life-threatening diseases worldwide. Headquartered in Foster City,
California, Gilead has operations in North America, Europe and
Australia. Visit Gilead on the World Wide Web at www.gilead.com.
About Merck
Merck & Co. Inc., which operates as Merck Sharp & Dohme (MSD) in
countries outside of the United States, is a global research-driven
pharmaceutical company dedicated to putting patients first. Established
in 1891, Merck currently discovers, develops, manufactures and markets
vaccines and medicines to address unmet medical needs. The Company
devotes extensive efforts to increase access to medicines through
far-reaching programs that not only donate Merck medicines but also help
deliver them to the people who need them. Merck also publishes unbiased
health information as a not-for-profit service. For more information,
visit www.merck.com.
Forward-Looking Statements
Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that term is
defined in the Private Securities Litigation Reform Act of 1995
regarding product development. Such forward-looking statements are based
on current expectations and involve inherent risks and uncertainties,
including factors that could delay, divert or change any of them, and
could cause actual outcomes and results to differ materially from
current expectations. No forward-looking statement can be guaranteed.
Among other risks, there can be no guarantee that the combination
product will receive regulatory approval in the European Union or other
geographies, or, if approved, will be commercially successful. Nor is
there any guaranty that discussions among the three companies regarding
agreements for manufacturing, commercialization and distribution of
ATRIPLA in the European Union will be successfully concluded or
implemented. Forward-looking statements in this press release should be
evaluated together with the many uncertainties that affect Bristol-Myers
Squibb's business, particularly those identified in the cautionary
factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K
for the year ended December 31, 2005 and in our Quarterly Reports on
Form 10-Q. Bristol-Myers Squibb undertakes no obligation to publicly
update any forward-looking statement, whether as a result of new
information, future events or otherwise.
Gilead Forward-Looking Statement
This press release includes forward-looking statements, within the
meaning of the Private Securities Litigation Reform Act of 1995, that
are subject to risks, uncertainties and other factors, including the
risk that ATRIPLA may not be approved in the European Union or other
markets and the risk that physicians and regulatory agencies may not see
advantages of ATRIPLA over other antiretrovirals and may therefore be
reluctant to prescribe the product. These risks, uncertainties and other
factors could cause actual results to differ materially from those
referred to in the forward-looking statements. The reader is cautioned
not to rely on these forward-looking statements. These and other risks
are described in detail in the Gilead Annual Report on Form 10-K for the
year ended December 31, 2005, filed with the U.S. Securities and
Exchange Commission. All forward-looking statements are based on
information currently available to Gilead and Gilead assumes no
obligation to update any such forward-looking statements.
Merck Forward-Looking Statement
This press release contains "forward-looking statements" as that term is
defined in the Private Securities Litigation Reform Act of 1995. These
statements are based on management's current expectations and involve
risks and uncertainties, which may cause results to differ materially
from those set forth in the statements. The forward-looking statements
may include statements regarding product development, product potential
or financial performance. No forward-looking statement can be
guaranteed, and actual results may differ materially from those
projected. Merck undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events, or otherwise. Forward-looking statements in this press
release should be evaluated together with the many uncertainties that
affect Merck's business, particularly those mentioned in the cautionary
statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31,
2005, and in its periodic reports on Form 10-Q and Form 8-K, which the
company incorporates by reference.
Full U.S. prescribing information for ATRIPLA is available at www.atripla.com.
Full U.S. prescribing information for SUSTIVA is available at www.bms.com.
Full U.S. prescribing information for Truvada, Viread and Emtriva is
available at www.gilead.com.
