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
ATRIPLA(TM) (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(R) 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(R). Emtricitabine and
tenofovir disoproxil fumarate are commercialized by Gilead Sciences
under the tradenames Emtriva(R) and Viread(R), respectively. The
compounds are commonly prescribed together as a once-daily, fixed-dose
tablet, marketed under the tradename Truvada(R) 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(R), Epivir(R), Epivir-HBV(R),
Epzicom(TM), or Trizivir(R).
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(R) (emtricitabine) and 300 mg of Viread(R) (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-naive 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-naive 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.
EU Summary of Product Characteristics for Truvada, Viread,
Emtriva, SUSTIVA and Stocrin are available at
http://www.emea.eu.int/humandocs/Humans/EPAR/a-zepar.htm.
ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences,
LLC.
SUSTIVA is a registered trademark of Bristol-Myers Squibb Pharma
Company.
Stocrin is a registered trademark of Merck & Co., Inc.
Truvada, Viread and Emtriva are registered trademarks of Gilead
Sciences, Inc.
