AstraZeneca
(NYSE: AZN) today announced that on February 1, 2014, it completed its
acquisition of the entirety of Bristol-Myers Squibb’s interests in the
companies’ diabetes alliance. The acquisition gives AstraZeneca
ownership of the intellectual property and global rights for the
development, manufacture and commercialization of the diabetes business,
which in the U.S. includes ONGLYZA® (saxagliptin), KOMBIGLYZE™
XR (saxagliptin and metformin HCl extended release), FARXIGA™
(dapagliflozin), BYETTA® (exenatide), BYDUREON®
(exenatide extended-release for injectable suspension), Symlin®
(pramlintide acetate) and the investigational agent metreleptin.
On completion of the acquisition, AstraZeneca paid Bristol-Myers Squibb
$2.7 billion for initial consideration. AstraZeneca has also agreed to
pay up to $1.4 billion in regulatory, launch and sales payments, and
various sales-related royalty payments up until 2025, $600 million of
which relates to the approval of FARXIGA in the U.S. In addition,
AstraZeneca may make payments up to $225 million when certain assets are
subsequently transferred.
The transaction reinforces AstraZeneca’s long-term commitment to
patients with diabetes, a core strategic area and an important platform
for returning AstraZeneca to growth.
“AstraZeneca is firmly committed to working closely with healthcare
providers and the diabetes community to address the diverse medical
needs of the 25.8 million patients living with diabetes in the U.S.,”
said Paul Hudson, President, AstraZeneca US and Executive Vice
President, North America. “Under one leadership, this acquisition will
enable AstraZeneca to maximize the potential and expedite progress of
our innovative portfolio of non-insulin antidiabetic medicines.”
INDICATION and IMPORTANT SAFETY INFORMATION for ONGLYZA®
(saxagliptin) tablets
Indication and Limitations of Use for ONGLYZA:
ONGLYZA (saxagliptin) is indicated as an adjunct to diet and
exercise to improve glycemic control in adults with type 2 diabetes
mellitus in multiple clinical settings.
ONGLYZA should not be used for the treatment of type 1 diabetes mellitus
or diabetic ketoacidosis.
ONGLYZA has not been studied in patients with a history of pancreatitis.
Important Safety Information for ONGLYZA (saxagliptin):
Contraindications
-
History of a serious hypersensitivity reaction to ONGLYZA (saxagliptin)
(eg, anaphylaxis, angioedema, or exfoliative skin conditions)
Warnings and Precautions
-
Pancreatitis: There have been postmarketing reports of acute
pancreatitis in patients taking ONGLYZA (saxagliptin). After
initiating ONGLYZA, observe patients carefully for signs and symptoms
of pancreatitis. If pancreatitis is suspected, promptly discontinue
ONGLYZA and initiate appropriate management. It is unknown whether
patients with a history of pancreatitis are at increased risk of
developing pancreatitis while using ONGLYZA.
-
Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin:
When ONGLYZA was used in combination with a sulfonylurea or with
insulin, medications known to cause hypoglycemia, the incidence of
confirmed hypoglycemia was increased over that of placebo used in
combination with a sulfonylurea or with insulin. Therefore, a lower
dose of the insulin secretagogue or insulin may be required to
minimize the risk of hypoglycemia when used in combination with
ONGLYZA.
-
Hypersensitivity Reactions: There have been postmarketing
reports of serious hypersensitivity reactions in patients treated with
ONGLYZA, including anaphylaxis, angioedema, and exfoliative skin
conditions. Onset of these reactions occurred within the first 3
months after initiation of treatment with ONGLYZA, with some reports
occurring after the first dose. If a serious hypersensitivity reaction
is suspected, discontinue ONGLYZA, assess for other potential causes
for the event, and institute alternative treatment for diabetes. Use
caution in patients with a history of angioedema to another DPP-4
inhibitor as it is unknown whether they will be predisposed to
angioedema with ONGLYZA.
-
Macrovascular Outcomes: There have been no clinical studies
establishing conclusive evidence of macrovascular risk reduction with
ONGLYZA or any other antidiabetic drug.
Most Common Adverse Reactions
-
Most common adverse reactions reported in ≥5% of patients treated with
ONGLYZA (saxagliptin) and more commonly than in patients
treated with control were upper respiratory tract infection (7.7%,
7.6%), headache (7.5%, 5.2%), nasopharyngitis (6.9%, 4.0%) and urinary
tract infection (6.8%, 6.1%).
-
When used as add-on combination therapy with a thiazolidinedione, the
incidence of peripheral edema for ONGLYZA 2.5 mg, 5 mg, and placebo
was 3.1%, 8.1% and 4.3%, respectively.
-
Confirmed hypoglycemia was reported more commonly in patients treated
with ONGLYZA 2.5 mg and ONGLYZA 5 mg compared to placebo in the add-on
to glyburide trial (2.4%, 0.8% and 0.7%, respectively), with ONGLYZA 5
mg compared to placebo in the add-on to insulin (with or without
metformin) trial (5.3% and 3.3%, respectively), with ONGLYZA 2.5 mg
compared to placebo in the renal impairment trial (4.7% and 3.5%,
respectively), and with ONGLYZA 5 mg compared to placebo in the add-on
to metformin plus sulfonylurea trial (1.6% and 0.0%, respectively).
Drug Interactions
Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin
exposure, the dose of ONGLYZA (saxagliptin) should be limited to
2.5 mg when coadministered with a strong CYP3A4/5 inhibitor (eg,
atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole,
nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).
Use in Specific Populations
-
Patients with Renal Impairment: The dose of ONGLYZA
(saxagliptin) is 2.5 mg once daily for patients with moderate
or severe renal impairment, or with end-stage renal disease requiring
hemodialysis (creatinine clearance [CrCl] ≤50 mL/min). ONGLYZA should
be administered following hemodialysis. ONGLYZA has not been studied
in patients undergoing peritoneal dialysis. Assessment of renal
function is recommended prior to initiation of ONGLYZA and
periodically thereafter.
-
Pregnant and Nursing Women: There are no adequate and
well-controlled studies in pregnant women. ONGLYZA, like other
antidiabetic medications, should be used during pregnancy only if
clearly needed. It is not known whether saxagliptin is secreted in
human milk. Because many drugs are secreted in human milk, caution
should be exercised when ONGLYZA (saxagliptin) is administered to a
nursing woman.
-
Pediatric Patients: Safety and effectiveness of ONGLYZA in
pediatric patients have not been established.
Please click
here for US Full Prescribing Information for ONGLYZA (saxagliptin)
2.5 mg and 5 mg tablets and click
here for Medication Guide.
INDICATION and IMPORTANT SAFETY INFORMATION for KOMBIGLYZE™ XR
(saxagliptin and metformin HCl extended-release) tablets
Indication and Limitations of Use for KOMBIGLYZE XR:
KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) is
indicated as an adjunct to diet and exercise to improve glycemic control
in adults with type 2 diabetes mellitus when treatment with both
saxagliptin and metformin is appropriate.
KOMBIGLYZE XR should not be used for the treatment of type 1 diabetes
mellitus or diabetic ketoacidosis.
KOMBIGLYZE XR has not been studied in patients with a history of
pancreatitis.
Important Safety Information for KOMBIGLYZE XR:
BOXED WARNING: LACTIC ACIDOSIS
Lactic acidosis is a rare, but serious, complication that can occur
due to metformin accumulation. The risk increases with conditions such
as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal
impairment, and acute congestive heart failure.
The onset of lactic acidosis is often subtle, accompanied only by
nonspecific symptoms such as malaise, myalgias, respiratory distress,
increasing somnolence, and nonspecific abdominal distress.
Laboratory abnormalities include low pH, increased anion gap, and
elevated blood lactate.
If acidosis is suspected, KOMBIGLYZE XR (saxagliptin and metformin
HCI extended-release) should be discontinued and the patient
hospitalized immediately. [See Warnings and Precautions]
Contraindications
-
Renal impairment (eg, serum creatinine levels ≥1.5 mg/dL for men, ≥1.4
mg/dL for women, or abnormal creatinine clearance)
-
Hypersensitivity to metformin hydrochloride
-
Acute or chronic metabolic acidosis, including diabetic ketoacidosis
-
History of a serious hypersensitivity reaction to KOMBIGLYZE XR
(saxagliptin and metformin HCI extended-release) or saxagliptin (eg,
anaphylaxis, angioedema, or exfoliative skin conditions)
Warnings and Precautions
-
The reported incidence of lactic acidosis in patients receiving
metformin is very low (approximately 0.03 cases/1000 patient-years).
When it occurs, it is fatal in approximately 50% of cases. Reported
cases of lactic acidosis have occurred primarily in diabetic patients
with significant renal insufficiency.
-
Patients with congestive heart failure requiring pharmacologic
management, in particular those with unstable or acute congestive
heart failure who are at risk of hypoperfusion and hypoxemia, are at
increased risk of lactic acidosis.
-
Lactic acidosis risk increases with the degree of renal dysfunction
and patient age. The risk may be significantly decreased by use of
minimum effective dose of metformin and regular monitoring of renal
function. Careful renal monitoring is particularly important in the
elderly. KOMBIGLYZE XR (saxagliptin and metformin HCI
extended-release) should not be initiated in patients ≥80 years of age
unless measurement of creatinine clearance demonstrates that renal
function is not reduced.
-
Withhold KOMBIGLYZE XR in the presence of any condition associated
with hypoxemia, dehydration, or sepsis.
-
There have been postmarketing reports of acute pancreatitis in
patients taking saxagliptin. After initiating KOMBIGLYZE XR, observe
patients carefully for signs and symptoms of pancreatitis. If
pancreatitis is suspected, promptly discontinue KOMBIGLYZE XR and
initiate appropriate management. It is unknown whether patients with a
history of pancreatitis are at increased risk of developing
pancreatitis while using KOMBIGLYZE XR (saxagliptin and metformin HCI
extended-release).
-
Before initiation of KOMBIGLYZE XR, and at least annually thereafter,
renal function should be assessed and verified as normal.
-
KOMBIGLYZE XR is not recommended in patients with hepatic impairment.
-
Metformin may lower vitamin B12 levels. Measure hematological
parameters annually.
-
Warn patients against excessive alcohol intake.
-
KOMBIGLYZE XR should be suspended for any surgical procedure (except
minor procedures not associated with restricted intake of food and
fluids), and should not be restarted until patient’s oral intake has
resumed and renal function is normal.
-
Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
-
Saxagliptin: When saxagliptin was used in combination with a
sulfonylurea or with insulin, medications known to cause
hypoglycemia, the incidence of confirmed hypoglycemia was
increased over that of placebo used in combination with a
sulfonylurea or with insulin. Therefore, a lower dose of the
insulin secretagogue or insulin may be required to minimize the
risk of hypoglycemia when used in combination with KOMBIGLYZE XR.
-
Metformin: Hypoglycemia does not occur in patients receiving
metformin alone under usual circumstances of use, but could occur
when caloric intake is deficient, when strenuous exercise is not
compensated by caloric supplementation, during concomitant use
with other glucose-lowering agents (such as sulfonylureas or
insulin), or with use of ethanol. Elderly, debilitated, or
malnourished patients and those with adrenal or pituitary
insufficiency or alcohol intoxication are particularly susceptible
to hypoglycemic effects.
-
Intravascular contrast studies with iodinated materials can lead to
acute alteration of renal function and have been associated with
lactic acidosis in patients receiving metformin. KOMBIGLYZE XR should
be temporarily discontinued at the time of or prior to the procedure,
and withheld for 48 hours after the procedure and reinstituted only
after renal function is normal.
-
There have been postmarketing reports of serious hypersensitivity
reactions in patients treated with saxagliptin, including anaphylaxis,
angioedema, and exfoliative skin conditions. Onset of these reactions
occurred within the first 3 months after initiation of treatment with
saxagliptin, with some reports occurring after the first dose. If a
serious hypersensitivity reaction is suspected, discontinue KOMBIGLYZE
XR (saxagliptin and metformin HCI extended-release), assess for other
potential causes for the event, and institute alternative treatment
for diabetes. Use caution in patients with a history of angioedema to
another DPP-4 inhibitor as it is unknown whether they will be
predisposed to angioedema with KOMBIGLYZE XR.
-
There have been no clinical studies establishing conclusive evidence
of macrovascular risk reduction with KOMBIGLYZE XR or any other
anti-diabetic drug.
Adverse Reactions
-
Adverse reactions reported in >5% of patients treated with metformin
extended-release and more commonly than in patients treated with
placebo were: diarrhea (9.6% vs 2.6%) and nausea/vomiting (6.5% vs
1.5%).
-
Adverse reactions reported in ≥5% of patients treated with saxagliptin
and more commonly than in patients treated with placebo were: upper
respiratory tract infection (7.7% vs 7.6%), urinary tract infection
(6.8% vs 6.1%), and headache (6.5% vs 5.9%).
-
Adverse reactions reported in ≥5% of treatment-naive patients treated
with coadministered saxagliptin and metformin immediate-release (IR)
and more commonly than in patients treated with metformin IR alone
were: headache (7.5% vs 5.2%) and nasopharyngitis (6.9% vs 4.0%).
-
Confirmed hypoglycemia was reported more commonly in patients treated
with saxagliptin 5 mg compared to placebo in the add-on to insulin
(with or without metformin) trial (5.3% and 3.3%, respectively). Among
the patients using insulin with metformin, the incidence of confirmed
hypoglycemia was 4.8% with saxagliptin vs 1.9% with placebo. Confirmed
hypoglycemia was reported more commonly with saxagliptin 5 mg compared
to placebo in the add-on to metformin plus sulfonylurea trial (1.6%
and 0.0%, respectively).
Drug Interactions
Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin
exposure, limit KOMBIGLYZE XR (saxagliptin and metformin HCI
extended-release) to 2.5 mg/1000 mg once daily when coadministered with
a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin, indinavir,
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir,
saquinavir, and telithromycin).
Use in Specific Populations
-
Pregnant and Nursing Women: There are no adequate and
well-controlled studies in pregnant women. KOMBIGLYZE XR (saxagliptin
and metformin HCI extended-release) should be used during pregnancy
only if clearly needed. It is not known whether saxagliptin or
metformin are secreted in human milk. Because many drugs are secreted
in human milk, caution should be exercised when KOMBIGLYZE XR is
administered to a nursing woman.
-
Pediatric Patients: Safety and effectiveness of KOMBIGLYZE XR
in pediatric patients have not been established.
Please click
here for US Full Prescribing Information for KOMBIGLYZE XR
(saxagliptin and metformin HCI extended-release) (5/500*5/1000*2.5/1000
mg tablets), including Boxed WARNING about lactic acidosis, and click
here for Medication Guide.
INDICATION AND LIMITATION OF USE FOR FARXIGA™ (dapagliflozin)
FARXIGA (dapagliflozin) is indicated as an adjunct to diet and exercise
to improve glycemic control in adults with type 2 diabetes mellitus.
FARXIGA is not recommended for patients with type 1 diabetes mellitus or
for the treatment of diabetic ketoacidosis.
IMPORTANT SAFETY INFORMATION FOR FARXIGA
Contraindications
-
History of a serious hypersensitivity reaction to FARXIGA
(dapagliflozin)
-
Severe renal impairment, end stage renal disease, or patients on
dialysis
Warnings and Precautions
-
Hypotension: FARXIGA (dapagliflozin) causes intravascular
volume contraction. Symptomatic hypotension can occur after initiating
FARXIGA, particularly in patients with impaired renal function (eGFR
<60 mL/min/1.73 m2), elderly patients, or patients on
loop diuretics. Before initiating FARXIGA in patients with one or more
of these characteristics, assess and correct volume status. After
initiating therapy, monitor for signs and symptoms of hypotension.
-
Impairment in Renal Function: FARXIGA (dapagliflozin) increases
serum creatinine and decreases eGFR. Elderly patients and patients
with impaired renal function may be more susceptible to these changes.
Adverse reactions related to renal function can occur after initiating
FARXIGA. Before initiating FARXIGA, evaluate renal function and
monitor periodically thereafter. Discontinue FARXIGA when eGFR is
persistently <60 mL/min/1.73 m2.
-
Hypoglycemia with Concomitant Use with Insulin and Insulin
Secretagogues: Insulin and insulin secretagogues are known to
cause hypoglycemia. FARXIGA can increase the risk of hypoglycemia when
combined with these agents. Consider a lower dose of insulin or the
insulin secretagogue to reduce the risk of hypoglycemia when used in
combination with FARXIGA.
-
Genital Mycotic Infections: FARXIGA increases the risk of
genital mycotic infections. Patients with a history of genital mycotic
infections were more likely to develop genital mycotic infections.
Monitor and treat appropriately.
-
Increases in Low-Density Lipoprotein Cholesterol (LDL-C): Increases
in LDL-C occur with FARXIGA. After initiating FARXIGA, monitor LDL-C
and treat per standard of care.
-
Bladder cancer: Across 22 clinical studies, newly diagnosed
cases of bladder cancer were reported in 0.17% of FARXIGA-treated
patients and 0.03% of placebo/comparator-treated patients. After
excluding patients in whom exposure to study drug was <1 year at the
time of diagnosis of bladder cancer, there were 4 cases with FARXIGA
and no cases with placebo/comparator. Bladder cancer risk factors and
hematuria (a potential indicator of pre-existing tumors) were balanced
between treatment arms at baseline. There were too few cases to
determine whether the emergence of these events is related to FARXIGA.
There
are insufficient data to determine whether FARXIGA has an effect on
pre-existing bladder tumors. FARXIGA should not be used in patients
with active bladder cancer. Use with caution in patients with a prior
history of bladder cancer.
-
Macrovascular Outcomes: There have been no clinical studies
establishing conclusive evidence of macrovascular risk reduction with
FARXIGA or any other antidiabetic drug.
Adverse Reactions
-
In a pool of 12 placebo-controlled studies, the most common adverse
reactions (≥5%) treated with FARXIGA (dapagliflozin) 5 mg, 10 mg, and
placebo respectively were female genital mycotic infections (8.4% vs
6.9% vs 1.5%), nasopharyngitis (6.6% vs 6.3% vs 6.2%), and urinary
tract infections (5.7% vs 4.3% vs 3.7%).
Use in Specific Populations
-
Pregnant Women: There are no adequate and well-controlled
studies of FARXIGA (dapagliflozin) in pregnant women. Consider
appropriate alternative therapies, especially during the second and
third trimesters.
-
Nursing Mothers: It is not known whether FARXIGA is excreted in
human milk. Because of the potential for serious adverse reactions in
nursing infants from FARXIGA, discontinue nursing or discontinue
FARXIGA.
-
Geriatric Use: A higher proportion of patients ≥65 years
treated with FARXIGA had adverse reactions related to volume depletion
and renal impairment or failure compared to patients treated with
placebo. No FARXIGA dose change is recommended based on age.
Please click here for
US Full Prescribing Information and click
here for Medication Guide for FARXIGA (dapagliflozin) 5 mg and 10 mg
tablets.
INDICATION and IMPORTANT SAFETY INFORMATION for BYETTA® (exenatide)
Injection
Indication and Important Limitations of Use for BYETTA:
BYETTA (exenatide) is indicated as an adjunct to diet and exercise to
improve glycemic control in adults with type 2 diabetes mellitus.
-
Not a substitute for insulin and should not be used in patients with
type 1 diabetes or diabetic ketoacidosis.
-
Concurrent use with prandial insulin has not been studied and cannot
be recommended.
-
BYETTA has been associated with acute pancreatitis, including fatal
and non-fatal hemorrhagic or necrotizing pancreatitis, based on
postmarketing data. It is unknown whether patients with a history of
pancreatitis are at increased risk for pancreatitis while using
BYETTA; consider other antidiabetic therapies for these patients.
Important Safety Information for BYETTA:
Contraindications
-
BYETTA (exenatide) is contraindicated in patients with prior severe
hypersensitivity reactions to exenatide or to any of the product
components.
Warnings and Precautions
-
Pancreatitis: Based on postmarketing data BYETTA (exenatide) has
been associated with acute pancreatitis, including fatal and non-fatal
hemorrhagic or necrotizing pancreatitis. After initiation and dose
increases of BYETTA, observe patients carefully for pancreatitis
(including persistent severe abdominal pain, sometimes radiating to
the back, with or without vomiting). If pancreatitis is suspected,
BYETTA should be discontinued promptly and should not be restarted if
pancreatitis is confirmed.
-
Hypoglycemia: Increased risk of hypoglycemia when used in
combination with a sulfonylurea (SU) or when used with a
glucose-independent insulin secretagogues (eg, meglitinides).
Clinicians may consider reducing the SU dose in patients receiving
BYETTA to reduce the risk of hypoglycemia. When used with insulin,
evaluate and consider reducing the insulin dose in patients at
increased risk of hypoglycemia.
-
Renal Impairment: Should not be used in patients with severe
renal impairment or end-stage renal disease. Use with caution in
patients with renal transplantation or when initiating or escalating
the dose in patients with moderate renal failure. Postmarketing
reports of altered renal function, including increased serum
creatinine, renal impairment, worsened chronic renal failure, and
acute renal failure, sometimes requiring hemodialysis and kidney
transplantation.
-
Gastrointestinal Disease: Because exenatide is commonly
associated with gastrointestinal adverse reactions, BYETTA is not
recommended in patients with severe gastrointestinal disease (eg,
gastroparesis).
-
Immunogenicity: Patients may develop antibodies to exenatide.
In 3 registration trials, antibody levels were measured in 90% of
patients, with up to 4% of patients having high-titer antibodies and
attenuated glycemic response. If worsening of or failure to achieve
adequate glycemic control occurs, consider alternative antidiabetic
therapy.
-
Hypersensitivity: Postmarketing reports of serious
hypersensitivity reactions (eg, anaphylaxis and angioedema). If this
occurs, patients should discontinue BYETTA and other suspect
medications and promptly seek medical advice.
-
Macrovascular Outcomes: No clinical studies establishing
conclusive evidence of macrovascular risk reduction with BYETTA
(exenatide) or any other antidiabetic drug.
Most Common Adverse Reactions (≥5%)
-
24-week monotherapy trial vs placebo (PBO): nausea (8% vs 0%).
-
Three 30-week combination trials of BYETTA (exenatide) added to
metformin (MET) and/or SU vs PBO: nausea (44% vs 18%), vomiting (13%
vs 4%), and diarrhea (13% vs 6%), feeling jittery (9% vs 4%),
dizziness (9% vs 6%), headache (9% vs 6%), dyspepsia (6% vs 3%).
-
16-week trial of BYETTA added to thiazolidinedione (TZD) ± MET vs PBO:
nausea (40% vs 15%), vomiting (13% vs 1%), dyspepsia (7% vs 1%),
diarrhea (6% vs 3%).
-
30-week trial of BYETTA added to insulin glargine ± MET and/or TZD vs
PBO: nausea (41% vs 8%), vomiting (18% vs 4%), diarrhea (18% vs 8%),
headache (14% vs 4%), constipation (10% vs 2%), dyspepsia (7% vs 2%),
asthenia (5% vs 1%).
-
Hypoglycemia: BYETTA as monotherapy vs PBO, 3.8% (10 mcg) and
5.2% (5 mcg) vs 1.3%; BYETTA vs PBO, with metformin (MET): 5.3% (10
mcg) and 4.5% (5 mcg) vs 5.3%; with SU, 35.7% (10 mcg) and 14.4% (5
mcg) vs 3.3%; with MET + SU, 27.8% (10 mcg) and 19.2% (5 mcg) vs
12.6%; with TZD, 10.7% (10 mcg) vs 7.1%; with insulin glargine, 24.8%
(10 mcg) vs 29.5%.
-
Withdrawals: monotherapy trial: 2 of 155 BYETTA patients
withdrew due to headache and nausea vs 0 PBO-treated patients. Three
30-week combination trials of BYETTA added to MET and/or SU vs PBO:
nausea (3% vs <1%), vomiting (1% vs 0). 16-week trial of BYETTA added
to TZD ± MET vs PBO: nausea (9%) and vomiting (5%), with <1% PBO
patients withdrawing due to nausea. 30-week trial of BYETTA added to
insulin glargine ± MET and/or TZD vs PBO: nausea (5.1% vs 0), vomiting
(2.9% vs 0).
Drug Interactions
-
Oral Medications: BYETTA (exenatide) slows gastric emptying and
can reduce the extent and rate of absorption of orally administered
drugs. Use with caution with medications that have a narrow
therapeutic index or require rapid gastrointestinal absorption. Oral
medications dependent on threshold concentrations for efficacy, such
as contraceptives or antibiotics, should be taken at least 1 hour
before BYETTA.
-
Warfarin: Postmarketing reports of increased international
normalized ratio (INR) sometimes associated with bleeding with
concomitant use of warfarin. Monitor INR frequently until stable upon
initiation or alteration of BYETTA (exenatide).
Use in Specific Populations
-
Pregnant and Nursing Women: Based on animal data, BYETTA
(exenatide) may cause fetal harm and should be used during pregnancy
only if the potential benefit justifies the potential risk to the
fetus. To report drug exposure during pregnancy call 1-800-633-9081.
When administered to a nursing woman, a decision should be made
whether to discontinue nursing or discontinue BYETTA.
-
Pediatric Patients: Use in pediatric patients is not
recommended as safety and effectiveness have not been established.
Please click
here for the US full Prescribing Information for BYETTA® (exenatide)
injection 5 mcg and 10 mcg, and click
here for the Medication Guide.
INDICATION and IMPORTANT SAFETY INFORMATION for BYDUREON® (exenatide
extended-release for injectable suspension)
Indication and Important Limitations of Use for BYDUREON:
BYDUREON (exenatide extended-release for injectable suspension) is
indicated as an adjunct to diet and exercise to improve glycemic control
in adults with type 2 diabetes mellitus in multiple clinical settings.
-
Because of the uncertain relevance of the rat thyroid C-cell tumor
findings to humans, prescribe only to patients for whom potential
benefits are considered to outweigh potential risk.
-
Not recommended as first-line therapy for patients who have inadequate
glycemic control on diet and exercise.
-
Not a substitute for insulin, should not be used in patients with type
1 diabetes or diabetic ketoacidosis, and cannot be recommended for use
with insulin.
-
BYDUREON and BYETTA® (exenatide) injection both contain the
same active ingredient, exenatide, and should not be used together.
-
Exenatide has been associated with acute pancreatitis, including fatal
and non-fatal hemorrhagic or necrotizing pancreatitis, based on
postmarketing data. It is unknown whether patients with a history of
pancreatitis are at increased risk for pancreatitis while using
BYDUREON (exenatide extended-release for injectable suspension);
consider other antidiabetic therapies for these patients.
Important Safety Information for BYDUREON:
BOXED WARNING: RISK OF THYROID C-CELL TUMORS
Exenatide extended-release causes an increased incidence in thyroid
C-cell tumors at clinically relevant exposures in rats compared to
controls. It is unknown whether BYDUREON (exenatide extended-release for
injectable suspension) causes thyroid C-cell tumors, including
medullary thyroid carcinoma (MTC), in humans, as human relevance could
not be determined by clinical or nonclinical studies. BYDUREON is
contraindicated in patients with a personal or family history of MTC and
in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
Routine serum calcitonin or thyroid ultrasound monitoring is of
uncertain value in patients treated with BYDUREON. Patients should be
counseled regarding the risk and symptoms of thyroid tumors.
Contraindications
-
Patients with a personal or family history of MTC and in patients with
Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
-
Patients with prior serious hypersensitivity reactions to exenatide or
to any of the product components.
Warnings and Precautions
-
Pancreatitis: Based on postmarketing data, exenatide has been
associated with acute pancreatitis, including fatal and non-fatal
hemorrhagic or necrotizing pancreatitis. After initiation of BYDUREON
(exenatide extended-release for injectable suspension), observe
patients carefully for pancreatitis (persistent severe abdominal pain,
sometimes radiating to the back, with or without vomiting). If
pancreatitis is suspected, BYDUREON should be discontinued promptly
and should not be restarted if pancreatitis is confirmed.
-
Hypoglycemia: Increased risk of hypoglycemia when used in
combination with a sulfonylurea (SFU). Clinicians may consider
reducing the SFU dose to minimize risk of hypoglycemia. It is possible
that use of BYDUREON (exenatide extended-release for injectable
suspension) with other glucose-independent insulin secretagogues (eg,
meglitinides) could increase the risk of hypoglycemia.
-
Renal Impairment: Should not be used in patients with severe
renal impairment or end-stage renal disease. Use with caution in
patients with renal transplantation or moderate renal failure.
Postmarketing reports of altered renal function with exenatide,
including increased serum creatinine, renal impairment, worsened
chronic renal failure, and acute renal failure, sometimes requiring
hemodialysis and kidney transplantation.
-
Gastrointestinal Disease: Because exenatide is commonly
associated with gastrointestinal adverse reactions, BYDUREON is not
recommended in patients with severe gastrointestinal disease (eg,
gastroparesis).
-
Immunogenicity: Patients may develop antibodies to exenatide.
In 5 registration trials, attenuated glycemic response was associated
in 6% of BYDUREON-treated patients with antibody formation. If
worsening of or failure to achieve adequate glycemic control occurs,
consider alternative antidiabetic therapy.
-
Hypersensitivity: Postmarketing reports of serious
hypersensitivity reactions (eg, anaphylaxis and angioedema). If this
occurs, patients should discontinue BYDUREON and other suspect
medications and promptly seek medical advice.
-
Macrovascular Outcomes: No clinical studies establishing
conclusive evidence of macrovascular risk reduction with BYDUREON or
any other antidiabetic drug.
Withdrawals
-
In 5 comparator-controlled, 24- to 30-week BYDUREON (exenatide
extended-release for injectable suspension) trials, the incidence of
withdrawal due to adverse events was 4.9% for BYDUREON, 4.9% for
BYETTA, and 2.0% for other comparators. The most common adverse
reactions leading to withdrawal for BYDUREON, BYETTA, and comparators
respectively were nausea (0.5%, 1.5%, 0.3%), injection-site nodule
(0.5%, 0.0%, 0.0%), diarrhea (0.3%, 0.4%, 0.3%), injection-site
reaction (0.2%, 0.0%, 0.0%), and headache (0.2%, 0.0%, 0.0%). One
percent of BYDUREON patients withdrew due to injection-site adverse
reactions.
Most Common Adverse Reactions (≥5%)
-
BYDUREON (exenatide extended-release for injectable suspension)
vs BYETTA (exenatide):
-
24-week trial: nausea (14% vs 35%), diarrhea (9.3% vs
4.1%), injection-site erythema (5.4% vs 2.4%).
-
30-week trial: nausea (27% vs 33.8%), diarrhea (16.2% vs
12.4%), vomiting (10.8% vs 18.6%), injection-site pruritus (18.2%
vs 1.4%), constipation (10.1% vs 6.2%), gastroenteritis viral
(8.8% vs 5.5%), gastroesophageal reflux disease (7.4% vs 4.1%),
dyspepsia (7.4% vs 2.1%), injection-site erythema (7.4% vs 0.0%),
fatigue (6.1% vs 3.4%), headache (6.1% vs 4.8%), injection-site
hematoma (5.4% vs 11.0%).
-
BYDUREON vs titrated insulin glargine: nausea (12.9% vs 1.3%),
headache (9.9% vs 7.6%), diarrhea (9.4% vs 4.0%), injection-site
nodule (6.0% vs 0.0%).
-
Combination trial vs sitagliptin and pioglitazone: nausea
(24.4% vs 9.6% and 4.8%), diarrhea (20.0% vs 9.6% and 7.3%), vomiting
(11.3% vs 2.4% and 3.0%), headache (9.4% vs 9.0% and 5.5%),
constipation (6.3% vs 3.6% and 1.2%), fatigue (5.6% vs 0.6% and 3.0%),
dyspepsia (5.0% vs 3.6% and 2.4%), decreased appetite (5.0% vs 1.2%
and 0.0%), injection-site pruritus (5.0% vs 4.8% and 1.2%).
-
Monotherapy trial vs sitagliptin, pioglitazone, and metformin:
nausea (11.3% vs 3.7%, 4.3%, and 6.9%), diarrhea (10.9% vs 5.5%, 3.7%,
and 12.6%), injection-site nodule (10.5% vs 6.7%, 3.7%, and 10.2%),
constipation (8.5% vs 2.5%, 1.8%, and 3.3%), headache (8.1% vs 9.2%,
8.0%, and 12.2%), dyspepsia (7.3% vs 1.8%, 4.9%, and 3.3%).
-
Hypoglycemia: No major hypoglycemia was reported for BYDUREON-
or comparator-treated patients in five 24- to 30-week trials. Minor
hypoglycemia incidences for BYDUREON vs comparator-treated patients
were as follows: 24-week trial vs BYETTA: with SFU, 12.5% vs 11.8%;
without SFU, 0.0% for both; 30-week trial vs BYETTA: with SFU, 14.5%
vs 15.4%; without SFU, 0.0% vs 1.1%; monotherapy trial vs sitagliptin,
pioglitazone, and metformin: 2.0% vs 0.0% (all comparators);
combination trial vs sitagliptin and pioglitazone: 1.3% vs 3.0% and
1.2%; vs titrated insulin glargine, with SFU, 20.0% vs 43.9%; without
SFU, 3.7% vs 19.1%.
-
Injection-site reactions were observed more frequently in
BYDUREON-treated patients (17.1%) vs patients treated with BYETTA
(12.7%), titrated insulin glargine (1.8%), or placebo injection
(6.4%-13.0%). Injection-site reactions were observed in 14.2% of
antibody-positive patients vs 3.1% of antibody-negative patients, with
higher incidence in those with higher-titer antibodies. BYETTA-treated
patients had similar incidence between antibody-positive and
antibody-negative patients (5.8% vs 7.0%). Small, asymptomatic,
subcutaneous injection-site nodules are seen with the use of BYDUREON
(exenatide extended-release for injectable suspension).
Drug Interactions
-
Oral Medications: BYDUREON (exenatide extended-release for
injectable suspension) slows gastric emptying and can reduce the rate
of absorption of orally administered drugs. Use with caution with oral
medications.
-
Warfarin: Postmarketing reports with exenatide of increased
international normalized ratio (INR) sometimes associated with
bleeding with concomitant use of warfarin. Monitor INR frequently
until stable upon initiation or alteration of BYDUREON.
Use in Specific Populations
-
Pregnant and Nursing Women: Based on animal data, BYDUREON
(exenatide extended-release for injectable suspension) may cause fetal
harm and should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus. To report drug exposure
during pregnancy call 1-800-633-9081. When administered to a nursing
woman, a decision should be made whether to discontinue nursing or to
discontinue BYDUREON.
-
Pediatric Patients: Use in pediatric patients is not
recommended as safety and effectiveness have not been established.
Please click
here for US Full Prescribing Information for BYDUREON (exenatide
extended-release for injectable suspension) 2mg, including Boxed
WARNING regarding risk of thyroid C-cell tumors, and click
here for the Medication Guide.
INDICATIONS and IMPORTANT SAFETY INFORMATION for Symlin® (pramlintide
acetate) Injection
Indications:
Symlin® (pramlintide acetate) is indicated as adjunct
treatment in adults with type 1 or type 2 diabetes who use mealtime
insulin therapy and who have failed to achieve desired glucose control
despite optimal insulin therapy (with or without a concurrent
sulfonylurea agent and/or metformin in type 2 diabetes).
Important Safety Information:
BOXED WARNING: SEVERE HYPOGLYCEMIA
SYMLIN (pramlintide acetate) is used with insulin and has been
associated with an increased risk of insulin induced severe
hypoglycemia, particularly in patients with type 1 diabetes. When severe
hypoglycemia associated with SYMLIN use occurs, it is seen within 3
hours following a SYMLIN injection. If severe hypoglycemia occurs while
operating a motor vehicle, heavy machinery, or while engaging in other
high-risk activities, serious injuries may occur. Appropriate patient
selection, careful patient instruction, and insulin dose adjustments are
critical elements for reducing this risk.
Contraindications
-
Known hypersensitivity to SYMLIN (pramlintide acetate) or
any of its components, including metacresol
-
Confirmed diagnosis of gastroparesis
-
Hypoglycemia unawareness
Warnings
Proper patient selection is critical to safe and effective use of
SYMLIN (pramlintide acetate): Review HbA1c, recent blood glucose
monitoring data, history of insulin-induced hypoglycemia, current
insulin regimen, and body weight before initiation of therapy. Only
consider SYMLIN for patients with insulin-using type 2 or type 1
diabetes who fulfill the following criteria:
-
have failed to achieve adequate glycemic control despite
individualized insulin management
-
are receiving ongoing care under the guidance of a healthcare
professional skilled in insulin-use and supported by a diabetes
educator
Do NOT consider SYMLIN for patients meeting any of the following
criteria:
-
poor compliance with current insulin regimen
-
poor compliance with prescribed self-blood glucose monitoring
-
HbA1c >9%
-
recurrent severe hypoglycemia requiring assistance during the past 6
months
-
presence of hypoglycemia unawareness
-
confirmed diagnosis of gastroparesis
-
require the use of drugs that stimulate gastrointestinal motility
-
pediatric patients
Hypoglycemia: SYMLIN (pramlintide acetate) alone does not cause
hypoglycemia. However, SYMLIN is indicated to be co-administered with
insulin therapy and in this setting SYMLIN increases the risk of
insulin-induced severe hypoglycemia, particularly in patients with type
1 diabetes. Severe hypoglycemia associated with SYMLIN occurs within the
first 3 hours following a SYMLIN injection. Serious injuries may occur
if severe hypoglycemia occurs while operating a motor vehicle, heavy
machinery, or while engaging in other high-risk activities. Therefore,
when introducing SYMLIN therapy, appropriate precautions need to be
taken to avoid increasing the risk for insulin-induced severe
hypoglycemia. These precautions include frequent pre- and post-meal
glucose monitoring combined with an initial 50% reduction in pre-meal
doses of short-acting insulin. The addition of any antihyperglycemic
agent such as SYMLIN to an existing regimen of one or more
antihyperglycemic agents (e.g., insulin, sulfonylurea), or other agents
that can increase the risk of hypoglycemia may necessitate further
insulin dose adjustments; closely monitor blood glucose.
Precautions
Never mix SYMLIN (pramlintide acetate) and insulin:
Administer as separate injections. Mixing can alter the pharmacokinetics
of both products.
Allergy: Local allergies such as redness, swelling, or itching at
the site of injection may occur. The incidence of systemic allergic
reactions was 5% for SYMLIN plus insulin vs. 4%-5% for placebo plus
insulin.
Drug Interactions: SYMLIN slows gastric emptying. Do not
administer with drugs that alter gastrointestinal motility (e.g.,
anticholinergic agents such as atropine) or that slow the intestinal
absorption of nutrients (e.g., α-glucosidase inhibitors). SYMLIN
(pramlintide acetate) has the potential to delay the absorption of
concomitantly administered oral medications; if rapid onset is a
critical determinant of effectiveness (such as analgesics), the agent
should be administered at least 1 hour prior to or 2 hours after SYMLIN
injection.
Pregnant and Nursing Women: No adequate and well controlled
studies have been conducted in pregnant women. It is unknown whether
SYMLIN is excreted in human milk. SYMLIN should only be used in
pregnancy or while nursing if the potential benefit justifies the
potential risk.
Adverse Reactions
Most common adverse events reported in ≥ 5% of patients treated with
SYMLIN (pramlintide acetate) plus insulin and with greater incidence
than in patients treated with placebo plus insulin were:
-
Type 2 Diabetes: nausea (28% vs. 12%), headache (13% vs. 7%), anorexia
(9% vs. 2%), vomiting (8% vs. 4%), abdominal pain (8% vs. 7%), fatigue
(7% vs. 4%), dizziness (6% vs. 4%), coughing (6% vs. 4%), pharyngitis
(5% vs. 2%).
-
Type 1 Diabetes: nausea (48% vs. 17%), anorexia (17% vs. 2%),
inflicted injury (14% vs. 10%), vomiting (11% vs. 7%), arthralgia (7%
vs. 5%), fatigue (7% vs. 4%), allergic reaction (6% vs. 5%), dizziness
(5% vs. 4%).
The incidence for severe hypoglycemic adverse events in
placebo-controlled trials with SYMLIN plus insulin vs. placebo plus
insulin and with greater incidence than in patients treated with placebo
plus insulin were:
-
Type 2 Diabetes: Patient-ascertained severe hypoglycemia at 0-3 months
(8.2% vs. 2.1%) and at >3-6 months (4.7% vs. 2.4%). Medically assisted
severe hypoglycemia at 0-3 months (1.7% vs. 0.7%).
-
Type 1 Diabetes: Patient-ascertained severe hypoglycemia at 0-3 months
(16.8% vs. 10.8%) and at >3-6 months (11.1% vs. 8.7%). Medically
assisted severe hypoglycemia at 0-3 months (7.3% vs. 3.3%) and at >3-6
months (5.2% vs. 4.3%).
Please click
here for US Full Prescribing Information for SYMLIN (pramlintide
acetate) 60mcg and 120mcg injection, including Boxed WARNING for
severe hypoglycemia, and click
here for the Medication Guide.
About Type 2 Diabetes
Diabetes is estimated to affect 25.8 million people in the U.S. and more
than 382 million people worldwide. The prevalence of diabetes is
projected to reach more than 592 million people worldwide by 2035. Type
2 diabetes accounts for approximately 90-95 percent of all cases of
diagnosed diabetes. Type 2 diabetes is a chronic disease characterized
by pathophysiologic defects leading to elevated glucose levels. Over
time, this sustained hyperglycemia contributes to further progression of
the disease. Significant unmet needs still exist, as many patients
remain inadequately controlled on their current glucose-lowering regimen.
About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical business
that focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of cardiovascular,
metabolic, respiratory, inflammation, autoimmune, oncology, infection
and neuroscience diseases. AstraZeneca operates in over 100 countries
and its innovative medicines are used by millions of patients worldwide.
For more information please visit: www.astrazeneca.com.
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