Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2245
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Avastin (Injection, Solution)
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Do not initiate
AVASTIN until at least 28 days following major surgery. The
surgical incision should be fully healed prior to initiation of
AVASTIN.<br/>Metastatic
Carcinoma of the Colon or Rectum: AVASTIN,
used in combination with intravenous
5���FU���based chemotherapy, is administered as
an intravenous infusion (5 mg/kg or 10 mg/kg)
every 14 days. The
recommended dose of AVASTIN, when used in combination with
bolus���IFL, is 5 mg/kg. The
recommended dose of AVASTIN, when used in combination with
FOLFOX4, is 10 mg/kg.<br/>Non���Squamous, Non���Small Cell Lung Cancer: The
recommended dose of AVASTIN is 15 mg/kg, as an IV
infusion every 3 weeks.<br/>Dose Modifications: There are
no recommended dose reductions for the use of AVASTIN.
If needed, AVASTIN should be either discontinued or
temporarily suspended as described below. AVASTIN
should be permanently discontinued in patients who develop
gastrointestinal perforation, (gastrointestinal perforation,
fistula formation in the gastrointestinal tract,
intra���abdominal abscess), fistula formation involving
an internal organ, wound dehiscence requiring medical
intervention, serious bleeding, a severe arterial thromboembolic
event, nephrotic syndrome, hypertensive crisis or hypertensive
encephalopathy. In patients developing RPLS, discontinue AVASTIN
and initiate treatment of hypertension, if present. (See
WARNINGS: Reversible Posterior Leukoencephalopathy
Syndrome.) Temporary
suspension of AVASTIN is recommended in patients with evidence
of moderate to severe proteinuria pending further evaluation and
in patients with severe hypertension that is not controlled with
medical management. The risk of continuation or temporary
suspension of AVASTIN in patients with moderate to severe
proteinuria is unknown. AVASTIN
should be suspended at least several weeks prior to elective
surgery. (See WARNINGS: Gastrointestinal
Perforation and Wound Healing
Complications and PRECAUTIONS: Surgery). AVASTIN should not be
resumed until the surgical incision is fully healed.<br/>Preparation for
Administration: AVASTIN
should be diluted for infusion by a healthcare professional
using aseptic technique. Withdraw the necessary amount of
AVASTIN to obtain the required dose and dilute in a total volume
of 100 mL of 0.9% Sodium Chloride
Injection, USP. Discard any unused portion left in a
vial, as the product contains no preservatives. Parenteral drug
products should be inspected visually for particulate matter and
discoloration prior to administration. Diluted
AVASTIN solutions for infusion may be stored at
2��C���8��C
(36��F���46��F) for up to
8 hours. No incompatibilities between AVASTIN and
polyvinylchloride or polyolefin bags have been observed. AVASTIN infusions should not be
administered or mixed with dextrose solutions.<br/>Administration: DO NOT ADMINISTER AS AN IV PUSH OR
BOLUS. The initial AVASTIN dose should be
delivered over 90 minutes as an IV infusion
following chemotherapy. If the first infusion is well tolerated,
the second infusion may be administered over
60 minutes. If the 60���minute infusion is well
tolerated, all subsequent infusions may be administered over
30 minutes.<br/>Stability and
Storage: AVASTIN
vials must be refrigerated at 2���8��C
(36���46��F). AVASTIN vials should be protected
from light. Store in the original carton until time of use.
DO NOT FREEZE. DO NOT
SHAKE.
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| dailymed-instance:descripti... |
AVASTIN (Bevacizumab) is a recombinant
humanized monoclonal IgG1 antibody that binds to and inhibits the
biologic activity of human vascular endothelial growth factor (VEGF) in
in vitro and
in vivo assay
systems. Bevacizumab contains human framework regions and the
complementarity���determining regions of a murine antibody that
binds to VEGF (1). Bevacizumab is produced in a
Chinese Hamster Ovary mammalian cell expression system in a nutrient
medium containing the antibiotic gentamicin and has a molecular weight
of approximately 149 kilodaltons. AVASTIN is a clear to
slightly opalescent, colorless to pale brown, sterile, pH 6.2
solution for intravenous (IV) infusion. AVASTIN is supplied in
100 mg and 400 mg preservative���free,
single���use vials to deliver 4 mL or 16 mL of
AVASTIN (25 mg/mL). The 100 mg product is formulated
in 240 mg��,�����trehalose dihydrate,
23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg
polysorbate 20, and Water for Injection, USP. The 400 mg
product is formulated in 960 mg��,�����trehalose dihydrate, 92.8 mg
sodium phosphate (monobasic, monohydrate), 19.2 mg sodium
phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20,
and Water for Injection, USP.
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| dailymed-instance:clinicalP... |
MECHANISM OF ACTION: Bevacizumab
binds VEGF and prevents the interaction of VEGF to its receptors
(Flt���1 and KDR) on the surface of endothelial cells.
The interaction of VEGF with its receptors leads to endothelial
cell proliferation and new blood vessel formation in in vitro models of
angiogenesis. Administration of Bevacizumab to xenotransplant
models of colon cancer in nude (athymic) mice caused reduction
of microvascular growth and inhibition of metastatic disease
progression.<br/>PHARMACOKINETICS: The
pharmacokinetic profile of Bevacizumab was assessed using an
assay that measures total serum Bevacizumab concentrations
(i.e., the assay did not distinguish between free
Bevacizumab and Bevacizumab bound to VEGF ligand). Based on a
population pharmacokinetic analysis of 491 patients who
received 1 to 20 mg/kg of AVASTIN weekly, every
2 weeks, or every 3 weeks, the estimated
half���life of Bevacizumab was approximately
20 days (range 11���50 days). The
predicted time to reach steady state was 100 days. The
accumulation ratio following a dose of 10 mg/kg of
Bevacizumab every 2 weeks was 2.8. The
clearance of Bevacizumab varied by body weight, by gender, and
by tumor burden. After correcting for body weight, males had a
higher Bevacizumab clearance (0.262 L/day vs.
0.207 L/day) and a larger V(3.25 L vs. 2.66 L) than
females. Patients with higher tumor burden (at or above median
value of tumor surface area) had a higher Bevacizumab clearance
(0.249 L/day vs. 0.199 L/day)
than patients with tumor burdens below the median. In a
randomized study of 813 patients (Study 1),
there was no evidence of lesser efficacy (hazard ratio for
overall survival) in males or patients with higher tumor burden
treated with AVASTIN as compared to females and patients with
low tumor burden. The relationship between Bevacizumab exposure
and clinical outcomes has not been explored.<br/>SPECIAL POPULATIONS: Analyses of
demographic data suggest that no dose adjustments are necessary
for age or sex. Patients with renal
impairment. No studies have been conducted to examine
the pharmacokinetics of Bevacizumab in patients with renal
impairment. Patients with hepatic
dysfunction. No studies have been conducted to examine
the pharmacokinetics of Bevacizumab in patients with hepatic
impairment.
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| dailymed-instance:contraind... |
None.
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| dailymed-instance:supply |
AVASTIN is supplied
as 4 mL and 16 mL of a sterile solution in
single���use glass vials to deliver 100 and
400 mg of Bevacizumab per vial, respectively. Single unit
100 mg carton: Contains one 4 mL vial of
AVASTIN(25 mg/mL). NDC 50242���060���01 Single unit
400 mg carton: Contains one 16 mL vial of
AVASTIN(25 mg/mL). NDC
50242���061���01
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| dailymed-instance:genericDr... | |
| dailymed-instance:boxedWarn... |
WARNINGS:<br/>GASTROINTESTINAL
PERFORATIONS: AVASTIN
administration can result in the development of gastrointestinal
perforation, in some instances resulting in fatality.
Gastrointestinal perforation, sometimes associated with
intra���abdominal abscess, occurred throughout treatment
with AVASTIN (i.e., was not correlated to duration of
exposure). The incidence of gastrointestinal perforation
(gastrointestinal perforation, fistula formation, and/or
intra���abdominal abscess) in patients with colorectal
cancer and in patients with non���small cell lung cancer
(NSCLC) receiving AVASTIN was 2.4% and 0.9%, respectively. The
typical presentation was reported as abdominal pain associated
with symptoms such as constipation and vomiting.
Gastrointestinal perforation should be included in the
differential diagnosis of patients presenting with abdominal
pain on AVASTIN. AVASTIN therapy should be permanently
discontinued in patients with gastrointestinal perforation. (See
WARNINGS: Gastrointestinal Perforations
and DOSAGE AND
ADMINISTRATION: Dose Modifications
.)<br/>WOUND HEALING
COMPLICATIONS: AVASTIN
administration can result in the development of wound
dehiscence, in some instances resulting in fatality. AVASTIN
therapy should be permanently discontinued in patients with
wound dehiscence requiring medical intervention. The appropriate
interval between termination of AVASTIN and subsequent elective
surgery required to avoid the risks of impaired wound
healing���wound dehiscence has not been determined. (See
WARNINGS: Wound Healing
Complications and DOSAGE AND
ADMINISTRATION: Dose Modifications
.)<br/>Hemorrhage: Fatal
pulmonary hemorrhage can occur in patients with NSCLC treated
with chemotherapy and AVASTIN. The incidence of severe or fatal
hemoptysis was 31% in patients with squamous histology and 2.3%
in patients with NSCLC excluding predominant squamous histology.
Patients with recent hemoptysis (���1���2 tsp of
red blood) should not receive AVASTIN. (See WARNINGS: Hemorrhage , ADVERSE REACTIONS: Hemorrhage , and DOSAGE AND
ADMINISTRATION: Dose Modifications
.)
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| dailymed-instance:activeMoi... | |
| dailymed-instance:inactiveI... | |
| dailymed-instance:possibleD... |
diseasome-diseases:1173,
diseasome-diseases:1693,
diseasome-diseases:1694,
diseasome-diseases:181,
diseasome-diseases:2175,
diseasome-diseases:2789,
diseasome-diseases:3004,
diseasome-diseases:3020,
diseasome-diseases:319,
diseasome-diseases:3365,
diseasome-diseases:4136,
diseasome-diseases:602,
diseasome-diseases:698,
diseasome-diseases:701,
diseasome-diseases:833
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| dailymed-instance:precautio... |
GENERAL: Use AVASTIN
with caution in patients with known hypersensitivity to AVASTIN
or any component of this drug product.<br/>INFUSION REACTIONS: In clinical
studies, infusion reactions with the first dose of AVASTIN were
uncommon (<3%) and severe reactions occurred in 0.2% of
patients. Infusion reactions reported in the clinical trials and
postmarketing experience include hypertension, hypertensive
crises associated with neurologic signs and symptoms, wheezing,
oxygen desaturation, NCI���CTC Grade 3
hypersensitivity, chest pain, headaches, rigors, and
diaphoresis. Adequate information on rechallenge is not
available. AVASTIN infusion should be interrupted in all
patients with severe infusion reactions and appropriate medical
therapy administered. There are
no data regarding the most appropriate method of identification
of patients who may safely be retreated with AVASTIN after
experiencing a severe infusion reaction.<br/>SURGERY: AVASTIN
therapy should not be initiated for at least 28 days
following major surgery. The surgical incision should be fully
healed prior to initiation of AVASTIN. Because of the potential
for impaired wound healing, AVASTIN should be suspended prior to
elective surgery. The appropriate interval between the
last dose of AVASTIN and elective surgery is unknown; however,
the half���life of AVASTIN is estimated to be
20 days (see CLINICAL
PHARMACOLOGY: Pharmacokinetics ) and the interval chosen should take into
consideration the half���life of the drug. (See WARNINGS: Gastrointestinal Perforations
and Wound Healing
Complications .)<br/>CARDIOVASCULAR
DISEASE: Patients
were excluded from participation in AVASTIN clinical trials if,
in the previous year, they had experienced clinically
significant cardiovascular disease. In an exploratory analysis
pooling the data from five randomized,
placebo���controlled, clinical trials conducted in
patients without a recent history of clinically significant
cardiovascular disease, the overall incidence of arterial
thromboembolic events, the incidence of fatal arterial
thromboembolic events, and the incidence of cardiovascular
thromboembolic events were increased in patients receiving
AVASTIN plus chemotherapy as compared to chemotherapy
alone.<br/>LABORATORY TESTS: Blood
pressure monitoring should be conducted every two to
three weeks during treatment with AVASTIN. Patients who
develop hypertension on AVASTIN may require blood pressure
monitoring at more frequent intervals. Patients with
AVASTIN���induced or���exacerbated hypertension
who discontinue AVASTIN should continue to have their blood
pressure monitored at regular intervals. Patients
receiving AVASTIN should be monitored for the development or
worsening of proteinuria with serial urinalyses. Patients with a
2+ or greater urine dipstick reading should undergo further
assessment, e.g., a 24���hour urine collection.
(See WARNINGS: Proteinuria and DOSAGE AND
ADMINISTRATION: Dose Modifications
.)<br/>DRUG INTERACTIONS: No formal
drug interaction studies with anti���neoplastic agents
have been conducted. In Study 1, patients with colorectal cancer
were given irinotecan/5���FU/leucovorin
(bolus���IFL) with or without AVASTIN. Irinotecan
concentrations were similar in patients receiving
bolus���IFL alone and in combination with AVASTIN. The
concentrations of SN38, the active metabolite of irinotecan,
were on average 33% higher in patients receiving
bolus���IFL in combination with AVASTIN when compared
with bolus���IFL alone. In Study 1, patients receiving
bolus���IFL plus AVASTIN had a higher incidence of
NCI���CTC Grade 3���4 diarrhea and
neutropenia. Due to high inter���patient variability and
limited sampling, the extent of the increase in SN38 levels in
patients receiving concurrent irinotecan and AVASTIN is
uncertain. In
Study 6, based on limited data, there did not appear to
be a difference in the mean exposure of either carboplatin or
paclitaxel when each was administered alone or in combination
with AVASTIN. However, 3 of the 8 patients receiving AVASTIN
plus paclitaxel/carboplatin had substantially lower paclitaxel
exposure after four cycles of treatment (at Day 63)
than those at Day 0, while patients receiving
paclitaxel/carboplatin without AVASTIN had a greater paclitaxel
exposure at Day 63 than at Day 0.<br/>CARCINOGENESIS,
MUTAGENESIS, IMPAIRMENT OF FERTILITY: No
carcinogenicity data are available for AVASTIN in animals or
humans. AVASTIN may
impair fertility. Dose���related decreases in ovarian
and uterine weights, endometrial proliferation, number of
menstrual cycles, and arrested follicular development or absent
corpora lutea were observed in female cynomolgus monkeys treated
with 10 or 50 mg/kg of AVASTIN for 13 or
26 weeks. Following a 4���or 12���week
recovery period, which examined only the high���dose
group, trends suggestive of reversibility were noted in the two
females for each regimen that were assigned to recover. After
the 12���week recovery period, follicular maturation
arrest was no longer observed, but ovarian weights were still
moderately decreased. Reduced endometrial proliferation was no
longer observed at the 12���week recovery time point,
but uterine weight decreases were still notable, corpora lutea
were absent in 1 out of 2 animals, and the number of
menstrual cycles remained reduced (67%).<br/>PREGNANCY CATEGORY
C: AVASTIN has
been shown to be teratogenic in rabbits when administered in
doses that approximate the human dose on a mg/kg basis. Observed
effects included decreases in maternal and fetal body weights,
an increased number of fetal resorptions, and an increased
incidence of specific gross and skeletal fetal alterations.
Adverse fetal outcomes were observed at all doses tested. Angiogenesis is critical to fetal development and the
inhibition of angiogenesis following administration of AVASTIN
is likely to result in adverse effects on pregnancy. There are
no adequate and well���controlled studies in pregnant
women. AVASTIN should be used during pregnancy or in any woman
not employing adequate contraception only if the potential
benefit justifies the potential risk to the fetus. All patients
should be counseled regarding the potential risk of AVASTIN to
the developing fetus prior to initiation of therapy. If the
patient becomes pregnant while receiving AVASTIN, she should be
apprised of the potential hazard to the fetus and/or the
potential risk of loss of pregnancy. Patients who discontinue
AVASTIN should also be counseled concerning the prolonged
exposure following discontinuation of therapy
(half���life of approximately 20 days) and the
possible effects of AVASTIN on fetal development.<br/>NURSING MOTHERS: It is not
known whether AVASTIN is secreted in human milk. Because human
IgG1 is secreted into human milk, the potential for absorption
and harm to the infant after ingestion is unknown. Women should
be advised to discontinue nursing during treatment with AVASTIN
and for a prolonged period following the use of AVASTIN, taking
into account the half���life of the product,
approximately 20 days
[range 11���50 days]. (See
CLINICALPHARMACOLOGY:Pharmacokineticss.)<br/>PEDIATRIC USE: The safety
and effectiveness of AVASTIN in pediatric patients has not been
studied. However, physeal dysplasia was observed in juvenile
cynomolgus monkeys with open growth plates treated for
four weeks with doses that were less than the
recommended human dose based on mg/kg and exposure. The
incidence and severity of physeal dysplasia were
dose���related and were at least partially reversible
upon cessation of treatment.<br/>GERIATRIC USE: In
Study 1, NCI���CTC Grade 3���4
adverse events were collected in all patients receiving study
drug (396 bolus���IFL plus placebo;
392 bolus���IFL plus AVASTIN; 109
5���FU/LV plus AVASTIN), while NCI���CTC
Grade 1 and 2 adverse events were collected
in a subset of 309 patients. There were insufficient
numbers of patients 65 years and older in the subset in
which NCI���CTC Grade 1���4 adverse
events were collected to determine whether the overall adverse
event profile was different in the elderly as compared to
younger patients. Among the 392 patients receiving
bolus���IFL plus AVASTIN, 126 were at least
65 years of age. Severe adverse events that occurred at
a higher incidence (���2%) in the elderly when compared
to those less than 65 years were asthenia, sepsis, deep
thrombophlebitis, hypertension, hypotension, myocardial
infarction, congestive heart failure, diarrhea, constipation,
anorexia, leukopenia, anemia, dehydration, hypokalemia, and
hyponatremia. The effect of AVASTIN on overall survival was
similar in elderly patients as compared to younger patients. In
Study 3, patients age 65 and older receiving AVASTIN
plus FOLFOX4 had a greater relative risk as compared to younger
patients for the following adverse events: nausea, emesis,
ileus, and fatigue. In
Study 5, patients age 65 and older receiving
carboplatin, paclitaxel, and AVASTIN had a greater relative risk
for proteinuria as compared to younger patients. Of the
742 patients enrolled in Genentech���sponsored
clinical studies in which all adverse events were captured, 212
(29%) were age 65 or older and 43 (6%) were age 75 or older.
Adverse events of any severity that occurred at a higher
incidence in the elderly as compared to younger patients, in
addition to those described above, were dyspepsia,
gastrointestinal hemorrhage, edema, epistaxis, increased cough,
and voice alteration. In an
exploratory, pooled analysis of 1745 patients treated
in five randomized, controlled studies, there were 618 (35%)
patients age 65 or older and 1127 patients less than
65 years of age. The overall incidence of arterial
thromboembolic events was increased in all patients receiving
AVASTIN with chemotherapy as compared to those receiving
chemotherapy alone, regardless of age. However, the increase in
arterial thromboembolic events incidence was greater in patients
65 and over (8.5% vs. 2.9%) as compared to
those less than 65 (2.1% vs. 1.4%). (See
WARNINGS: Arterial Thromboembolic Events )
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| dailymed-instance:overdosag... |
The highest dose tested in humans (20 mg/kg IV) was
associated with headache in nine of 16 patients and with severe
headache in three of 16 patients.
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| dailymed-instance:genericMe... |
bevacizumab
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| dailymed-instance:fullName |
Avastin (Injection, Solution)
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| dailymed-instance:adverseRe... |
The most serious
adverse reactions in patients receiving AVASTIN were: The most common
adverse events in patients receiving AVASTIN were asthenia, pain,
abdominal pain, headache, hypertension, diarrhea, nausea, vomiting,
anorexia, stomatitis, constipation, upper respiratory infection,
epistaxis, dyspnea, exfoliative dermatitis, and proteinuria.<br/>Adverse Reactions
in Clinical Trails: Because
clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug
cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
The adverse reaction information from clinical trials does,
however, provide a basis for identifying the adverse events that
appear to be relatedto drug use and for approximating rates. The data
described below reflect exposure to AVASTIN in 1529 patients,
including 665 receiving AVASTIN for at least 6 months
and 199 receiving AVASTIN for at least one year.
AVASTIN was studied primarily in placebo- and
active���controlled trials (n = 501, and n = 1028,
respectively).<br/>Gastrointestinal Perforation: The
incidence of gastrointestinal perforation across all
studies ranged from 0���3.7%. The incidence of
gastrointestinal perforation, in some cases fatal, in
patients with mCRC receiving AVASTIN alone or in
combination with chemotherapy was 2.4% compared to 0.3%
in patients receiving only chemotherapy. The incidence
of gastrointestinal perforation in NSCLC patients
receiving AVASTIN was 0.9% compared to 0% in patients
receiving only chemotherapy. (See WARNINGS: Gastrointestinal
Perforations and DOSAGE AND
ADMINISTRATION: Dose Modifications
.)<br/>Non-Gastrointestinal Fistula Formation: (See WARNINGS: Non���Gastrointestinal Fistula
Formation and DOSAGE AND
ADMINISTRATION: Dose
Modifications .)<br/>Would
Healing Complications: The
incidence of post���operative wound healing
and/or bleeding complications was increased in patients
with mCRC receiving AVASTIN as compared to patients
receiving only chemotherapy. Among patients requiring
surgery on or within 60 days of receiving study
treatment, wound healing and/or bleeding complications
occurred in 15% (6/39) of patients receiving
bolus���IFL plus AVASTIN as compared to 4%
(1/25) of patients who received bolus���IFL
alone. In the same study, the incidence of wound
dehiscence was also higher in the
AVASTIN���treated patients (1% vs.
0.5%).<br/>Hemorrhage: Severe or fatal hemorrhages, including hemoptysis,
gastrointestinal bleeding, hematemesis, CNS hemorrhage,
epistaxis, and vaginal bleeding occurred up to
five���fold more frequently in
AVASTIN���treated patients compared to patients
treated with chemotherapy alone. NCI���CTC
Grade 3���5 hemorrhagic events occurred
in 4.7% of NSCLC patients and 5.2% of mCRC patients
receiving AVASTIN compared to 1.1% and 0.7% for the
control groups respectively. (See WARNINGS: Hemorrhage .) The
incidence of epistaxis was higher (35% vs. 10%) in
patients with mCRC receiving bolus���IFL plus
AVASTIN compared with patients receiving
bolus���IFL plus placebo. These events were
generally mild in severity (NCI���CTC
Grade 1) and resolved without medical
intervention. Additional mild to moderate hemorrhagic
events reported more frequently in patients receiving
bolus���IFL plus AVASTIN when compared to those
receiving bolus���IFL plus placebo included
gastrointestinal hemorrhage (24% vs. 6%), minor gum
bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%).
(See WARNINGS: Hemorrhage and DOSAGE AND
ADMINISTRATION: Dose Modifications
.)<br/>Arterial
Thromboembolic Events: The
incidence of arterial thromboembolic events was
increased in NSCLC patients receiving PC plus AVASTIN
(3.0%) compared with patients receiving PC alone (1.4%).
Five events were fatal in the PC plus AVASTIN arm,
compared with 1 event in the PC alone arm. This
increased risk is consistent with that observed in
patients with mCRC. (See WARNINGS: Arterial Thromboembolic Events
, DOSAGEAND
ADMINISTRATION: Dose Modifications
and PRECAUTIONS:Geriatric Use .)<br/>Venous
Thromboembolic Events: The
incidence of NCI���CTC grade 3���4
venous thromboembolic events was higher in patients with
mCRC or NSCLC receiving AVASTIN with chemotherapy as
compared to those receiving chemotherapy alone. In
addition, in patients with mCRC, the risk of developing
a second subsequent thromboembolic event in patients
receiving AVASTIN and chemotherapy is increased compared
to patients receiving chemotherapy alone. In Study 1,
53 patients (14%) on the bolus���IFL
plus AVASTIN arm and 30 patients (8%) on the
bolus���IFL plus placebo arm received full dose
warfarin following a venous thromboembolic event. Among
these patients, an additional thromboembolic event
occurred in 21% (11/53) of patients receiving
bolus���IFL plus AVASTIN and 3% (1/30) of
patients receiving bolus���IFL alone. The
overall incidence of NCI���CTC Grade
3���4 venous thromboembolic events in Study 1
was 15.1% in patients receiving bolus���IFL plus
AVASTIN and 13.6% in patients receiving
bolus���IFL plus placebo. In Study 1, the
incidence of the following NCI���CTC Grade 3 and
4 venous thromboembolic events was higher in patients
receiving bolus���IFL plus AVASTIN as compared
to patients receiving bolus���IFL plus placebo:
deep venous thrombosis (34 vs. 19 patients) and
intra���abdominal venous thrombosis (10 vs. 5
patients).<br/>Hypertension: Fatal CNS hemorrhage complicating AVASTIN induced
hypertension can occur. In
Study 1 the incidences of hypertension and of
severe hypertension were increased in patients with mCRC
receiving AVASTIN compared to those receiving
chemotherapy alone (see Table 3). Among patients with severe hypertension in the AVASTIN
arms, slightly over half the patients (51%) had a
diastolic reading greater than 110 mmHg associated with
a systolic reading less than 200 mmHg. Similar results were seen in patients receiving AVASTIN
alone or in combination with FOLFOX4 or carboplatin and
paclitaxel. (See WARNINGS: Hypertension and DOSAGE AND
ADMINISTRATION: Dose Modifications
.)<br/>Neutropenia
and Infection: An
increased incidence of neutropenia has been reported in
patients receiving AVASTIN and chemotherapy compared to
chemotherapy alone. In Study 1, the incidence
of NCI���CTC Grade 3 or 4 neutropenia
was increased in patients with mCRC receiving
IFL+AVASTIN (21%) compared to patients receiving IFL
alone (14%). In Study 5, the incidence of
NCI���CTC Grade 4 neutropenia was
increased in patients with NSCLC receiving PC plus
AVASTIN (26.2%) compared with patients receiving PC
alone (17.2%). Febrile neutropenia was also increased
(5.4% for PC plus AVASTIN vs. 1.8% for PC alone). There
were 19 (4.5%) infections with NCI���CTC
Grade 3 or 4 neutropenia in the PC plus AVASTIN
arm of which 3 were fatal compared to 9 (2%) neutropenic
infections in patients receiving PC alone, of which none
were fatal. During the first 6 cycles of treatment, the
incidence of serious infections including pneumonia,
febrile neutropenia, catheter infections and wound
infections was increased in the PC plus AVASTIN arm [58
patients (13.6%)] compared to the PC alone arm [29
patients (6.6%)].<br/>Proteinuria: (See WARNINGS:
Proteinuria , DOSAGE AND
ADMINISTRATION:
Dose Modifications
, and PRECAUTIONS:
Geriatric Use .)<br/>Immunogenicity: As
with all therapeutic proteins, there is a potential for
immunogenicity. The incidence of antibody development in
patients receiving AVASTIN has not been adequately
determined because the assay sensitivity was inadequate
to reliably detect lower titers. Enzyme linked
immunosorbent assays (ELISAs) were performed on sera
from approximately 500 patients treated with AVASTIN,
primarily in combination with chemotherapy. High titer
human anti���AVASTIN antibodies were not
detected. Immunogenicity data are highly dependent on the
sensitivity and specificity of the assay. Additionally,
the observed incidence of antibody positivity in an
assay may be influenced by several factors, including
sample handling, timing of sample collection,
concomitant medications, and underlying disease. For
these reasons, comparison of the incidence ofantibodies
to AVASTIN with the incidence of antibodies to other
products may be misleading.<br/>Metastatic
Carcinoma of the Colon and Rectum: The data in
Tables 4 and 5 were obtained in Study 1. All
NCI���CTC Grade 3 and 4 adverse events and selected NCI���CTC Grade 1 and 2 adverse events
(hypertension, proteinuria, thromboembolic events) were reported
for the overall study population. The median age was 60, 60%
were male, 79% were Caucasian, 78% had a colon primary lesion,
56% had extra���abdominal disease, 29% had prior
adjuvant or neoadjuvant chemotherapy, and 57% had ECOG
performance status of 0. The median duration of exposure to
AVASTIN was 8 months in Arm 2 and 7 months in Arm 3. Severe and
life threatening (NCI���CTC Grade 3 and 4) adverse
events, which occurred at a higher incidence (���2%) in
patients receiving bolus���IFL plus AVASTIN as compared
to bolus���IFL plus placebo, are presented in Table 4. NCI���CTC Grade 1���4 adverse events which
occurred at a higher incidence (���5%) in patients
receiving bolus���IFL plus AVASTIN as compared to the
bolus���IFL plus placebo arm, are presented in Table 5. The data in
Table 6 were obtained in
Study 3. Only NCI���CTC Grade 3���5
non���hematologic and Grade 4���5 hematologic
adverse events related to treatment were reported. The median
age was 61 years, 40% were female, 87% were Caucasian, 99%
received prior chemotherapy for metastatic colorectal cancer,
26% had received prior radiation therapy, and the 49% had an
ECOG performance status of 0. Selected NCI���CTC Grade
3���5 non���hematologic and Grade 4���5
hematologic adverse events which occurred at a higher incidence
in patients receiving FOLFOX4 plus AVASTIN as compared to those
who received FOLFOX4 alone, are presented in Table 6. These data are
likely to under���estimate the true adverse event rates
due to the reporting mechanisms used in Study 3.<br/>Non���Squamous, Non���Small Cell Lung Cancer: The data in
Table
7 were obtained in Study 5. Only NCI���CTC
Grade 3���5 non���hematologic and Grade
4���5 hematologic adverse events were reported. The
median age was 63, 46% were female, no patients had received
prior chemotherapy, 76% had Stage IV disease, 12% had Stage IIIB
disease with malignant pleural effusion, 11% had recurrent
disease, and 40% had an ECOG performance status of 0. The median
duration of exposure to AVASTIN was 4.9 months. NCI CTC
Grade 3, 4, and 5 adverse events that occurred at a���2% higher incidence in patients receiving PC plus
AVASTIN as compared with PC alone are presented in Table
7.<br/>Other Serious
Adverse Events: The
following additional serious adverse events occurred in at least
one subject treated with AVASTIN in clinical studies or
post���marketing experience. Body as a Whole:
polyserositis Digestive: intestinal necrosis,
mesenteric venous occlusion, anastomotic
ulceration Hemic and lymphatic: pancytopenia Respiratory: nasal septum
perforation
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| dailymed-instance:warning |
GASTROINTESTINAL
PERFORATIONS: AVASTIN
administration can result in the development of gastrointestinal
perforation, in some instances resulting in fatality.
Gastrointestinal perforation, sometimes associated with
intra���abdominal abscess, occurred throughout treatment
with AVASTIN (i.e., was not correlated to duration of
exposure). The incidence of gastrointestinal perforation
(gastrointestinal perforation, fistula formation, and/or
intra���abdominal abscess) in patients with colorectal
cancer and in patients with non���small cell lung cancer
(NSCLC) receiving AVASTIN was 2.4% and 0.9%, respectively. The
typical presentation was reported as abdominal pain associated
with symptoms such as constipation and vomiting.
Gastrointestinal perforation should be included in the
differential diagnosis of patients presenting with abdominal
pain on AVASTIN. AVASTIN therapy should be permanently
discontinued in patients with gastrointestinal perforation. (See
WARNINGS: Gastrointestinal Perforations
and DOSAGE AND
ADMINISTRATION: Dose Modifications
.)<br/>WOUND HEALING
COMPLICATIONS: AVASTIN
administration can result in the development of wound
dehiscence, in some instances resulting in fatality. AVASTIN
therapy should be permanently discontinued in patients with
wound dehiscence requiring medical intervention. The appropriate
interval between termination of AVASTIN and subsequent elective
surgery required to avoid the risks of impaired wound
healing���wound dehiscence has not been determined. (See
WARNINGS: Wound Healing
Complications and DOSAGE AND
ADMINISTRATION: Dose Modifications
.)<br/>Hemorrhage: Fatal
pulmonary hemorrhage can occur in patients with NSCLC treated
with chemotherapy and AVASTIN. The incidence of severe or fatal
hemoptysis was 31% in patients with squamous histology and 2.3%
in patients with NSCLC excluding predominant squamous histology.
Patients with recent hemoptysis (���1���2 tsp of
red blood) should not receive AVASTIN. (See WARNINGS: Hemorrhage , ADVERSE REACTIONS: Hemorrhage , and DOSAGE AND
ADMINISTRATION: Dose Modifications
.)
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| dailymed-instance:indicatio... |
AVASTIN, in combination with intravenous
5���fluorouracil���based chemotherapy, is indicated for
first- or second���line treatment of patients with metastatic
carcinoma of the colon or rectum. AVASTIN, in combination with carboplatin and
paclitaxel, is indicated for first���line treatment of patients
with unresectable, locally advanced, recurrent or metastatic
non-squamous, non-small cell lung cancer.
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| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Avastin
|