Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/94
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ARIXTRA (Injection, Solution)
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ARIXTRA Injection is administered by subcutaneous
injection once daily.<br/>Deep Vein Thrombosis Prophylaxis
Following Hip Fracture, or Hip or Knee Replacement Surgeries: In patients undergoing
hip fracture, hip replacement, or knee replacement surgery, the recommended
dose of ARIXTRA is 2.5 mg administered by subcutaneous injection
once daily. After hemostasis has been established, the initial dose
should be given 6 to 8 hours after surgery. Administration before
6 hours after surgery has been associated with an increased risk of
major bleeding. The usual duration of administration is 5 to 9 days,
and up to 11 days administration has been tolerated. In patients
undergoing hip fracture surgery, an extended prophylaxis course of
up to 24 additional days is recommended. In patients undergoing
hip fracture surgery, a total of 32 days (peri-operative and
extended prophylaxis) has been tolerated. (See CLINICAL STUDIES, WARNINGS:
Laboratory Testing and ADVERSE REACTIONS.)<br/>Deep Vein Thrombosis Prophylaxis
Following Abdominal Surgery: In patients undergoing abdominal surgery, the recommended
dose of ARIXTRA is 2.5 mg administered by subcutaneous injection
once daily after hemostasis has been established. The initial dose
should be given 6 to 8 hours after surgery. Administration before
6 hours after surgery has been associated with an increased risk
of major bleeding. The usual duration of administration is 5 to 9 days,
andup to 10 days of ARIXTRA injection has been administered.<br/>Deep Vein Thrombosis and Pulmonary
Embolism Treatment: In patients with acute symptomatic DVT and in patients
with acute symptomatic PE the recommended dose of ARIXTRA is 5 mg
(body weight<50 kg), 7.5 mg (body weight 50-100 kg),
or 10 mg (body weight>100 kg) by subcutaneous injection
once daily (ARIXTRA treatment regimen). Treatment with ARIXTRA should
be continued for at least 5 days and until a therapeutic oral
anticoagulant effect is established (INR 2.0 to 3.0). Concomitant
treatment with warfarin sodium should be initiated as soon as possible,
usually within 72 hours. The usual duration of administration
of ARIXTRA is 5 to 9 days; up to 26 days of ARIXTRA injection
has been administered. (See CLINICAL STUDIES, WARNINGS: Laboratory
Testing and ADVERSE REACTIONS.)
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ARIXTRA (fondaparinux sodium)
Injection is a sterile solution containing fondaparinux sodium. It
is a synthetic and specific inhibitor of activated Factor X (Xa).
Fondaparinux sodium is methyl O-2-deoxy-6-O-sulfo-2-(sulfoamino)-��-D-glucopyranosyl-(1���4)-O-��-D-glucopyra-nuronosyl-(1���4)-O-2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-��-D-glucopyranosyl-(1���4)-O-2-O-sulfo-��-L-idopyranuronosyl-(1���4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-��-D-glucopyranoside,
decasodium salt. The molecular formula
of fondaparinux sodium is CHNNaOSand its molecular weight
is 1728. The structural formula is provided below: ARIXTRA
is supplied as a sterile, preservative-free injectable solution for
subcutaneous use. Each single dose, prefilled
syringe of ARIXTRA, affixed with an automatic needle protection system,
contains 2.5 mg of fondaparinux sodium in 0.5 mL, 5.0 mg
of fondaparinux sodium in 0.4 mL, 7.5 mg of fondaparinux
sodium in 0.6 mL, or 10.0 mg of fondaparinux sodium in 0.8 mL
of an isotonic solution of sodium chloride and water for injection.
The final drug product is a clear and colorless to slightly yellow
liquid with a pH between 5.0 and 8.0.
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Pharmacodynamics:<br/>Mechanism of Action: The antithrombotic activity of fondaparinux sodium
is the result of antithrombin III (ATIII)-mediated selective inhibition
of Factor Xa. By selectively binding to ATIII, fondaparinux sodium
potentiates (about 300 times) the innate neutralization of Factor
Xa by ATIII. Neutralization of Factor Xa interrupts the blood coagulation
cascade and thus inhibits thrombin formation and thrombus development. Fondaparinux sodium does not inactivate thrombin (activated
Factor II) and has no known effect on platelet function. At the recommended
dose, fondaparinux sodium does not affect fibrinolytic activity or
bleeding time.<br/>Anti-Xa Activity: The pharmacodynamics/pharmacokinetics of fondaparinux
sodium are derived from fondaparinux plasma concentrations quantified
via anti-Factor Xa activity. Only fondaparinux can be used to calibrate
the anti-Xa assay. (The international standards of heparin or LMWH
are not appropriate for this use.) As a result, the activity of fondaparinux
sodium is expressed as milligrams (mg) of the fondaparinux calibrator.
The anti-Xa activity of the drug increases with increasing drug concentration,
reaching maximum values in approximately 3 hours.<br/>Pharmacokinetics:<br/>Absorption: Fondaparinux sodium administered by subcutaneous
injection is rapidly and completely absorbed (absolute bioavailability
is 100%). Following a single subcutaneous dose of fondaparinux sodium
2.5 mg in young male subjects, Cof 0.34 mg/L
is reached in approximately 2 hours. In patients undergoing treatment
with fondaparinux sodium injection 2.5 mg, once daily, the peak
steady-state plasma concentration is, on average, 0.39-0.50 mg/L
and is reached approximately 3 hours post-dose. In these patients,
the minimum steady-state plasma concentration is 0.14-0.19 mg/L.
In patients with symptomatic deep vein thrombosis and pulmonary embolism
undergoing treatment with fondaparinux sodium injection 5 mg
(body weight<50 kg), 7.5 mg (body weight 50-100 kg)
and 10 mg (body weight>100 kg) once daily, the body-weight-adjusted
doses provide similar mean steady-state peaks and minimum plasma concentrations
across all body weight categories. The mean peak steady-state plasma
concentration is in the range of 1.20-1.26 mg/L. In these patients,
the mean minimum steady-state plasma concentration is in the range
of 0.46-0.62 mg/L.<br/>Distribution: In healthy
adults, intravenously or subcutaneously administered fondaparinux
sodium distributes mainly in blood and only to a minor extent in extravascular
fluid as evidenced by steady state and non-steady state apparent volume
of distribution of 7-11 L. Similar fondaparinux distribution
occurs in patients undergoing elective hip surgery or hip fracture
surgery. In vitro, fondaparinux
sodium is highly (at least 94%) and specifically bound to antithrombin
III (ATIII) and does not bind significantly to other plasma proteins
(including platelet Factor 4 [PF4]) or red blood cells.<br/>Metabolism: In vivo
metabolism of fondaparinux has not been investigated since the majority
of the administered dose is eliminated unchanged in urine in individuals
with normal kidney function.<br/>Elimination: In individuals
with normal kidney function fondaparinux is eliminated in urine mainly
as unchanged drug. In healthy individuals up to 75 years of age,
up to 77% of a single subcutaneous or intravenous fondaparinux dose
is eliminated in urine as unchanged drug in 72 hours. The elimination
half-life is 17-21 hours.<br/>Special Populations:<br/>Renal Impairment: Fondaparinux elimination is prolonged in patients
with renal impairment since the major route of elimination is urinary
excretion of unchanged drug. In patients undergoing prophylaxis following
elective hip surgery or hip fracture surgery, the total clearance
of fondaparinux is approximately 25% lower in patients with mild renal
impairment (creatinine clearance 50 to 80 mL/min), approximately
40% lower in patients with moderate renal impairment (creatinine clearance
30 to 50 mL/min), and approximately 55% lower in patients with
severe renal impairment (<30 mL/min) compared to patients
with normal renal function. A similar relationship between fondaparinux
clearance and extent of renal impairment was observed in DVT treatment
patients. (See CONTRAINDICATIONS and WARNINGS: Renal Impairment.)<br/>Hepatic Impairment: The pharmacokinetic properties of fondaparinux have
not been studied in patients with hepatic impairment.<br/>Elderly Patients: Fondaparinux elimination is prolonged in patients
older than 75 years. In studies evaluating fondaparinux sodium
2.5 mg prophylaxis in hip fracture surgery or elective hip surgery,
the total clearance of fondaparinux was approximately 25% lower in
patients older than 75 years as compared to patients younger
than 65 years. A similar relationship between fondaparinux clearance
and age was observed in DVT treatment patients.<br/>Patients Weighing Less Than
50 kg: Total clearance of fondaparinux sodium is decreased
by approximately 30% in patients weighing less than 50 kg (see
CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).<br/>Gender: The pharmacokinetic properties of fondaparinux sodium
are not significantly affected by gender.<br/>Race: Pharmacokinetic differences due to race have not
been studied prospectively. However, studies performed in Asian (Japanese)
healthy subjects did not reveal a different pharmacokinetic profile
compared to Caucasian healthy subjects. Similarly, no plasma clearance
differences were observed between black and Caucasian patients undergoing
orthopedic surgery.<br/>Drug Interactions: See PRECAUTIONS: Drug Interactions.
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ARIXTRA Injection is contraindicated in patients
with severe renal impairment (creatinine clearance<30 mL/min).
ARIXTRA is eliminated primarily by the kidneys, and such patients
are at increased risk for major bleeding episodes (see WARNINGS: Renal
Impairment). ARIXTRA prophylactic therapy
is contraindicated in patients with body weight<50 kg undergoing
hip fracture, hip replacement or knee replacement surgery, and abdominal
surgery. During the randomized clinical trials of prophylaxis in the
peri-operative period following hip fracture, hip replacement, or
knee replacement surgery, occurrence of major bleeding was doubled
in patients with a body weight<50 kg compared with those
with a body weight���50 kg (5.4% versus 2.1%). In the clinical
trial in patients undergoing abdominal surgery, the major bleeding
rate was also higher in patients with a body weight<50 kg
as compared to those with a body weight���50 kg (5.3% versus
3.3%), respectively. The use of ARIXTRA
is contraindicated in patients with active major bleeding, bacterial
endocarditis, in patients with thrombocytopenia associated with a
positive in vitro test for anti-platelet antibody in the presence
of fondaparinux sodium, or in patients with known hypersensitivity
to fondaparinux sodium.
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ARIXTRA Injection is available in the following
strengths and package sizes: 2.5 mg ARIXTRA
in 0.5 mL single dose prefilled syringe, affixed with a 27-gauge x��-inch needle with a blue automatic needle protection system NDC 0007-3230-02 2 Single Unit Syringes NDC 0007-3230-1110 Single Unit Syringes 5 mg ARIXTRA in 0.4 mL single dose prefilled syringe, affixed
with a 27-gauge x��-inch needle with an orange automatic needle
protection system NDC 0007-3232-022 Single
Unit Syringes NDC 0007-3232-1110 Single
Unit Syringes 7.5 mg ARIXTRA in 0.6 mL single
dose prefilled syringe, affixed with a 27-gauge x��-inch needle
with a magenta automatic needle protection system NDC 0007-3234-022 Single Unit Syringes NDC 0007-3234-11 10 Single Unit Syringes 10
mg ARIXTRA in 0.8 mL single dose prefilled syringe, affixed with a
27-gauge x��-inch needle with a violet automatic needle protectionsystem NDC 0007-3236-02 2 Single Unit Syringes NDC 0007-3236-1110 Single Unit Syringes Store at 25��C (77��F); excursions permitted
to 15���30��C (59���86��F) [See USP Controlled Room
Temperature]. Keep
out of the reach of children. Distributed
by GlaxoSmithKline Research Triangle Park, NC
27709 ARIXTRA is a registered trademark of GlaxoSmithKline. ��2008, GlaxoSmithKline. All rights reserved. April 2008ARX:1PI
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SPINAL/EPIDURAL HEMATOMAS: When neuraxial anesthesia (epidural/spinal anesthesia)
or spinal puncture is employed, patients anticoagulated or scheduled
to be anticoagulated with low molecular weight heparins, heparinoids,
or fondaparinux sodium for prevention of thromboembolic complications
are at risk of developing an epidural or spinal hematoma which can
result in long-term or permanent paralysis. The risk of these events is increased by the use of indwelling
epidural catheters for administration of analgesia or by the concomitant
use of drugs affecting hemostasis such as non-steroidal anti-inflammatory
drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The
risk also appears to be increased by traumatic or repeatedepidural
or spinal puncture. Patients should be frequently
monitored for signs and symptoms of neurologic impairment. If neurologic
compromise is noted, urgent treatment is necessary. The physician should consider the potential benefit versus risk
before neuraxial intervention in patients anticoagulated or to be
anticoagulated for thromboprophylaxis (see also WARNINGS: Hemorrhage
and PRECAUTIONS: Drug Interactions.)
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General: ARIXTRA Injection should
be administered according to the recommended regimen, especially with
respect to the timing of the first dose after surgery. In the hip
fracture, hip replacement, knee replacement, or abdominal surgery
clinical studies, the administration of ARIXTRA before 6 hours
after surgery has been associated with an increased risk of major
bleeding (see ADVERSE REACTIONS: Hemorrhage and DOSAGE AND ADMINISTRATION). ARIXTRA
Injection should be used with care in patients with a bleeding diathesis,
uncontrolled arterial hypertension, or a history of recent gastrointestinal
ulceration, diabetic retinopathy, and hemorrhage. ARIXTRA Injection should be used with caution in elderly patients
(see PRECAUTIONS: Geriatric Use). ARIXTRA
should be used with caution in patients with a low body weight (<50 kg)
for the treatment of PE and DVT. The needle
guard of the prefilled syringe of ARIXTRA contains dry natural latex
rubber that may cause allergic reactions in latex sensitive individuals. ARIXTRA Injection should not be mixed with other injections
or infusions. If thrombotic events occur
despite prophylaxis with ARIXTRA, appropriate therapy should be initiated.<br/>Laboratory Tests: Periodic routine complete blood counts (including
platelet count), serum creatinine level, and stool occult blood tests
are recommended during the course of treatment with ARIXTRA Injection. When administered at the recommended doses, routine
coagulation tests such as Prothrombin Time (PT) and Activated Partial
Thromboplastin Time (aPTT) are relatively insensitive measures of
ARIXTRA activity, and are therefore, unsuitable for monitoring. The anti-Factor Xa activity of fondaparinux sodium
can be measured by anti-Xa assay using the appropriate calibrator
(fondaparinux). Since the international standards of heparin or LMWH
are not appropriate calibrators, the activity of fondaparinux sodium
is expressed in milligrams (mg) of the fondaparinux and cannot be
compared with activities of heparin or low molecular weight heparins
(see CLINICAL PHARMACOLOGY: Pharmacodynamics and Pharmacokinetics
and WARNINGS: Laboratory Testing).<br/>Drug Interactions: In clinical studies performed with ARIXTRA, the
concomitant use of oral anticoagulants (warfarin), platelet inhibitors
(acetylsalicylic acid), NSAIDs (piroxicam), and digoxin did not significantly
affect the pharmacokinetics/pharmacodynamics of fondaparinux sodium.
In addition, ARIXTRA neither influenced the pharmacodynamics of warfarin,
acetylsalicylic acid, piroxicam, and digoxin, nor the pharmacokinetics
of digoxin at steady state. Agents that
may enhance the risk of hemorrhage should be discontinued prior to
initiation of therapy with ARIXTRA. If co-administration is essential,
close monitoring may be appropriate. In
an in vitro study in human liver microsomes, inhibition of CYP2A6
hydroxylation of coumarin by fondaparinux (200��M i.e.,
350 mg/L) was 17-28%. Inhibition of the other isozymes evaluated
(CYPs 2A1, 2C9, 2C19, 2D6, 3A4, and 3E1) was 0-16%. Since fondaparinux
does not markedly inhibit CYP450s (CYP1A2, CYP2A6, CYP2C9, CYP2C19,
CYP2D6, CYP2E1, or CYP3A4) in vitro,fondaparinux sodium is not expected to significantly interact with
other drugs in vivo by inhibition of metabolism mediated by these
isozymes. Since fondaparinux sodium does
not bind significantly to plasma proteins other than ATIII, no drug
interactions by protein-binding displacement are expected.<br/>Carcinogenesis, Mutagenesis,
Impairment of Fertility: No long-term studies in animals have been performed
to evaluate the carcinogenic potential of fondaparinux sodium. Fondaparinux sodium was not genotoxic in the Ames
test, the mouse lymphoma cell (L5178Y/TK) forward mutation
test, the human lymphocyte chromosome aberration test, the rat hepatocyte
unscheduled DNA synthesis (UDS) test, or the rat micronucleus test. At subcutaneous doses up to 10 mg/kg/day (about
32 times the recommended human dose based on body surface area),
fondaparinux sodium was found to have no effect on fertility and reproductive
performance of male and female rats.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in pregnant rats at subcutaneous
doses up to 10 mg/kg/day (about 32 times the recommended
human dose based on body surface area) and pregnant rabbits at subcutaneous
doses up to 10 mg/kg/day (about 65 times the recommended
human dose based on body surface area) and have revealed no evidence
of impaired fertility or harm to the fetus due to fondaparinux sodium.
There are, however, no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive
of human response, this drug should be used during pregnancy only
if clearly needed.<br/>Nursing Mothers: Fondaparinux sodium was found to be excreted in
the milk of lactating rats. However, it is not known whether this
drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when fondaparinux sodium is
administered to a nursing mother.<br/>Pediatric Use: Safety and effectiveness
of ARIXTRA in pediatric patients have not been established.<br/>Geriatric Use: ARIXTRA should
be used with caution in elderly patients. Over 3,000 patients, 65 years
and older, have received ARIXTRA 2.5 mg in randomized clinical
trials. Over 1,200 patients, 65 years and older, have received
the ARIXTRA treatment regimen in the DVT and PE treatment clinical
trials. The efficacy of ARIXTRA in the elderly (equal to or older
than 65 years) was similar to that seen in younger patients (younger
than65 years). In the peri-operative hip fracture, hip replacement,
or knee replacement surgery clinical trials with patients receiving
ARIXTRA 2.5 mg, the risk of major bleeding associated with use
of ARIXTRA increased with age: 1.8% (23/1,253) in patients<65 years,
2.2% (24/1,111) in those 65-74 years, and 2.7% (33/1,227) in
those���75 years. Serious adverse events increased with
age for patients receiving ARIXTRA. In patients undergoing 3 weeks
of extended prophylaxis following one week of peri-operative prophylaxis
after hip fracture surgery, the incidence of major bleeding was: 1.9%
(1/52) in patients<65 years, 1.4% (1/71) in those 65-74 years,
and 2.9% (6/204) in those���75 years. In the abdominal
surgery clinical trial, the risk of major bleeding associated with
use of ARIXTRA increased with age: 3.0% (19/644) in patients<65
years, 3.2% (16/507) in those 65-74 years, and 5.0% (14/282)
in those���75 years. In the DVT and PE treatment clinical trials
with patients receiving the ARIXTRA treatment regimen, the risk of
major bleeding associated with ARIXTRA increased with age: 0.6% (7/1,151)
in patients<65 years, 1.6% (9/560) in those 65-74 years,
and 2.1% (12/583) in those���75 years. Careful attention
to dosing directions and concomitant medications (especially anti-platelet
medication) is advised (see CLINICAL PHARMACOLOGY and PRECAUTIONS:
General). Fondaparinux sodium is substantially
excreted by the kidney, and the risk of toxic reactions to ARIXTRA
may be greater in patients with impaired renal function. Because elderly
patients are more likely to have decreased renal function, it may
be useful to monitor renal function (see CONTRAINDICATIONS and WARNINGS:
Renal Impairment).
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Symptoms/Treatment: There is no known antidote for ARIXTRA Injection.
Overdose of ARIXTRA may lead to hemorrhagic complications. Overdosage
associated with bleeding complications should lead to treatment discontinuation
and initiation of appropriate therapy. Data
obtained in patients undergoing chronic intermittent hemodialysis
suggest that clearance of ARIXTRA can increase by 20% during hemodialysis.
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fondaparinux sodium
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ARIXTRA (Injection, Solution)
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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 possible adverse events and for approximating
rates. The data described below reflect
exposure in 8,877 patients randomized to ARIXTRA Injection in controlled
trials of hip fracture, hip replacement, major knee, or abdominal
surgeries, and DVT and PE treatment. Patients received ARIXTRA primarily
in 2 large peri-operative dose-response trials (n = 989),
4 active-controlled peri-operative trials with enoxaparin sodium (n = 3,616),
and an extended prophylaxis trial (n = 327), an active-controlled
trial with dalteparin sodium (n = 1,425), a dose-response trial in
DVT treatment (n = 111), an active-controlled trial with
enoxaparin sodium in DVT treatment (n = 1,091), and an active-controlled
trial with heparin in PE treatment (n = 1,092) (see CLINICAL
STUDIES).<br/>Hemorrhage: During administration of ARIXTRA, the most common
adverse reactions were bleeding complications (see WARNINGS).<br/>Hip Fracture, Hip Replacement
and Knee Replacement Surgery: The rates of major bleeding events reported during
the hip fracture, hip replacement, or knee replacement surgery clinical
trials with ARIXTRA 2.5 mg Injection are provided in Tables 8 and
9 below. A separate analysis of major bleeding across
all randomized, controlled, peri-operative, prophylaxis clinical studies
of hip fracture, hip replacement, or knee replacement surgery according
to the time of the first injection of ARIXTRA after surgical closure
was performed in patients who received ARIXTRA only post-operatively.
In this analysis, the incidences of major bleeding were as follows:<4 hours was 4.8% (5/104), 4-6 hours was 2.3% (28/1196),
6-8 hours was 1.9% (38/1965). In all studies, the majority (���75%)
of the major bleeding events occurred during the first 4 days after
surgery.<br/>Abdominal Surgery: The rates of major bleeding reported during the
abdominal surgery clinical trial with ARIXTRA 2.5 mg are provided
in Table 10 below. A separate analysis of major bleeding according
to the time of the first injection of ARIXTRA after surgical closure
was performed. In this analysis the incidences of major bleeding were
as follows:<6 hours was 3.4% (9/263) and 6-8 hours was 2.9% (32/1112).<br/>Treatment of Deep Vein Thrombosis
and Pulmonary Embolism: The rates of bleeding events reported during the
DVT and PE clinical trials with the ARIXTRA injection treatment regimen
are provided in Table 11 below.<br/>Thrombocytopenia: See WARNINGS: Thrombocytopenia.<br/>Local Reactions: Mild local irritation (injection site bleeding,
rash, and pruritus) may occur following subcutaneous injection of
ARIXTRA.<br/>Elevations of Serum Aminotransferases: In the peri-operative prophylaxis randomized clinical
trials of 7��2 days asymptomatic increases in aspartate
(AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels greater
than 3 times the upper limit of normal of the laboratory reference
range have been reported in 1.7% and 2.6% of patients, respectively,
during treatment with ARIXTRA 2.5 mg Injection versus 3.2% and
3.9%, of patients, respectively, during treatment with enoxaparin
sodium 30 mg every 12 hours or 40 mg once daily enoxaparin
sodium. Such elevations are fully reversible and are rarely associated
with increases in bilirubin. In the extended prophylaxis clinical
trial no significant differences in aspartate (AST [SGOT]) and alanine
(ALT [SGPT]) aminotransferase levels between ARIXTRA 2.5 mg Injection
and placebo treated patients were observed. In the DVT and PE treatment clinical trials asymptomatic increases
in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase
levels greater than 3 times the upper limit of normal of the laboratory
reference range have been reported in 0.7% and 1.3% of patients, respectively,
during treatment with the ARIXTRA injection treatment regimen. In
comparison, these increases have been reported in 4.8% and 12.3%,
of patients, respectively, in the DVT treatment trial during treatment
with enoxaparin sodium 1 mg/kg every 12 hours, and in 2.9%
and 8.7%, of patients, respectively, in the PE treatment trial during
treatment with aPTT adjusted heparin. Since
aminotransferase determinations are important in the differential
diagnosis of myocardial infarction, liver disease, and pulmonary emboli,
elevations that might be caused by drugs like ARIXTRA should be interpreted
with caution.<br/>Other Adverse Events: Other adverse events that occurred during treatment
with ARIXTRA, or enoxaparin sodium in clinical trials with patients
undergoing hip fracture surgery, hip replacement surgery, or knee
replacement surgery and that occurred at a rate of at least 2% in
either treatment group, are provided in Table 12 below. Other adverse
events that occurred during treatment with ARIXTRA or dalteparin sodium
in clinical trials with patients undergoing abdominal surgery and
that occurred at a rate of at least 2% in either treatment group are
provided in Table 13 below. Other adverse events that occurred during
treatment with ARIXTRA, enoxaparin sodium, or heparin in the DVT and
PE treatment clinical trials and that occurred at a rate of at least
2% in any treatment group are provided in Table 14 below.<br/>Postmarketing Experience: The following adverse reactions have been identified
during post-approval use of ARIXTRA. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure. Rare cases of
elevated aPTT and heparin-induced thrombocytopenia have been reported.
A causal relationship of these events to fondaparinux has not been
established.
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ARIXTRA Injection is not intended for intramuscular
administration. ARIXTRA cannot be used
interchangeably (unit for unit) with heparin, low molecular weight
heparins or heparinoids, as they differ in manufacturing process,
anti-Xa and anti-IIa activity, units, and dosage. Each of these medicines
has its own instructions for use.<br/>Renal Impairment (See also
CONTRAINDICATIONS):<br/>Hip Fracture, Hip Replacement
and Knee Replacement Surgeries: Major bleeding in patients receiving prophylactic
therapy in hip fracture, hip replacement, or knee replacement surgery
occurred in 1.6% (25/1,565) of patients with normal renal function,
in 2.4% (31/1,288) with mild renal impairment, in 3.8% (19/504) with
moderate renal impairment, and in 4.8% (4/83) with severe renal impairment.
When ARIXTRA was used according to the recommended timing of the first
injection (6 to 8 hours after surgery), major bleeding occurred
in 1.8% (16/905) of patients with normal renal function, in 2.2% (15/675)with mild renal impairment, in 2.3% (6/265) with moderate renal impairment,
and in 0% (0/40) with severe renal impairment.<br/>Abdominal Surgery: Major bleeding in patients receiving prophylactic
therapy in abdominal surgery occurred in 2.1% (13/606) of patients
with normal renal function, in 3.6% (22/613) with mild renal impairment,
in 6.7% (12/179) with moderate renal impairment, and in 7.1% (1/14)
with severe renal impairment. When ARIXTRA was used according to the
recommended timing of the first injection (6 to 8 hours after
surgery), major bleeding occurred in 2.1% (10/467) of patients with
normal renal function, in 3.3% (16/481) with mild renal impairment,
in 5.8% (8/137) with moderate renal impairment, and in 7.7%(1/13)
with severe renal impairment.<br/>Treatment of Deep Vein Thrombosis
and Pulmonary Embolism: Major bleeding in patients receiving treatment for
DVT and PE occurred in 0.4% (4/1,132) of patients with normal renal
function, in 1.6% (12/733) with mild renal impairment, in 2.2% (7/318)
with moderate renal impairment, and in 7.3% (4/55) with severe renal
impairment. ARIXTRA should be used with
caution in patients with moderate renal impairment (creatinine clearance
30-50 mL/min). (See CLINICAL PHARMACOLOGY: Special Populations,
Renal Impairment.) Renal function should
be assessed periodically in patients receiving ARIXTRA. The drug should
be discontinued immediately in patients who develop severe renal impairment
while on therapy. After discontinuation of ARIXTRA, its anticoagulant
effects may persist for 2-4 days in patients with normal renal
function (i.e., at least 3-5 half-lives). The anticoagulant effects
of ARIXTRA may persist even longer in patients with renal impairment
(see CLINICAL PHARMACOLOGY).<br/>Hemorrhage: ARIXTRA Injection, like other anticoagulants, should
be used with extreme caution in conditions with increased risk of
hemorrhage, such as congenital or acquired bleeding disorders, active
ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic
stroke, or shortly after brain, spinal, or ophthalmological surgery,
or in patients treated concomitantly with platelet inhibitors.<br/>Laboratory Testing: Because routine coagulation tests such as Prothrombin
Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively
insensitive measures of the activity of ARIXTRA and international
standards of heparin or LMWH are not calibrators to measure anti-Factor
Xa activity of ARIXTRA, if during therapy with ARIXTRA, unexpected
changes in coagulation parameters or major bleeding occurs, ARIXTRA
should be discontinued (see PRECAUTIONS: Laboratory Tests).<br/>Neuraxial Anesthesia and Post-operative
Indwelling Epidural Catheter Use: Spinal or epidural hematomas, which may result in
long-term or permanent paralysis, can occur with the use of anticoagulants
and neuraxial (spinal/epidural) anesthesia or spinal puncture. The
risk of these events may be higher with post-operative use of indwelling
epidural catheters or concomitant use of other drugs affecting hemostasis
such as NSAIDs (see Boxed Warning for Spinal/Epidural Hematomas).
In spontaneous post-marketing reports, there have been several cases
of epidural or spinal hematoma that have occurred in association with
the use of ARIXTRA by SC injection.<br/>Thrombocytopenia: Thrombocytopenia can occur with the administration
of ARIXTRA. Moderate thrombocytopenia (platelet counts between 100,000/mmand 50,000/mm) occurred at a rate of 3.0% in
patients given ARIXTRA 2.5 mg in the peri-operative hip fracture,
hip replacement or knee replacement surgery, and abdominal surgery
clinical trials. Severe thrombocytopenia (platelet counts less than
50,000/mm) occurred at a rate of 0.2% in patients given
ARIXTRA 2.5 mg in these clinical trials. During extended prophylaxis,
no cases of moderate or severe thrombocytopenia were reported. Moderate thrombocytopenia occurred at a rate of 0.5%
in patients given the ARIXTRA treatment regimen in the DVT and PE
treatment clinical trials. Severe thrombocytopenia occurred at a rate
of 0.04% in patients given the ARIXTRA treatment regimen in the DVT
and PE treatment clinical trials. Thrombocytopenia
of any degree should be monitored closely. If the platelet count falls
below 100,000/mm, ARIXTRA should be discontinued.
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ARIXTRA Injection is indicated for the prophylaxis
of deep vein thrombosis, which may lead to pulmonary embolism: ARIXTRA Injection is indicated for: (See DOSAGE AND ADMINISTRATION section for appropriate
dosage regimen.)
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| dailymed-instance:name |
ARIXTRA
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