KINGKHALIDNATIONALGUARDHOSPITAL
PHARMACY AND THERAPEUTICS COMMITTEE
DRUG EVALUATION
I Introduction:
1.
Brand, generic names and
synonyms:
2.
Related Agents on the Formulary:
3.
Dosage form and storage:
(ARIXTRA) Fondaparinux.
Enoxaparin, unfractionated heparin.
Single-dose, prefilled syringes containing 2.5 mg, 5 mg, 7.5 mg, or 10 mg of
Fondaparinux.
Store at 59° to 86°F.
4.
FDA approval information:
FDA approval indication:
Approved December 2001.
Prophylaxis of deep vein thrombosis (DVT) in patients undergoing surgery for
hip replacement, knee replacement, hip fracture (including extended
prophylaxis following hip fracture surgery), or abdominal surgery (in patients at
risk for thromboembolic complications); treatment of acute pulmonary embolism
(PE); treatment of acute DVT without PE.
Canadian labeling: Additional uses (not approved in U.S.): Unstable angina or
non-ST segment elevation myocardial infarction (UA/NSTEMI) for the
prevention of death and subsequent MI; ST segment elevation MI (STEMI)
for the prevention of death and myocardial reinfarction.
Potential Non FDA approved uses
(off label use):
Prophylaxis of DVT in patients with a history of heparin-induced
thrombocytopenia (HIT); treatment of acute thrombosis (unrelated to HIT) in
patients with a past history of HIT; acute symptomatic superficial vein
thrombosis (≥5 cm in length) of the legs.
Acute coronary syndrome.
Registered in the Kingdom:
5.

Yes
 No
y
Therapeutic Class, mechanism of action:
Anticoagulant (Antithrombotic),Arixtra (fondaparinux sodium) exhibits antithrombotic activity(Factor Xa Inhibitor),
which is the result of antithrombin III (ATIII)-mediated selective inhibition of Factor Xa. By selectively binding to
ATIII, fondaparinux sodium activates the innate neutralization of Factor Xa by ATIII. This neutralization interupts the
blood coagulation cascade and thus inhibits thrombin formation and thrombus development.
6.
Pharmacokinetic considerations :
 A:Absorption:Absolute bioavailability—100%.
 D:Distribution: Vd: 7-11 L; mainly in blood.

M:Metabolism:Because the majority of the drug is eliminated unchanged in the urine, the metabolism has
not been studied.
 E :Excretion:Elimination—17 to 21 hours, Renally—In patients with normal renal function following a single
subcutaneous or intravenous dose of fondaparinux, up to 77% of the dose is eliminated in the urine as
unchanged drug in 72 hours.
7.
Monitoring Requirements:
Periodic monitoring of CBC, platelet count, serum creatinine, occult blood testing of stools recommended. Anti-Xa
activity of fondaparinux can be measured by the assay if fondaparinux is used as the calibrator. PT and aPTT are
insensitive measures of fondaparinux activity. If unexpected changes in coagulation parameters or major bleeding
occur, discontinue fondaparinux (elevated aPTT associated with bleeding events have been reported in postmarketing
data).
Reference Range:
Note: Routine monitoring is not recommended; the following fondaparinux-specific anti-Xa concentrations have been
reported (Garcia, 2012):
Thromboprophylaxis dose: Anti-Xa activity at 3 hours post dose: ~ 0.39-0.5 mg/L
Therapeutic dosing (eg, 7.5 mg once daily): Anti-Xa activity at 3 hours post dose: 1.2-1.26 mg/L.
8.
Use in special population:

Pregnancy category and use during lactation: category,
Adverse events were not observed in animal reproduction studies. Based on case reports, small amounts of
fondaparinux have been detected in the umbilical cord following multiple doses during pregnancy (Dempfle, 2004).
Use of fondaparinux in pregnancy should be limited to those women who have severe allergic reactions to heparin,
including heparin-induced thrombocytopenia, and who cannot receive danaparoid (Guyatt, 2012).

Lactation:
Excretion in breast milk unknown/use caution.

Breast-Feeding Considerations
It is not known if fondaparinux is excreted into breast milk. The manufacturer recommends caution be used if
administered to nursing women. The use of alternative anticoagulants is preferred (Guyatt, 2012).

Elderly:Elimination is prolonged in patients older than 75 y. In studies evaluating fondaparinux 2.5 mg
prophylaxis in hip fracture surgery or elective hip surgery, the total Cl of fondaparinux was approximately
25% lower in patients older than 75 y. A similar relationship between fondaparinuxCl and age was observed
in DVT treatment patients.
Renal or hepatic impairments :Fondaparinux is renally eliminated and thus contraindicated in patients
with severe renal impairment (creatinine clearance < 30 ml/min).


Renal Function Impairment:
Elimination is prolonged. In patients undergoing prophylaxis following elective hip surgery or hip fracture surgery,
the total Cl of fondaparinux is approximately 25% lower in patients with mild renal impairment (CrCl 50 to 80
mL/min), approximately 40% lower in patients with moderate renal impairment (CrCl 30 to 50 mL/min), and
approximately 55% lower in patients with severe renal impairment (less than 30 mL/min) compared with patients
with healthy renal function. A similar relationship between fondaparinuxCl and extent of renal impairment was
observed in deep vein thrombosis (DVT) treatment patients.

9.
Hepatic Function Impairment:
Following a single dose of 7.5 mg in patients with moderate hepatic impairment (Child-Pugh class B),
C max and AUC were decreased by 22% and 39%, respectively. In addition, a higher incidence of hemorrhage
was observed in these patients. Pharmacokinetics have not been studied in patients with severe hepatic
impairment.
Adverse drug reactions (with % whenever possible);
As with all anticoagulants, bleeding is the major adverse effect. Hemorrhage may occur at any site. Risk appears
increased by a number of factors including renal dysfunction, age (>75 years), and weight (<50 kg).
>10%:
Central nervous system: Fever (4% to 14%)
Gastrointestinal: Nausea (3% to 11%)
Hematologic: Anemia (1% to 20%)
1% to 10%:
Cardiovascular: Edema (9%), hypotension (4%), hypertension (2%), chest pain (1%), thrombosis PCI catheter
(without heparin 1%)
Central nervous system: Insomnia (4% to 5%), headache (2% to 5%), dizziness (4%), confusion (3%), pain
(2%), anxiety (1%)
Dermatologic: Rash (8%), purpura (4%), bullous eruption (3%), bruising (1%)
Endocrine & metabolic: Hypokalemia (1% to 4%)
Gastrointestinal: Constipation (5% to 9%), vomiting (1% to 6%), diarrhea (2% to 3%), dyspepsia (2%),
abdominal pain (1%)
Genitourinary: Urinary tract infection (2% to 4%), urinary retention (3%)
Hematologic: Minor bleeding (2% to 4%), moderate thrombocytopenia (50,000-100,000/mm3: 3%), hematoma
(3%), major bleeding (1% to 3%), prothrombin decreased (1%), risk of major bleeding increased as high
as 5% in patients receiving initial dose <6 hours following surgery
Hepatic: ALT increased (≤3%), AST increased (≤2%)
Local: Injection site reaction (bleeding, rash, pruritus)
Neuromuscular & skeletal: Back pain (1%), leg pain (1%)
Respiratory: Cough (2%), pneumonia (2%), epistaxis (1%)
Miscellaneous: Wound drainage increased (5%)
<1% (Limited to important or life-threatening): aPTT increased (associated with bleeding), heparin-induced
thrombocytopenia (1 case report), hepatic dysfunction, severe thrombocytopenia (<50,000/mm 3)
Drug- drug interaction:
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant
effect of Anticoagulants. Risk C: Monitor therapy
Anticoagulants: May enhance the anticoagulant effect of other Anticoagulants. Risk C: Monitor therapy
Apixaban: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically,
the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy
Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI
ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential
prothrombotic effects of some estrogens and progsetin-estrogen combinations may counteract anticoagulant
effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk
of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances.
Refer to related guidelines for specific recommendations. Risk D: Consider therapy modification
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of
Anticoagulants. Bleeding may occur. Risk D: Consider therapy modification
Ibritumomab: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to
an increased risk of bleeding. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor
therapy
Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleedingrelated events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in
patients with a platelet count of less than 50,000/uL. Risk X: Avoid combination
Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic
effects of some progestins and progsetin-estrogen combinations may counteract anticoagulant effects.
Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of
procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer
to related guidelines for specific recommendations. Risk D: Consider therapy modification
Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects
of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapy
Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Risk X: Avoid combination
Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph
for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Risk
C: Monitor therapy
Tibolone: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab
and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Risk
C: Monitor therapy
Vitamin E: May enhance the anticoagulant effect of Anticoagulants. Vitamin E may also increase the overall risk for
bleeding. Risk C: Monitor therapy
Drug- food interactions: No drug –food interaction.
Contraindications and precautions :
Contraindications :
Serious hypersensitivity (eg, angioedema, anaphylactoid/anaphylactic reactions) to fondaparinux or any component of
the formulation; severe renal impairment (Clcr <30 mL/minute); body weight <50 kg (prophylaxis); active major
bleeding; bacterial endocarditis; thrombocytopenia associated with a positivein vitro test for antiplatelet antibody in
the presence of fondaparinux.
Warning and precautions :
Concerns related to adverse effects:
• Bleeding: Monitor patient closely for signs or symptoms of bleeding. Certain patients are at increased risk of
bleeding. Risk factors include bacterial endocarditis; congenital or acquired bleeding disorders; active
ulcerative or angiodysplastic GI diseases; severe uncontrolled hypertension; hemorrhagic stroke; or use
shortly after brain, spinal, or ophthalmology surgery; in patients treated concomitantly with platelet
inhibitors; recent GI bleeding; thrombocytopenia or platelet defects; renal impairment; hepatic
impairment; hypertensive or diabetic retinopathy; or in patients undergoing invasive procedures. Risk of
major bleeding may be increased if initial dose is administered earlier than recommended (initiation
recommended at 6-8 hours following surgery). Do not administer with other agents that increase the risk
of hemorrhage unless they are essential for the management of the underlying condition (eg, warfarin for
treatment of VTE). Although considered an insensitive measure of fondaparinux activity, there have been
postmarketing reports of bleeding associated with elevated aPTT. Discontinue if bleeding occurs.
• Thrombocytopenia: Has occurred with administration, including very rare reports of thrombocytopenia with
thrombosis similar to heparin-induced thrombocytopenia (HIT); however, has been used in patients with
current or history of HIT due to a lack of an immune-mediated effect on platelets (Guyatt [ACCP], 2012;
Savi, 2005). Use is contraindicated in patients with thrombocytopenia associated with a positive in vitrotest
for antiplatelet antibodies in the presence of fondaparinux. Monitor patients closely and discontinue
therapy if platelets fall to <100,000/mm 3 and/or thrombosis develops.
Disease-related concerns:
• Renal impairment: Use with caution in patients with moderate renal dysfunction (Cl cr 30-50 mL/minute);
contraindicated in patients with Clcr <30 mL/minute. Periodically monitor renal function; discontinue if
severe dysfunction or labile function develops.
Special populations:
• Elderly: Use with caution in the elderly; elimination half-life prolonged in patients >75 years of age.
• Patients <50 kg: Use with caution in patients <50 kg who are being treated for DVT/PE; fondaparinux
clearance may be decreased, increasing the risk for bleeding; dosage reduction recommended.
Contraindicated in patients <50 kg when used for prophylactic therapy.
Dosage form specific issues:
• Latex: The needle guard contains natural latex rubber.
Other warnings/precautions:
• Appropriate use: For subcutaneous administration; not for I.M. administration. Do not use interchangeably
(unit for unit) with low molecular weight heparins, heparin, or heparinoids.
• Appropriate use: Surgical patients: Discontinue use 24 hours prior to CABG and dose with unfractionated
heparin per institutional practice (Jneid, 2012).
• Neuraxial anesthesia: [U.S. Boxed Warning]: Spinal or epidural hematomas, including subsequent
paralysis, may occur with recent or anticipated neuraxial anesthesia (epidural or spinal
anesthesia) or spinal puncture in patients anticoagulated with LMWH, heparinoids, or
fondaparinux. Consider risk versus benefit prior to spinal procedures; risk is increased by the use of
concomitant agents which may alter hemostasis, the use of indwelling epidural catheters for analgesia, a
history of spinal deformity or spinal surgery, as well as a history of traumatic or repeated epidural or spinal
punctures. Patient should be observed closely for bleeding and signs and symptoms of neurological
impairment if therapy is administered during or immediately following diagnostic lumbar puncture, epidural
anesthesia, or spinal anesthesia.
• Percutaneous coronary intervention (PCI): The administration of fondaparinux as the sole anticoagulant isnot
recommended during PCI due to an increased risk for guiding-catheter thrombosis. Use of an
anticoagulant with antithrombin activity (eg, unfractionated heparin) is recommended as adjunctive
therapy to PCI even if prior treatment with fondaparinux (must take into account whether GP IIb/IIIa
antagonists have been administered) (Levine, 2011).
10-Dosing :
Usual Adult Dose for Deep Vein Thrombosis:
less than 50 kg:
5 mg administered by subcutaneous injection once daily given in conjunction with warfarin sodium therapy.
50 to 100 kg:
7.5 mg administered by subcutaneous injection once daily given in conjunction with warfarin sodium therapy.
100 or more kg:
10 mg administered by subcutaneous injection once daily given in conjunction with warfarin sodium therapy.
Usual Adult Dose for Pulmonary Embolism:
less than 50 kg:
5 mg administered by subcutaneous injection once daily given in conjunction with warfarin sodium therapy.
50 to 100 kg:
7.5 mg administered by subcutaneous injection once daily given in conjunction with warfarin sodium therapy.
100 or more kg:
10 mg administered by subcutaneous injection once daily given in conjunction with warfarin sodium therapy.
Treatment should be continued for a least 5 days and until a therapeutic oral anticoagulant effect is established (INR
2.0 to 3.0). Concomitant treatment with warfarin should be initiated as soon as possible, usually within 72 hours. The
usual duration of therapy is 5 to 9 days, although up to 26 days of therapy has been given.
Usual Adult Dose for Deep Vein Thrombosis Prophylaxis after Abdominal Surgery:
less than 50 kg:
Fondaparinux prophylactic therapy is contraindicated for use in patients weighing less than 50 kg undergoing
abdominal surgery.
50 or more kg:
2.5 mg subcutaneously once a day. 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 10 days of therapy has been administered.
Usual Adult Dose for Deep Vein Thrombosis – Prophylaxis:
less than 50 kg:
Fondaparinux prophylactic therapy is contraindicated for use in patients weighing less than 50 kg undergoing hip
fracture, hip replacement or knee replacement surgery.
50 or more kg:
2.5 mg subcutaneously once a day. 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 therapy is 5 to 9 days, and up to 11 days therapy 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 (perioperative and extended prophylaxis) has been
tolerated.
Usual Adult Dose for Deep Vein Thrombosis Prophylaxis after Hip Replacement Surgery:
less than 50 kg:
Fondaparinux prophylactic therapy is contraindicated for use in patients weighing less than 50 kg undergoing hip
fracture, hip replacement or knee replacement surgery.
50 or more kg:
2.5 mg subcutaneously once a day. 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 therapy is 5 to 9 days, and up to 11 days therapy 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 (perioperative and extended prophylaxis) has been
tolerated.
Usual Adult Dose for Deep Vein Thrombosis Prophylaxis after Knee Replacement Surgery:
less than 50 kg:
Fondaparinux prophylactic therapy is contraindicated for use in patients weighing less than 50 kg undergoing hip
fracture, hip replacement or knee replacement surgery.
50 or more kg:
2.5 mg subcutaneously once a day. 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 therapy is 5 to 9 days, and up to 11 days therapy 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 (perioperative and extended prophylaxis) has been
tolerated.
Renal Dose Adjustments:
CrCl less than 30 mL/min: drug is contraindicated.
CrCl greater 30 and less than 50 mL/min: use with caution - 2.5 mg subcutaneously once a day.
Liver Dose Adjustments:
Data not available.
Dose Adjustments:
Fondaparinux prophylactic therapy is contraindicated for use in patients weighing less than 50 kg undergoing hip
fracture, hip replacement, knee replacement, or abdominal surgery.
II
Study
1
Clinical trial analysis and critique :
Design
Mention Number of
patients (N) in the study:
- 20078 pts with ACS.
Randomized –double
blinded –double dummy
trial.
From Multicenter.
Methods
Objective of the study: Compared the efficacy and
safety of enoxaparin in high risk patients with
unstable angina or myocardial infarction without
ST-segments elevation.
Inclusion criteria: Patients were eligible if they met
one of the following criteria:
-Age of at least 60 year.
-An elevted creatine kinase MB or troponin.
--Electrocardiographic changes indicative of
ischemia.
Exclusion criteria:
-Patients with contraindications to LMWH.
Recent hemorrhagic stroke.-Indications for anticoagulation other than an
Results
Primary endpoint:
. (Death- MI-refractory ischemia)
Secondary endpoint:
death and myocardial infarction.
Adverse effect: bleeding.
Author conclusion:
Fondaparinux at dose of 2.5mg daily
is similar to enoxaparin in the short
trem in preventing ischemic events
among patients with acute coronary
syndrome without ST- segments
elevation but its associated with
substinally less bleeding .
Therefore fondaparinux ia an attractive
ACS.
-Serum creatinine level of at least 3mg/dl
Follow up and intervention: Fondaparinux.2.5mg
daily.
Patients were followed for minimum of 90 days and a
maximum of 180 days ,prespecified secondary outcomes
included the fowllwing :death or myocardial infraction
,or refractory ischemia and the individual components of
theses composite outcomes at 30 days and at the end of
the study.
Information on strokes was also systematically collected
.the primary safety outcomes was major bleeding at day
nine.
option as an anticoagulant in the shot
trem care of patients with acute
coronary syndrome .
Critical Appraisal of the Topic (CAT ☼):
Validity:.
- Patients were randomized to treatment groups.
- Treatment and control groups were similar at the beginning of the trial.
- Randomization was concealed.
- Both patients and investigators are unaware (double binded)of treatment allocation.
- All patients who underwent randomization were analyzed.
- Patients received other strandard treatments at the investigators discreticn.
- Compliance wasn’t measured
- No contamination..
- The study was sponsored by sanofi Aventis and Galaxosmithkline.
Results:
Major bleeding at day nine :
EER=0.02 ,CER=0.07
RR= EER-CER = 0.05. so fondaparinux decrease the risk bleeding.
ARR=CER-EER= -0.05 ( significant difference )
RRR=1- RR=1-0.05=0.95
NNH=1/ARR=1/0.05=20
At day thirty:
EER=0.03 CER=0.04
RR= -0.01
ARR= 0.01
RRR=1-RR= 1-(-)0.01 = 0.99
NNH=100
At day 180:
EER= 0.04 CER=0.05
RR=0.09
ARR=0.01
RRR=1-RR=1-0.09= .91
NNH=100
Death or MI or stroke:
AT DAY NINE :
EER=.04 CER=0.04
RR=0
ARR= 0
RRR=1-RR= 1-0= 0
NNH=
AT day 30:
EER=0.06 CER=.07
RR=0.01
ARR=0.01
RRR=0.99
NNH=100
AT DAY 1800;
EER=0.11 CER=0.123
RR=0.013
ARR=0.013
RRR=0.987
NNH=153. (SO FONDAPARINUX MORE SAFER).
Applicability:
The treatment is feasible in my setting.
The exclusion and inclusion criteria are similar to my patients .
The potential benefits of treatment outwieght the potential harms of treatment .
Fondaparinux is like enoxaparin no tablet dosage form available so the patients will accept to receive it because no difference
between fondaparinux and enoxaparin.
Grade and level of evidence: high level of evidence.
Comment (Funding or sponsorship should be included):
Suppoted by sanofi Aventis and Galaxosmithkline.
VI Conclusion:
Argument FOR addition:
-
The reduced rate of bleeding with fondaparinux were consistently
observed in all the sub groups examined .
Improves long term mortality and morbidity.
Argument AGAINST addition:
Fondaparinux 2.5 mg daily is similar to enoxaparin in the short term in preventing
ischemic events among patients with acute coronary syndromes without ST-segments elevation.
X References
-Uptodate.
-Drug.com.
-Micromedx.
-Comparison of fondaparinux and enoxaparin in acute coronary syndrome.
-http://us.gsk.com/products/assets/us_arixtra.pdf.