Danaparoid

Summary

Danaparoid is a heparinoid with anticoagulant and antithrombotic

activities used for the treatment of acute episode of Heparin-Induced
Thrombocytopenia (HIT), and for prophylaxis in patients with a history
of HIT.
Brand Names
Orgaran

Generic Name
Danaparoid

DrugBank Accession Number

DB06754

Background

Danaparoid is a low-molecular-weight heparinoid with an average

molecular weight of 5500 Daltons consisting of a mixture of
glycosaminoglycans 2. The active constituents are heparan, dermatan
and Chondroitin sulfate 5, and they are isolated from the porcine
intestinal mucosa Label. Danaparoid possesses a potent antithrombic
activity that works by inhibiting activated factor X (Factor Xa) and
activated factor II (Factor IIa). It is chemically distinct from heparin by
containing different protein binding properties, thus has lower cross-
reactivity in heparin-intolerant patients. Danaproid is used in the
treatment of heparin-induced thrombocytopenia (HIT) as an off-label
indication and prevention of post-operative deep venous thrombosis
(DVT). While it was initially approved by the FDA as Orgaran™,
danaparoid was withdrawn by Organon International on August 14,
2002, due to a shortage in drug substance by the manufacturer. The
use of Orgaran™ was discontinued in the United States however it is
available in several other countries including European countries and
Japan. Danaparoid sodium is the common salt form in therapeutic
preparations and is typically administered subcutaneously.
Type
Small Molecule

Groups
Approved, Withdrawn

Synonyms
Not Available

PHARMACOLOGY
Indication
 Indicated for the prophylaxis of post-operative deep venous thrombosis
(DVT), which may lead to pulmonary embolism (PE), in patients
undergoing elective hip replacement surgery Label.

Associated Conditions

 Deep Vein Thrombosis caused by Major Abdominal Surgery

 Deep Vein Thrombosis caused by Orthopedic Surgery
 Deep Vein Thrombosis caused by Thoracic Surgery
 Heparin Induced Thrombocytopenia (HIT)
 Non-hemorrhagic stroke
Contraindications & Blackbox Warnings

Pharmacodynamics

Danaparoid contains a mixture of heparan sulfate, dermatan sulfate

and chondroitin sulfate in amounts of approximately 84%, 12% and
4%, respectively 3. Danaparoid is as an antithrombotic agent that
prevents the formation of fibrin in the coagulation pathway. It has a
high antifactor Xa to antifactor IIa (thrombin) activity that primarily
works via antithrombin III-mediated inhibition of factor Xa 3. The ratio of
antifactor Xa to antifactor II activity is ≥ 20:1 3. Danaparoid has a minor
effect on platelet function and aggregation Label. In a worldwide
compassionate-use programme involving a total of 667 patients with
heparin-induced thrombocytopenia (HIT), treatment with danaparoid
resulted in 93% of successful outcomes in resolving HIT 3.
In healthy volunteers, danaparoid caused significantly less prolongation
o f the activated partial thromboplastin time (APTT) and was
associated with a significantly lower thrombin time than unfractionated
heparin (UFH) and low molecular weight heparins (LMWHs) 3.
Danaparoid displays lower lipolytic activity than UFH in vitro and in
healthy individuals, leading to lower plasma levels of free fatty acids 3.
Danaparoid has been associated with the cross-reactivity with
pathogenic heparin-induced platelet-factor 4 (PF4) antibodies, which
occurs in about 10 % or more by in vitro testing 1. The clinical relevance
of this effect is not fully understood 1.
Mechanism of action

In the coagulation cascade leading to clot formation, factor X and factor

II requires activation to promote subsequent conversion of fibrinogen to
fibrin. The mechanism of action of danaparoid resulting in
anticoagulant and antithrombic effects involves a complex interaction
between 2 components, factor IIa and in particular, factor Xa 3. Via
binding to antithrombin and inducing a conformational change 4,
danaparoid enhances and catalyzes the the binding of factor Xa to
antithrombin, which induces antithrombin-mediated inactivation of
factor Xa. This leads to inhibition of thrombin generation and
subsequently, thrombus formation 2. Danaparoid also weakly enhances
antithrombin III and heparin cofactor II inactivation of factor IIa 2. There
is evidence that danaparoid also suppresses the activation of factor IX
 which, in conjunction with simultaneous inhibition of factor X, may lead
to antithrombic effects 3.
TARGET ACTIONS ORGANISM

AAntithrombin-III positive allosteric modulator Humans

Absorption

Pharmacokinetic studies on danaparoid are based on the kinetics of its

anticoagulant activities, which are mostly antifactor Xa and antifactor
IIa activities. The bioavailability of danaparoid is 100% following
subcutaneous administration Label. Following administration of single
subcutaneous doses of 750, 1500, 2250, and 3250 anti-Xa units of
danaparoid, the peak plasma anti-Xa activities were 102.4, 206.1,
283.9, and 403.4 mU/mL, respectively Label. The time to reach maximum
anti-Xa activity is approximately 2-5 hours Label.
Volume of distribution

Pharmacokinetic studies on danaparoid are based on the kinetics of its

anticoagulant activities, which are mostly anti factor Xa and anti factor
IIa activities. The volumes of distribution of anti-Xa and anti-IIa
activities are 9.1 L and 7.3-9.0 L, respectively 3.
Protein binding

Not Available
Metabolism

There is no evidence of hepatic metabolism and danaparoid is unlikely

to undergo cellular metabolism 3.
Route of elimination

Renal excretion is the main route of elimination, accounting for

approximately 40-50% of the total clearance of antifactor Xa activity
following intravenous administration of danaparoid 3. Therefore in
patients with severe renal impairment, the elimination half-life of anti-
Xa activity may be prolonged Label.
Half-life

Pharmacokinetic studies on danaparoid are based on the kinetics of its

anticoagulant activities, which are mostly anti factor Xa and anti factor
IIa activities. The elimination half-life ranges from 19.2 to 24.5 hours
during anti-Xa activity and ranges from 1.8 to 4.3 hours during anti-IIa
activity 3.
Clearance

Pharmacokinetic studies on danaparoid are based on the kinetics of its

anticoagulant activities, which are mostly anti factor Xa and anti factor
IIa activities. Total plasma clearance is about 0.36 L/h during anti-Xa
activity, which may be accelerated with higher body surface area Label.
Total plasma clearance during anti-IIa activity ranges from 2.3 to 3 L 3.
Adverse Effects
Toxicity

Subcutaneous administration of a single dose at 3800 anti-Xa units/kg,

which is 20.5 times the recommended dose for humans based on body
surface area, was found to be lethal to female rats. Lethal effects were
seen in male rats when administering a single subcutaneous dose at
15200 anti-Xa units/kg, which is approximately 82 times the
recommended human dose based on body surface area Label. In rats, the
symptoms of acute toxicity following intravenous administration
included respiratory depression, prostration and twitching Label.
Accidental overdosage of danaparoid may lead to severe bleeding
complications. While protamine sulfate may partially neutralize the anti-
Xa actions of danaparoid, there is no evidence that it is capable of
reducing severe non-surgical bleeding during treatment of danaparoid.
In case of serious bleeding, danaparoid should be discontinued and
blood transfusions should be administered if necessary. Withdrawal of
danaparoid is expected to restore the coagulation balance without
rebound phenomenon Label.
There is no evidence of danaparoid to have a potential to induce
carcinogenesis, mutagenesis and impairment of fertility Label.
Pathways
Not Available

Pharmacogenomic Effects/ADRs 
Not Available

INTERACTIONS
Drug Interactions 
This information should not be interpreted without the help of a healthcare provider.
If you believe you are experiencing an interaction, contact a healthcare provider
immediately. The absence of an interaction does not necessarily mean no
interactions exist.

 
Danaparoid Sodium is a heparinoid representing a mixture of low-molecular
weight sulfated glycosaminoglycans: heparan (not heparin) sulfate (84%),
dermatan sulfate (12%), and chondroitin sulfate (4%). Danaparoid is obtained
from porcine intestinal mucosa after the removal of heparin. The mean
molecular weight of danaparoid is 5500 daltons. Danaparoid Sodium is used
for prophylaxis of deep-vein thrombosis in patients undergoing general or
orthopaedic surgery, and in the management of thromboembolic disease in
patients with history of heparin-induced thrombocytopenia.
OverviewPrimary
CharactersticsIndicationsPharmacokineticsContraindicationsDrug
InteractionsSide EffectsDosageHigh Risk GroupsWarning / PrecautionsStorage
ConditionsInterference in PathologyBrands of Danaparoid
SodiumManufacturers of Danaparoid Sodium
It is of Synthetic origin. . The Molecular Weight of Danaparoid Sodium is
5500.00.
Danaparoid Sodium is primarily indicated in conditions like Endometrial
thinning before intra-uterine surgery, Prophylaxis of venous thromboembolism.
Oral absorption of Danaparoid Sodium is found to be 100% . Plasma half life is
24 hours.
Danaparoid Sodium is contraindicated in conditions like Peptic
ulcer, Traumatic injury, Acute musculoskeletal disorders, Relief of sore
throat, Initial treatment of acute conditions, Pain management, General
dose, Following coronary bypass surgery.
No data regarding the interactions of Danaparoid Sodium was found.
The symptomatic adverse reactions produced by Danaparoid Sodium are more
or less tolerable and if they become severe, they can be treated
symptomatically, these include Hypersensitivity reactions, Thrombocytopenia,
Hemorrhage, Bruising or pain at injection site.

Drug should not be given to patients suffering from Liver Malfunction.

If prescribing authority justifies the benefits of the drug against the possible
damages he/she should reevaluate them and consult the reference material and
previous studies.

Hepatic and renal impairment (avoid for prophylaxis if severe); pregnancy and
breast-feeding. Presence of sulphite in ampoules may (especially in patients
with asthma) lead to hypersensitivity (with bronchospasm and shock)
  

Danaparoid (Orgaran) - Uses, Dose, Side effects, MOA, Brands

Danaparoid (Orgaran) is a low molecular weight heparinoid that acts as an anticoagulant by
inhibiting thrombin generation. It also inhibits antithrombin III mediated factor Xa activity.
Danaparoid (Orgaran) Uses:
Note: Not approved in the US
 Catheter patency:
o Occasionally flush for maintaining the patency of catheters, IV lines, and
access ports
 Deep vein thrombosis:
o It’s used to prevent  DVT after orthopedic, thoracic, or
abdominal surgery and in patients with diagnosed non-
hemorrhagic stroke.
 Heparin-induced thrombocytopenia:
o To treat heparin-induced thrombocytopenia (HIT)
Danaparoid (Orgaran) Dose in Adults
Note: Dosing is suggested as manufacturer labeling unless otherwise noted. Dose expressed
as anti-Xa units.
Danaparoid (Orgaran) Dose in the Prevention of DVT following orthopedic,
major abdominal, or thoracic surgery:
 Subcutaneous: 750 units 2 times a day for 2 weeks;
  it’s suggested for patients to take prophylactic therapy preoperatively and take the last
preoperative dose 1-4 hours ahead of surgery.
Danaparoid (Orgaran) dose in the Prevention of DVT in stroke (non-
hemorrhagic):
 The first intravenous single dose is up to 1,000 units
 Maintenance dose: Subcutaneous dose of 750 units is given every 12 hours for 7-14
days
Danaparoid (Orgaran) Dose in the HIT:
 Prevention of DVT (with current or past HIT):
Note:
 An intravenous bolus of 1,250 units can be administered if found clinically important
(ie, current HIT) and it can also be started as a maintenance regimen without giving a
bolus in the following manner via subcutaneous route if the weight is:
o ≤90 kg:
 Present HIT or history of HIT: 750 units in every 8-12 hours for 7-10
days
o >90 kg:
 Present HIT: 1,250 units every 8 to 12 hours for 7 to 10 days;
 History of HIT: 1,250 units every 12 hours or 750 units every 8
hours for 7 to 10 days
 Treatment of DVT/PE:
o Starting Intravenous dose: If thrombosis is <5 days old and weight is:
o ≤55 kg give 1,250 to 1,500 units;
o 55 to 90 kg: 2,250 to 2,500 units;
o >90 kg: 3,750 units; followed by a maintenance intravenous infusion or
maintenance subcutaneous injections.
Note: If thrombosis is ≥5 days old, give an intravenous bolus dose of 1,250 units followed by
maintenance dose through subcutaneous routes.
 Maintenance:
o Intravenous infusion (after Intravenous bolus is given):
 if Thrombosis is <5 days old administer 400 units/hour for 4 hours,
then 300 units/hour for 4 hours, followed with 150 to 200 units/hour
for 5 to 7 days;
 The rate can be adjusted according to the target anti-Xa level.
 Maintenance:
o Subcutaneous injections (after Intravenous bolus administered):
 If Thrombosis is <5 days old and the weight is
o ≤55 kg administer 1,500 units in every 12 hours;
o 55 to 90 kg administer 2,000 units every 12 hours;
o >90 kg administer 1,750 units every 8 hours for 4 to 7 days.
 Thrombosis ≥5 days old:
o ≤90 kg: 750 units every 8 to 12 hours;
o >90 kg: 750 units every 8 hours or 1,250 units every 8 to 12 hours
Danaparoid (Orgaran) Dose in the HIT/surgical thromboprophylaxis:
 Nonvascular surgery: subcutaneous route:
o ≤90 kg:
 750 units 1 to 4 hours preoperatively then at ≥6
hours postoperatively, then by 750 units every 12
hours starting on 1st day postoperatively and
continue it for 7 to 10 days
 o >90 kg:
 750 units 1 to 4 hours preoperatively and then at ≥6 hours
postoperatively, then by 750 units every 8 hours or 1,250 units every
12 hours starting on 1st-day post-operatively and then continue for 7
to 10 days
 Embolectomy:
o 55 to 90 kg:
 Intravenously give 2,250 to 2,500 units as a bolus preoperatively,
then through subcutaneous route give 1,250 units every 12 hours,
starting ≥6 hours postoperatively
o Note:
 After a few days of therapy, it can be switched to a lower
subcutaneous dose of 750 units every 8 to 12 hours or anticoagulant
therapy via the oral route.
o >90 kg:
 Intravenously give 2,250 to 2,500 units as a bolus preoperatively,
then 150 to 200 units/hour starting ≥6 hours postoperatively for 5 to
7 days.
 Note: After a few days of intravenous therapy, it can be switched to
the subcutaneous route giving 750 units every 8 to 12 hours or
anticoagulant therapy via the oral route.
Dose in the HIT/ cardiac procedures:
Note: Other therapies may be preferred (eg, bivalirudin); the long half-life and irreversibility
of danaparoid make it a poor choice in these settings. Refer to the product labeling for dosing
recommendations.
 Catheter patency:
o 750 units mixed with normal saline 50 mL.
o The catheter can be flushed with 5 to 10 mL of the solution if required.
 Conversion to oral anticoagulant therapy (OAC):
o It is recommended to maintain a sufficient antithrombotic effect with
danaparoid before starting on oral anticoagulant (OAC) therapy.
o Monitor PT/INR before discontinuation of danaparoid.
o Note: Within 5 hours of use of danaparoid, the Laboratory values may be
doubtful.
 Conversion of SubQ danaparoid to OAC (based on current danaparoid dose):
o 750 units per 12 hours of Danaparoid:
 Start OAC, while maintaining danaparoid therapy until PT/INR is
therapeutic; could be up to 5 days.
o 1,250 units per 12 hours of Danaparoid:
 Start OAC along with decreasing danaparoid to 750 units per 12
hours; maintaining danaparoid therapy until PT/INR is therapeutic;
could be up to 5 days.
 Conversion of intravenous danaparoid to oral anticoagulant:
o Start oral anticoagulant simultaneously with danaparoid infusion
intravenously (maximum 300 units/hour);
o Once INR is therapeutic stop intravenous infusion (maximum INR: 3.0).
o With any risk of bleeding, the dose of intravenous infusion should be
decreased to 75 units/hour and OAC commencement stopped for 24 hours or
the route of IV infusion of danaparoid changed to subcutaneous route in a
dose of 1,250 units per 12 hours and conversion of SubQ danaparoid to OAC
regimen followed as advised (i.e: decreasing to 750 units per 12 hours prior
to initiating OAC ).
 Use in Children:
Not indicated.
Pregnancy Risk Category: B
 No unfavorable events were observed during animal reproduction studies.
 According to the manufacturer, this has not been reported to cause any congenital
anomaly in the foetus during pregnancy.
 Pregnancy is not recommended unless it is considered medically necessary.
 Danaparoid is not able to cross the placenta. It is preferred for pregnant women with
HIT.
Danaparoid use during breastfeeding:
 After maternal use of danaparoid, only low levels of anti-Xa activity were found in
breastmilk.
 However, since it is not absorbed orally, it is unlikely that it will cause adverse
reactions in a nursing infant.
 Breast-feeding may continue to be allowed with danaparoid.
 According to the manufacturer's recommendations, women who use danaparoid
should not breastfeed.
Danaparoid (Orgaran) Dose in Kidney Disease:
Note:
 The half-life of Danaparoid is increased in renal dysfunction;
 Monitor anti-Xa levels. Dosage reduction can be needed, mostly when the
maintenance doses are being administered.
 Mild or moderate impairment:
o There are no dosage adjustments provided in the manufacturer's labeling.
 Severe impairment (serum creatinine ≥ 220 micromol/L [≥2.5 mg/dL]):
o While giving the starting dose, the need of decreasing the dose, or stopping
the therapy for some time can be needed to avoid getting plasma anti-Xa
from being accumulated. the plasma level can be monitored with an
unvarying anti-Xa activity>0.5 anti-Xa units.
 Hemodialysis:
o Intravenous: give 1,500 to 3,750 units via IV route before dialysis session.
Note: Dose is dependent upon:
 the regularity of dialysis regimen (eg, daily dialysis vs every-other-day or less
frequently)
 weight of the patient  (less dose for patients <55 kg)
 if plasma anti-factor Xa levels >400 units/L or
 the patient not on daily dialysis it shall not be administered prior to dialysis and if
fibrin threads are present in the bubble chamber 1,500 units can be administered.
Hemofiltration:
 IV: initially 55 to 90 kg:
o 2,500 units as a bolus,
o then 600 units/hour for 4 hours, then 400 units/hour for 4 hours,
o then 200 to 600 units/hour to maintain adequate anti-Xa levels.
Note: If the patient is <55 kg, decrease bolus dose to 2,000 units, followed by 400 units/hour
for 4 hours, and then 150 to 400 units/hour to maintain anti-Xa levels of 500 to 1,000 units/L.
Dose in Liver Disease:
There are no dosage adjustments provided in manufacturer's labeling.
Frequency not always defined. As with all anticoagulants, bleeding is the major adverse effect
of danaparoid. Hemorrhage may occur at virtually any site. Risk is dependent on multiple
variables.
Side Effects of Danaparoid (Orgaran):
 Central Nervous System:
o Pain
 Dermatologic:
o Skin Rash
 Gastrointestinal:
o Nausea
o Constipation
 Genitourinary:
o Urinary Retention
 Hematologic & Oncologic:
o Leukocytosis
 Infection:
o Infection
 Local:
o Hematoma At Injection Site
 Respiratory:
o Pneumonia
 Miscellaneous:
o Fever
Rare side effects of Danaparoid (Orgaran):
 Cardiovascular:
o Atrial Fibrillation
o Cerebral Infarction
o Decreased Blood Pressure (Arterial)
o Deep Vein Thrombosis
o Hypotension
o Peripheral Edema
 Central Nervous System:
o Cerebral Hemorrhage
o Confusion
o Fatigue
o Hemiparesis
o Insomnia
o Loss Of Consciousness
o Restlessness
 Genitourinary:
o Hematuria
o Urinary Incontinence
o Urinary Tract Hemorrhage (Including Microscopic)
o Urine Abnormality
 Hematologic & Oncologic:
o Bruise
o Hematoma
o Hemorrhage (Dose-Related)
o Thrombocytopenia
  Hypersensitivity:
o Hypersensitivity Reaction
 Infection:
o Sepsis
 Neuromuscular & Skeletal:
o Muscle Spasm
o Tremor
 Respiratory:
o Apnea
o Asthma
Contraindications to Danaparoid (Orgaran):
 Hypersensitivity to danaparoid or any other component of the formulation (including
sulfurites);
 History of thrombocytopenia after receiving danaparoid, or when danaparoid is
associated with a positive antiplatelet antibody in vitro test;
 Hemorrhagic stroke (without systemic emoli);
 History of thrombosis caused by danaparoid
 Acute hemorhagic stroke
 major blood clotting disorder;
 Uncontrollable active bleeding;
 Hemorrhagic severe diathesis
 Acute or subacute bacterial heart disease;
 Active gastric or duodenal ulcer
 Surgery of the CNS, eyes or ears; diabetes or hemorhagic retinalopathy;
 Hypertension uncontrolled and severe
 Other conditions and diseases that can increase hemorhage risk
 Contraindicated intramuscular use
Warnings and precautions
 Bleeding
o Watch out for bleeding symptoms or signs in patients.
o Some patients are more at risk of bleeding than others (eg patients with
severe hepatic diseases, patients who have had knee surgery or any other
invasive procedure, and patients receiving platelet inhibitors in combination
with the procedure, elderly).
o Discontinue if bleeding occurs.
NotificationRoutine clotting tests are not appropriate for monitoring anticoagulant activity of
danaparoid danaparoid.

o The only way to determine anti-factorXa levels is by using the available
methods, but it may not correlate well with efficacy.
o Danaparoid is not effectively antagonized by protamine sulfate.
o There is no other antidote available. Therefore, extreme caution must be
taken when monitoring the dose and factor Xa inhibition effects.
o In emergency situations, plasmapheresis might be an effective way to reduce
anti-Xa levels.
 Hyperkalemia:
o Monitor for hyperkalemia. Hyperkalemia can be caused by Heparin, which
affects aldosterone. Similar reactions may occur with danaparoid.
 Hepatic impairment
o Patients with hepatic impairment should be cautious.
  Peptic ulcer disease:
o Patients with a history or peptic ulcer disease should be cautious.
 Prosthetic heart valves:
o Patients with prosthetic heart valves have not been shown to be safe or
effective in thromboprophylaxis.
 Renal impairment
o Extra care is required if you administer medication to someone with renal
impairment. It is possible to adjust the dosage.
 Stroke
To rule out hemorhagic stroke, CT should be performed before beginning
o
therapy.
 Thrombocytopenia:
o Patients with a history or risk factors for thrombocytopenia (either congenital,
heparin-induced, or platelet defects) should be treated with caution.
o Cross-reactivity of Danaparoid should be tested for patients with heparin-
induced bleeding as per the manufacturer. If positive other therapies are
available, they should be used.
o If there are any clinical signs of a positive cross-reaction, such as an increase
in platelet count, thrombosis or skin necrosis, Danaparoid use should be
stopped immediately
o If necessary, therapy can be resumed after confirmation of negative tests for
antiplatelet antibodies.
o The cross-reactivity between heparins or danaparoid may be diagnosed by
cutting allergy tests.
Danaparoid: Drug Interaction
Note: Drug Interaction Categories:
 Risk Factor C: Monitor When Using Combination
 Risk Factor D: Consider Treatment Modification
 Risk Factor X: Avoid Concomitant Use
Risk Factor C (Monitor
therapy).
Antiplatelet Agents (e.g. P2Y12
May increase the anticoagulant effects of Anticoagulants.
inhibitors NSAIDs, SSRIs etc.)

Bromperidol May increase the toxic/adverse effects of Anticoagulants.

Caplacizumab May increase the anticoagulant effects of Anticoagulants.

Anticoagulants can increase the toxic/adverse effects of

Collagenase Systemic. In particular, there may be an
Collagenase (Systemic)
increase in the risk of bleeding and/or bruising at the
injection site.

Dasatinib May increase the anticoagulant effects of Anticoagulants.

Anticoagulants can increase the toxic/adverse effects of

Deferasirox Deferasirox. Specifically, the risk for GI ulceration/irritation
or GI bleeding may be increased.

Deoxycholic Acid Anticoagulants can increase the toxic/adverse effects of

Deoxycholic Acid. The risk of bleeding or bruising may
 increase in the treatment area.

Fat Emulsion (Fish oil-based) May increase the anticoagulant effects of Anticoagulants.

Anticoagulants can increase the toxic/adverse effects of

Ibritumomab Tiuxetan Ibritumomab Tiuxetan. Both agents could increase bleeding
risk.

Ibrutinib May increase the toxic/adverse effects of Anticoagulants.

Inotersen May increase the anticoagulant effects of Anticoagulants.

May increase the toxic/adverse effects of

Limaprost
Anticoagulants. There may be an increase in bleeding risk.

Anticoagulants can increase the toxic/adverse effects of

Nintedanib
Nintedanib. Particularly, bleeding risks may be increased.

Nonsteroidal Anti-
May increase the anticoagulant effects of Anticoagulants.
Inflammatory Drugs

Anticoagulants can increase the toxic/adverse effects of

Obinutuzumab Obinutuzumab. In particular, there may be an increase in
the risk of bleeding-related complications.

Omega-3 Fatty Acids May increase the anticoagulant effects of Anticoagulants.

May decrease the therapeutic effects of

Anticoagulants. Oritavancin can artificially increase
Oritavancin laboratory results used to measure anticoagulant
effectiveness. This could make it difficult to determine if
anticoagulant doses should be decreased.

Pentosan Polysulfate Sodium May increase the anticoagulant effects of Anticoagulants.

May increase the toxic/adverse effects of

Prostacyclin Analogues Anticoagulants. Combining these anticoagulants may
increase the risk of bleeding from the combination.

Salicylates May increase the anticoagulant effects of Anticoagulants.

Sugammadex May increase the anticoagulant effects of Anticoagulants.

Sulodexide May increase the anticoagulant effects of Anticoagulants.

May decrease the therapeutic effects of

Anticoagulants. Telavancin can artificially increase
Telavancin laboratory results used to measure anticoagulant
effectiveness. This could make it difficult to determine the
correct dose.

May increase the anticoagulant effects of

Thrombolytic Agents Anticoagulants. Management: Refer to the full drug
monograph for instructions on how alteplase can be used
 for acute ischemic stroke treatment with oral
Anticoagulants.

Tibolone May increase the anticoagulant effects of Anticoagulants.

Tipranavir May increase the anticoagulant effects of Anticoagulants.

Vitamin E (Systemic) May increase the anticoagulant effects of Anticoagulants.

Vitamin K antagonists (eg Vitamin K Antagonists may have an anticoagulant effect that
warfarin) is enhanced by anticoagulants.

Risk Factor D (Consider

therapy modifications)
Desirudin may have an anticoagulant effect that is enhanced
Desirudin
by taking anticoagulants.

Anticoagulants may have a lower anticoagulant

Estrogen Derivatives
effect. Particularly, some estrogens and progestin/estrogen
combination may have prothrombotic side effects that
could counteract anticoagulant properties. Management:
Consider the potential benefits of estrogens in relation to
the increased risk of thromboembolism and procoagulant
effects. Some circumstances may make estrogens
contraindicated. For more information, refer to the
guidelines. Tibolone is an exception.

Herbs
(Anticoagulant/Antiplatelet Can increase the toxic/adverse effects of
Properties) (eg, Alfalfa, Anise, Anticoagulants. Possible bleeding.
Bilberry)

Anticoagulants may have a reduced therapeutic

effect. Progestin-estrogen combination and some progestins
may have prothrombotic side effects that could counteract
anticoagulant properties. Management: Consider the pros
Progestins
and cons of progestins in relation to the possible increased
risk of thromboembolism or procoagulant effects. Some
circumstances may make progestins contraindicated. For
more information, refer to the guidelines.

Risk Factor X (Avoid

Combination)
May increase the anticoagulant effects of
Anticoagulants. Refer to the separate drug interaction
content as well as the full drug monograph content for
Apixaban
apixaban and vitamin K antagonists (eg warfarin,
Acenocoumarol) during anticoagulant transitions and
bridging periods.

Dabigatran Etexilate May increase the anticoagulant effects of

 Anticoagulants. Refer to the separate drug interaction
content as well as the full drug monograph content for
dabigatran, etexilate, and vitamin K antagonists (eg
warfarin, Acenocoumarol) during anticoagulant transition,
and bridging times.

May increase the anticoagulant effects of

Anticoagulants. Refer to the separate drug interaction and
full drug monograph contents regarding edoxaban and
vitamin K antagonists (eg warfarin, Acenocoumarol) during
Edoxaban anticoagulant transition or bridging periods. Management:
A limited amount of combined use may be recommended
during transitions from one anticoagulant treatment to
another. For specific information on switching anticoagulant
treatment, see the full edoxaban drug monograph.

Hemin May increase the anticoagulant effects of Anticoagulants.

Anticoagulants may have an adverse/toxic effect that can be

MiFEPRIStone
increased. In particular, bleeding risk may increase.

Omacetaxine's toxic/adverse effects may be exacerbated by

anticoagulants. In particular, bleeding-related events can be
Omacetaxine more common. Patients with a lower platelet count than
50,000/uL should not use anticoagulants and omacetaxine
simultaneously.

Rivaroxaban's anticoagulant effects may be enhanced by

anticoagulants. Refer to the separate drug interaction
content as well as the full drug monograph content for
Rivaroxaban
rivaroxaban use with vitamin K antagonists (eg warfarin,
Acenocoumarol) during anticoagulant Transition and
Bridging Periods.

Urokinase May increase the anticoagulant effects of Anticoagulants.

May increase the toxic/adverse effects of

Vorapaxar Anticoagulants. This combination may increase bleeding
risk.

 
Monitoring parameters:
1. Platelets (baseline, alternatively during week 1, two times a week in week 2 and 3,
and once a week after that);
2. occult blood or other signs of bleeding;
3. anti-Xa activity (if available).
How to administer Danaparoid (Orgaran)?
it can be administered through 2 routes
1. Intravenous (bolus, infusion): administer seperately
2. subcutaneous: switch sites of injection
Note: avoid IM route
Mechanism of action of Danaparoid (Orgaran):
 Inhibits factor IIa and Xa (anti-Xa effect >20 times anti IIa effects).
 Through thrombin generation inhibition, fibrin is prevented from entering the
coagulation pathway.
Onset of action:
 Peak effect: SubQ: Maximum antifactor Xa activities occur in 4-5 hours
Bioavailability:
 SubQ: ~100%
Half-life elimination:
 Anti-Xa activity: ~25 hours (renal impairment: 29-35 hours);
 Thrombin generation inhibition activity: ~7 hours
Excretion:
 Primarily urine

Tools

Specific Antidotes for Direct Oral Anticoagulant Reversal.

Originally published28 Oct

Direct oral anticoagulants (DOAC) are recommended as the preferred option

for the treatment and prevention of thromboembolic events because of a
favorable benefit–risk profile when compared with vitamin K antagonists.
Nevertheless, the fear of bleeding owing to the lack of a specific antidote has
been a major concern. Idarucizumab was marketed in 2018 for the reversal of
the thrombin inhibitor dabigatran. Recently, after the publication of the
ANNEXA-4 study, andexanet alfa, the antidote for factor Xa (FXa) inhibitors,
was approved.1 The results of this study question whether these antidotes
fulfill an unmet need and improve DOAC-treated patient outcomes.
Major bleeding occurs annually in 1% to 3% of DOAC-treated patients and
results in high mortality. The short half-life of DOACs compared with warfarin
obviates the use of an antidote in most cases. However, anticoagulant
reversal is unquestionably required in specific situations including urgent
invasive procedures, overdose, or life-threatening traumatic or spontaneous
bleeding. Because rapid vitamin K antagonist reversal reduces mortality of
patients facing major bleeding and minimizes hematoma expansion after
intracerebral hemorrhage, immediate reversal of DOAC should similarly
improve outcomes.2 This is based on the assumption that by reversing the
anticoagulant effects, the antidote restores hemostasis, stops hemorrhage,
and therefore reduces mortality. Ideally, the perfect antidote should induce
immediate, complete, and sustained reversal of the anticoagulant activity
correlated with clinical improvement, with no side effects, especially
thromboembolic, should be user friendly, and should be available at an
acceptable price.
Idarucizumab (Praxbind, Boehringer Ingelheim) is a humanized monoclonal
antibody fragment with structural analogies with thrombin that specifically
binds dabigatran with high affinity, forming complexes cleared by the kidneys.
The Food and Drug Administration approved idarucizumab for dabigatran
reversal in life-threatening or uncontrolled bleeding, or emergency
procedures. Indeed, the single-arm RE-VERSE AD study (Reversal Effects of
Idarucizumab on Active Dabigatran) demonstrated that intravenous infusion of
5 g idarucizumab provided immediate, effective (100% median maximum
percentage reversal), and sustained reversal of anticoagulant activity in 503
dabigatran-treated patients who had uncontrolled bleeding or faced
emergency surgery.3
Andexanet alfa (Andexxa, Portola) is a genetically modified FXa that acts as
a decoy to bind FXa inhibitors, including apixaban, rivaroxaban, and
edoxaban, but also low-molecular-weight heparins. It has no active site and is
therefore catalytically inactive. It has no membrane-binding Gla-domain, so it
is unable to assemble into the prothrombinase complex. The Food and Drug
Administration granted accelerated approval for patients treated with apixaban
or rivaroxaban, when reversal is needed because of life-threatening or
uncontrolled bleeding, beginning in May 2018 after the intermediate analysis
of the ANNEXA-4 study (The Andexanet Alfa, a Novel Antidote to the
Anticoagulation Effects of Factor Xa Inhibitors study). The European Medicine
Agency waited for the full cohort results in 2019 to grant a conditional
marketing authorization. This single-arm study confirmed that a bolus of
andexanet followed by a 2-hour infusion markedly reduced anti-FXa activity
(92% reduction) in patients with acute major bleeding receiving FXa inhibitors,
mainly apixaban and rivaroxaban.1
These encouraging results come with caveats. First the immediate biological
efficacy is questionable. The aim of reversal is to reduce anticoagulant activity
below a safety hemostatic threshold, usually defined by international
normalized ratio <1.3–1.5 for vitamin K antagonists and 50 ng/mL for
DOACs.4 After reversal, dabigatran activity was nearly undetectable in 99.4%
of the patients in RE-VERSE AD, whereas more than a quarter of the
rivaroxaban-treated patients in ANNEXA-4 maintained concentrations above
the threshold, suggesting a limited binding capacity of andexanet.1,3 Another
issue is the anticoagulation rebound (ie, the reappearance of biological
anticoagulant activity after neutralization). In RE-VERSE AD, late
anticoagulation rebound was observed in 23% of the patients, mainly after 12
hours, and was associated with recurrent or continued bleeding in 9% of
them, leading the investigators to consider readministration of
idarucizumab.3 This rebound results from dabigatran moving from
extravascular compartment into plasma in response to the concentration
gradient occurring after reversal. In contrast, in ANNEXA-4, anticoagulation
rebound occurred shortly after andexanet administration and was massive: 4
hours after the end of andexanet infusion, 75% of the patients had
rivaroxaban concentrations above 50 ng/mL, and more than 50% even above
100 ng/mL.1 Here, the rebound results from the short half-life of andexanet.
Once the perfusion is completed, anticoagulant activity rises to placebo levels
because andexanet neutralizes FXa inhibitors but does not eliminate them.
Nevertheless, sustained correction of coagulation is required for several hours
after bleeding, and even days in case of intracerebral hemorrhage. This time
is needed for the initial platelet clot to make a stable fibrin clot able to resist
further assault of anticoagulation. This was illustrated in RE-VERSE AD
where reincrease in dabigatran concentration after reversal induced the
recurrence of bleeding. This is also clearly stated in the guidelines for
perioperative management that recommend delaying therapeutic
anticoagulant resumption for 24 to 72 hours after scheduled surgery to
prevent bleeding from the surgical site. The extremely brief reversal of FXa
inhibitors with andexanet is therefore a strong limitation.
These antidotes also put potential thromboembolic risk into question. In RE-
VERSE AD and ANNEXA-4, thrombotic events were reported in 4.8% and
10% of the patients within 30 days after reversal, respectively.1,3 In the
absence of controlled groups, it is impossible to state whether
thromboembolic events reflect the inherent effect of the antidote or any
hypercoagulable state related to patient underlying conditions, increased by
DOAC interruption, inflammation, immobilization, or transfusion. However, it is
worth noting that whereas idarucizumab had no procoagulant activity in
animal models and in healthy volunteers, andexanet transiently increased
markers of thrombin formation, including levels of D-dimer and prothrombin
fragments 1+2.5 This has been attributed to the ability of andexanet to inhibit
the activity of tissue factor pathway inhibitor, resulting in increased tissue
factor–activated generation of FXa and thrombin. Until receipt of further data,
the Food and Drug Administration issued a black box warning for andexanet
regarding the increased risks of thrombotic events, cardiac arrest, and sudden
death.
Finally, limitations regarding practical aspects must be considered. Whereas
idarucizumab is administered as a single dosage of 2 vials for $3880,
andexanet is administered according to complex schemes including bolus
then infusion based on the DOAC, dosage, and timing of the last dose,
resulting in low or high regimens requiring the preparation of many vials,
announced for $24 750 and $49 500, respectively. Such prices and initial
limited supply may reduce andexanet accessibility. Rationalization of antidote
use must be anticipated. DOAC concentration measurement can help to avoid
unnecessary reversal when a concentration is already below the hemostatic
threshold, which affected more than 25% of the patients in RE-VERSE AD.3
Both antidotes received Food and Drug Administration accelerated approval.
This program allows approval based on a surrogate end point that is
reasonably likely to predict a real clinical benefit but requires confirmatory
studies to validate the anticipated benefit because surrogate markers do not
always translate into clinical outcomes. This is apparently the case in
ANNEXA-4 because reduction in anti-FXa activity was not predictive of
hemostatic efficacy.1 Portola is now conducting a randomized trial
(https://www.clinicaltrials.gov; Unique identifier: NCT03661528) to evaluate
andexanet versus standard of care in patients with intracerebral hemorrhage
receiving FXa inhibitors.1 This trial will definitively adjudicate the benefit of
andexanet. For other agents, uncertainty will persist: idarucizumab is fully
approved without an ongoing confirmatory controlled trial; activated and
nonactivated prothrombin complex concentrates, although recommended
when specific antidotes are not available, have never been rigorously
assessed.
The availability of specific antidotes provides reassurance, but whether DOAC
reversal translates into clinical improvements remains unknown and leaves
clinicians in an awkward position. In the absence of a robust evaluation, the
case is not closed.