Heparin

B01A - Antithrombotic agents ATC C05BA03 Oligosaccharide approved 2023 Parenteral Narrow therapeutic index

JFDA label: Lioton 1000 Gel

Mechanism of Action

Activator of Antithrombin-III — Antithrombin-III activator

Target	Action	Gene / class
Antithrombin-III efficacy	ACTIVATOR	SERPINC1 · Secreted protein

Indications

Approved

Anticoagulation

Off-label

Anticoagulant during percutaneous coronary intervention (PCI)
Interstitial cystitis (bladder pain syndrome)
Non–ST-elevation acute coronary syndrome
ST-elevation myocardial infarction (adjunct to fibrinolysis)
Valvular heart disease, bridge during oral anticoagulation interruption

Contraindications

Source: Curated · Lexicomp

History of heparin-induced thrombocytopenia (HIT) Absolute
Hypersensitivity to heparin or any component of the formulation (unless a life-threatening situation necessitates use and use of an alternative anticoagulant is not possible) Absolute
Severe thrombocytopenia Absolute
cases where the administration of sodium or chloride could be clinically detrimental (applies to large volume heparin 2 unit/mL IV solutions only) Absolute
not for use when appropriate blood coagulation tests cannot be obtained at appropriate intervals (applies to full-dose heparin only). Note: Some products contain benzyl alcohol as a preservative Absolute
their use in neonates, infants, or pregnant or breast-feeding mothers is contraindicated by some manufacturers Absolute
uncontrolled active bleeding except when due to disseminated intravascular coagulation (DIC) Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (4)

Not Known Chest pain · shock (including hemorrhagic shock) · thrombosis · vasospasm (allergic; possibly related to thrombosis)

Nervous system disorders (4)

Not Known Chills · dysesthesia (feet) · headache · peripheral neuropathy

Hepatobiliary disorders (1)

Not Known Increased liver enzymes

Renal and urinary disorders (2)

Not Known Erectile dysfunction (frequent or persistent erection) · hematuria

Blood and lymphatic system disorders (8)

Not Known Bruise (unexplained) · gingival hemorrhage · hematoma (rarely reported with deep subcutaneous injections; intramuscular injection [not recommended] is associated with a higher incidence of this effect) · hemorrhage · pulmonary hemorrhage · purpura · retroperitoneal hemorrhage · thrombocytopenia (see note)

Immune system disorders (2)

Not Known Anaphylactoid reaction · hypersensitivity reaction

Metabolism and nutrition disorders (4)

Not Known Adrenal hemorrhage · hyperkalemia (suppression of aldosterone synthesis) · hyperlipidemia (rebound; on discontinuation) · ovarian hemorrhage

Gastrointestinal disorders (5)

Not Known Constipation · hematemesis · melena · nausea · vomiting

Skin and subcutaneous tissue disorders (7)

Not Known Dermal ulcer (rarely reported with deep subcutaneous injections; intramuscular injection [not recommended] is associated with a higher incidence of this effect) · eczema · erythematous plaques (case reports) · localized erythema (rarely reported with deep subcutaneous injections; intramuscular injection [not recommended] is associated with a higher incidence of this effect) · skin necrosis · transient alopecia (delayed) · urticaria

Musculoskeletal and connective tissue disorders (1)

Not Known Osteoporosis (chronic therapy effect)

Eye disorders (2)

Not Known Allergic conjunctivitis · lacrimation

General disorders and administration site conditions (4)

Not Known Drug tolerance · fever · Local irritation · local pain (rarely reported with deep subcutaneous injections; intramuscular injection [not recommended] is associated with a high incidence of these effects)

Other (5)

Not Known and is marked by a progressive fall in platelet counts and · Frequency not defined. Thrombocytopenia has been reported to occur at an incidence between 0% and 30%. It is often of no clinical significance. However · immunologically mediated heparin-induced thrombocytopenia (HIT) has been estimated to occur in 1% to 2% of patients · in some cases · thromboembolic complications (skin necrosis, pulmonary embolism, gangrene of the extremities, cerebrovascular accident, or myocardial infarction)

Respiratory, thoracic and mediastinal disorders (5)

Not Known Asthma · bronchospasm (case reports) · epistaxis · hemoptysis · rhinitis

Dosing

Source: Lexicomp

Note: Many concentrations of heparin are available ranging from 1 unit/mL to 20,000 units/mL. Carefully examine each prefilled syringe or vial prior to use ensuring that the correct concentration is chosen. Heparin lock flush solution is intended only to maintain patency of IV devices and is not to be used for anticoagulant therapy. Acute coronary syndromes (off-label use): IV infusion (weight-based dosing per institutional nomogram recommended): STEMI: Adjunct to fibrinolysis (full-dose alteplase, reteplase, or tenecteplase): Initial bolus of 60 units/kg (maximum: 4,000 units), then 12 units/kg/hour (maximum: 1,000 units/hour) as continuous infusion. Adjust to target aPTT of 1.5 to 2 times control (approximately 50 to 70 seconds). Continue for a minimum of 48 hours, and preferably for the duration of hospitalization (up to 8 days) or until revascularization (if performed) (ACCF/AHA [O’Gara 2013]). NSTE-ACS: Initial bolus of 60 units/kg (maximum: 4,000 units), followed by an initial infusion of 12 units/kg/hour (maximum: 1,000 units/hour). Adjust to target aPTT of 1.5 to 2 times control (approximately 50 to 70 seconds). Recommended duration is 48 hours or until percutaneous coronary intervention (PCI) is performed. Note: If PCI is performed while patient on fondaparinux, 85 units/kg of heparin (60 units/kg if a GP IIb/IIIa inhibitor [eg, abciximab, eptifibatide, tirofiban] is used concomitantly) should be given immediately before PCI with subsequent heparin dosing based on the target activated clotting time (AHA/ACC [Amsterdam 2014]). Anticoagulation (Intermittent administration): IV: Initial: 10,000 units, then 50 to 70 units/kg (5,000 to 10,000 units) every 4 to 6 hours Atrial fibrillation (off-label use): Guidelines pertaining to peri-cardioversion use (ACCP [You 2012]): Patients with atrial fibrillation (for more than 48 hours or unknown duration) undergoing cardioversion: IV heparin to maintain an aPTT prolongation that corresponds to plasma heparin levels of 0.3 to 0.7 units/mL anti-Xa activity started at the time of transesophageal echocardiography (TEE) is recommended with cardioversion performed within 24 hours of the TEE if no thrombus is seen. Patients with atrial fibrillation (for 48 hours or less) undergoing cardioversion: Cardioversion may be performed without prolonged anticoagulation. However, anticoagulation with IV heparin to maintain an aPTT prolongation that corresponds to plasma heparin levels of 0.3 to 0.7 units/mL anti-Xa activity should be started at presentation in patients with no contraindications to anticoagulation. Emergency cardioversion in hemodynamically unstable patient: Cardioversion may be performed without prolonged anticoagulation. Anticoagulation with IV heparin to maintain an aPTT prolongation that corresponds to plasma heparin levels of 0.3 to 0.7 units/mL anti-Xa activity should be started prior to cardioversion in patients with no contraindications to anticoagulation. Cardiothoracic surgery (cardiopulmona

(For additional information see "Heparin (unfractionated): Pediatric drug information") Note: Many concentrations of heparin are available ranging from 1 unit/mL to 20,000 units/mL. Carefully examine each prefilled syringe or vial prior to use ensuring that the correct concentration is chosen. Heparin lock flush solution is intended only to maintain patency of IV devices and is not to be used for anticoagulant therapy. Thrombosis, treatment: Systemic heparinization: Infants: IV: Initial loading dose: 75 units/kg over 10 minutes; then initial continuous maintenance infusion at: 28 units/kg/hour; adjust dose to maintain an anti-Xa activity of 0.35 to 0.7 units/mL or an aPTT range that correlates to this anti-Xa range or a protamine titration range of 0.2 to 0.4 units/mL (ACCP [Monagle 2012]) Children and Adolescents: IV: Initial loading dose: 75 units/kg over 10 minutes, then initial continuous maintenance infusion at: 20 units/kg/hour; adjust dose to maintain an anti-Xa activity of 0.35 to 0.7 units/mL or an aPTT range that correlates to this anti-Xa range or a protamine titration range of 0.2 to 0.4 units/mL (ACCP [Monagle 2012]) Note: Because of variation among hospitals with reagents (lot numbers) and corresponding control of aPTT values, individual institutions should establish unique, institution-specific nomograms. Due to extensive variability within reagents and anti-Xa levels with corresponding aPTTs, a specific nomogram has not been provided; refer to guidelines for a specific nomogram (ACCP [Monagle 2012]).

Patients >60 years of age may have higher serum levels and clinical response (longer aPTTs) as compared to younger patients receiving similar dosages. Lower dosages may be required.

No dosage adjustment required; adjust therapeutic heparin according to aPTT or anti-Xa activity. Hemodialysis: Not dialyzable (NCS/SCCM [Frontera 2016])

No dosage adjustment required; adjust therapeutic heparin according to aPTT or anti-Xa activity.

Warnings & Precautions

Source: Lexicomp

Bleeding

May occur, including fatal events. Use with caution in patients with an increased risk of bleeding, including subacute bacterial endocarditis; congenital or acquired bleeding disorders; active ulcerative or angiodysplastic GI diseases; continuous GI tube drainage; severe uncontrolled hypertension; history of hemorrhagic stroke; use shortly after brain, spinal, or ophthalmologic surgery or other invasive procedures including spinal tap or spinal anesthesia; concomitant treatment with platelet inhibitors; recent GI bleeding; impaired hemostasis; thrombocytopenia or platelet defects; patients with hereditary antithrombin deficiency receiving concurrent antithrombin replacement therapy; severe liver disease; hypertensive or diabetic retinopathy; renal failure; or in patients (especially women) >60 years of age. Monitor patient closely for signs or symptoms of bleeding. Discontinue if bleeding occurs; severe hemorrhage or overdosage may require protamine (consult Protamine monograph for dosing recommendations).

Heparin resistance

Dose requirements >35,000 units/24 hours to maintain a therapeutic aPTT may occur in patients with antithrombin deficiency, increased heparin clearance, elevations in heparin-binding proteins, elevations in factor VIII and/or fibrinogen; frequently encountered in patients with fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, MI, cancer, and in postsurgical patients; measurement of anticoagulant effects using antifactor Xa levels may be of benefit.

Hyperkalemia

Monitor for hyperkalemia; can cause hyperkalemia by suppressing aldosterone production.

Hypersensitivity reactions

May occur; only in life-threatening situations when use of an alternative anticoagulant is not possible should heparin be cautiously used in patients with a documented hypersensitivity reaction. Some products are derived from animal tissue and may be contraindicated in patients with animal allergies (ie, pork); consult individual prescribing information.

Osteoporosis

May occur with prolonged use (>6 months) due to a reduction in bone mineral density.

Thrombocytopenia

May occur. Heparin-induced thrombocytopenia (HIT), a serious antibody-mediated reaction resulting from irreversible aggregation of platelets, may also occur. Patients who develop HIT may be at risk of developing a new thrombus (heparin-induced thrombocytopenia and thrombosis [HITT]). Monitor platelets closely; discontinue therapy and consider alternatives if platelets are 3 and/or thrombosis develops. HIT or HITT may be delayed and can occur up to several weeks after discontinuation of heparin. Use with extreme caution (for a limited duration) or avoid in patients with history of HIT, especially if administered within 100 days of HIT episode (Dager 2007; Warkentin 2001). Special populations:

Elderly

Use with caution in patients >60 years of age, particularly women; older adults can be more sensitive to heparin and a higher incidence of bleeding has been reported in these patients. May require lower doses. Dosage form specific issues:

Benzyl alcohol and derivatives

Some dosage forms may contain benzyl alcohol as a preservative. In neonates, large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome"); the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling. Use in neonates, infants, or pregnant or nursing mothers is contraindicated by some manufacturers; the use of preservative-free heparin is, therefore, recommended in these populations.

Sulfites

Some preparations contain sulfite which may cause allergic reactions. Other warnings/precautions:

Fatal medications errors

Many concentrations of heparin are available ranging from 1 unit/mL to 20,000 units/mL. Clinicians must carefully examine each prefilled syringe or vial prior to use ensuring that the correct concentration is chosen; fatal hemorrhages have occurred related to heparin overdose especially in pediatric patients.

Pregnancy & Lactation

Pregnancy

FDA category C

Safe

UFH and LMWH do not cross placenta — safe for fetus. LMWH preferred (more predictable, once daily). UFH near term for reversal with protamine

Lactation

Contraindicated

Heparin is not excreted into breast milk and can be used in breast-feeding women (Guyatt, 2012). Some products contain benzyl alcohol as a preservative; their use in breast-feeding women is contraindicated by some manufacturers due to the association of gasping syndrome in premature infants.

Monitoring

Efficacy	aPTT 1.5–2.5× control or anti-Xa level 0.3–0.7 IU/mL (unfractionated); therapeutic anticoagulation
Toxicity	Platelet count every 2–3 days (HIT monitoring); aPTT every 6 h when initiating; bleeding
Clinical pearl	LMWH does not require routine aPTT monitoring but anti-Xa can be checked in obesity (> 100 kg) or renal impairment.
Counseling	Any new thrombosis or significant platelet drop while on heparin should raise suspicion for HIT — report immediately.

Biology & Pharmacokinetics

Pharmacokinetics

Half-life	Age-related: Shorter half-life reported in premature neonates compared to adult patients

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Abciximab	major
Acalabrutinib	major
Alteplase	major
Anisindione	major
Anistreplase	major
Apixaban	major
Ardeparin	major
Argatroban	major
Avapritinib	major
Betrixaban	major
Bivalirudin	major
Cabozantinib	major
Cangrelor	major
Caplacizumab	major
Dalteparin	major
Danaparoid	major
Dasatinib	major
Deferasirox	major
Defibrotide	major
Desirudin	major
Dicoumarol	major
Drotrecogin alfa	major
Edoxaban	major
Enoxaparin	major
Eptifibatide	major
Fondaparinux	major
Ibritumomab tiuxetan	major
Ibrutinib	major
Inotersen	major
Ipilimumab	major
Lepirudin	major
Mifepristone	major
Omacetaxine mepesuccinate	major
Oritavancin	major
Panobinostat	major
Ponatinib	major
Ramucirumab	major
Regorafenib	major
Reteplase	major
Rivaroxaban	major

Showing 40 of 100+.

Registered Products (8)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Lioton 1000 Gel	Gel 100000 IU/100gm	30 g tube	ORIENT DRUG STORE CO	2.600
Contractubex Gel	Gel 1 g/100 g, 10 g/100 g, 5000 IU/100 g	20 g tube pack varies	Jarash Drug Store	4.710
Contractubex Gel	Gel 1 g/100 g, 10 g/100 g, 5000 IU/100 g	50 g tube pack varies	Jarash Drug Store	7.790
HEPARIN	Injection 25000 IU/ml	5 ml	Arab Company for Medical & Agricultural Products	—
Heparin Leo 5000 iu/ ml	Vial 5000 IU/ml	50 vial	Khoury Drug Store	—
Heparin Sodium Inj 25000I.U/5ml	Injection 3.00 mg/1 ml, 1.00 ml, 10000 mg/1 ml, 5000 IU/1 ml	10 vial	THE ARAB DRUG STORE P.S.C	—
Hikma Heparin 5000 Vials	Vial 5000 IU/ml	10 vial pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Hikma Heparin 5000 Vials	Vial 5000 IU/ml	1 vial pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	—