• Prophylaxis and treatment of venous thrombosis and pulmonary embolism;
• Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation;
• Treatment   of   acute   and   chronic   consumption   coagulopathies   (disseminated intravascular coagulation);
• Prevention of clotting in arterial and cardiac surgery;
• Prophylaxis and treatment of peripheral arterial embolism;
• Anticoagulant  use  in  blood  transfusions,  extracorporeal  circulation,  and  dialysis procedures.

Adjust the dosage of heparin according to the patient’s coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with heparin by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (SC) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injections.

 

Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration.

 

The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines:

 

Table   1:   Recommended   Adult   Full-Dose   Heparin   Regimens   for   Therapeutic Anticoagulant Effect

Method of Administration	Frequency	Recommended Dose*
Deep Subcutaneous (Intrafat) Injection Use a different site for each injection to prevent the development of hematoma	Initial Dose	333 units/kg subcutaneously
	Every 12 hours	250 units/kg subcutaneously
Intermittent Intravenous Injection	Initial Dose	10,000 units,  either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP
	Every 4 to 6 hours	5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP
Continuous Intravenous Infusion	Initial Dose	5,000 units by IV injection
	Continuous	20,000 to 40,000 units per 24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion

* Based on 150 lb (68 kg) patient

 

Method of administration

Care should be taken to ensure that the vial is not confused with a “catheter lock flush” vial or other vial of incorrect strength. Confirm the selection of the correct formulation and strength prior to administration of the drug.

 

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate.

 

When heparin is added to an infusion solution for continuous intravenous (IV) administration, invert the container at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution.

 

Administer heparin by intermittent IV injection, IV infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Heparin is not intended for intramuscular (IM) use.

 

Pediatric

Use preservative-free heparin in neonates and infants.

 

There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients:

 

Initial Dose                                 75 to 100 units/kg (IV bolus over 10 minutes)

 

Maintenance Dose                 Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements                                                               (average 28 units/kg/hour)

                                                  Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin,                                                       similar to weight- adjusted adult dosage.

 

Monitoring                              Adjust  heparin  to  maintain  aPTT  of  60  to  85  seconds, assuming this reflects an                                                            anti- Factor Xa level of 0.35 to 0.70.

 

Cardiovascular Surgery

Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes or 400 units per kilogram for those estimated to last longer than 60 minutes.

 

Low-Dose Prophylaxis of Postoperative Thromboembolism

The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma.

 

Blood Transfusion

Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation. Usually, 7,500 USP units of heparin are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood.

 

Converting to Warfarin

To ensure continuous anticoagulation when converting from heparin to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. heparin therapy may then be discontinued without tapering.

 

Converting to Dabigatran

For  patients  currently  receiving  intravenous  heparin,  stop  intravenous  infusion  of heparin immediately after administering the first dose of oral dabigatran; or for intermittent intravenous administration of heparin, start oral dabigatran 0 to 2 hours before the time that the next dose of heparin was to have been administered.

 

Extracorporeal Dialysis

Follow equipment manufacturers’ operating directions carefully. A dose of 25 to 30 units/kg followed by an infusion rate of 1,500 to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers’ recommendations are not available.

• History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis. • Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions). • In whom suitable blood coagulation tests (e.g., whole-blood clotting time, partial thromboplastin time) cannot be performed at appropriate intervals. This contraindication refers to full-dose heparin regimens only; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin.

Fatal Medication Errors

Do not use Heparin as a “catheter lock flush” product. Heparin is supplied in vials containing various strengths of heparin. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL heparin vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all Heparin vials to confirm the correct vial choice prior to administration of the drug.

 

Hemorrhage

Avoid using heparin in the presence of major bleeding, except when the benefits of heparin therapy outweigh the potential risks.

 

Hemorrhage can occur at virtually any site in patients receiving heparin. Fatal hemorrhages have occurred. Adrenal hemorrhage (with resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have occurred during anticoagulant therapy with heparin). A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. An unexplained fall in hematocrit or fall in blood pressure should lead to serious consideration of a hemorrhagic event.

 

Use  heparin  with  caution  in  disease  states  in  which  there  is  increased  risk  of hemorrhage, including:

• Cardiovascular – Subacute bacterial endocarditis, severe hypertension
• Surgical  –  During  and  immediately  following:  (a)  spinal  puncture  or  spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye.
• Hematologic – Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia, and some vascular purpuras.
• Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy – The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, reduce the heparin dose during concomitant treatment with antithrombin III (human).
• Gastrointestinal – Ulcerative lesions, continuous tube drainage of the stomach or small intestine, and clinical settings in which stress-induced gastrointestinal hemorrhage is possible.
• Other  –  Menstruation,  liver  disease  with  impaired  hemostasis,  severe  renal disease, or in patients with indwelling catheters.

 

Heparin-Induced  Thrombocytopenia  and  Heparin-Induced  Thrombocytopenia  and Thrombosis

Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction resulting   from   irreversible   aggregation   of   platelets.   HIT   may   progress   to   the development of venous and arterial thromboses, a condition known as heparin-induced thrombocytopenia and thrombosis (HITT). Thrombotic events may also be the initial presentation  for  HITT.  These  serious  thromboembolic  events  include  deep  vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. Monitor  thrombocytopenia of any degree closely. If the platelet count falls below 100,000/mm³ or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant.

 

HIT and HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT.

 

Benzyl Alcohol Toxicity

Use preservative-free heparin in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants may be more likely to develop toxicity.

 

Thrombocytopenia

Thrombocytopenia in patients receiving heparin has been reported at frequencies up to 30%. It can occur 2 to 20 days (average 5 to 9) following the onset of heparin therapy. Obtain  platelet  counts  before  and  periodically  during  heparin  therapy.  Monitor thrombocytopenia of any degree closely. If the count falls below 100,000/mm³ or if recurrent thrombosis develops, promptly  discontinue heparin,  evaluate for  HIT  and HITT, and, if necessary, administer an alternative anticoagulant.

 

Coagulation Testing and Monitoring

When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration.

 

Heparin Resistance

Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted.

 

Hypersensitivity

Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations.

 

Because heparin is derived from animal tissue, it should be used with caution in patients with a history of allergy.

 

Pediatric Use

There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience.

 

Carefully examine all heparin vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which heparin vials have been confused with “catheter lock flush” vials.

 

Geriatric Use

There are limited adequate and well-controlled studies in patients 65 years and older, however a higher incidence of bleeding has been reported in patients over 60 years of age, especially women. Lower doses of heparin may be indicated in these patients.

Drugs Enhancing Heparin Effect

Drugs that interfere with platelet aggregation – These drugs (e.g., systemic salicylates, NSAIDs including celecoxib and ibuprofen, glycoprotein IIb/IIIa antagonists, thienopyridines, dipyridamole, hydroxychloroquine, dextran) may induce bleeding. Use heparin with caution in patients receiving such agents.

 

Antithrombin  III  (human)  –  The  anticoagulant  effect  of  heparin  is  enhanced  by concurrent treatment with antithrombin III (human) in patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, a reduced dosage of heparin is recommended during treatment with antithrombin III (human).

 

Drugs Decreasing Heparin Effect

Digitalis, tetracyclines, nicotine, nitrates, and antihistamines may partially counteract the anticoagulant action of heparin. Monitor patients’ coagulation tests appropriately.

 

Drug-Laboratory Test Interactions

Elevated aminotransferase levels – Significant elevations of AST and ALT levels without elevation in bilirubin or alkaline phosphatase have occurred in patients (and healthy subjects) who have received heparin. Because aminotransferase determinations are important in the differential diagnoses of certain conditions including myocardial infarction, liver disease, and pulmonary emboli, elevations in aminotransferase levels that may be related to heparin use should be interpreted with caution.

 

Prothrombin time – Heparin may prolong the one-stage prothrombin time. Therefore, when heparin is given with warfarin, allow a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose of heparin to elapse before blood is drawn to obtain a valid prothrombin time.

Pregnancy

Pregnancy Category C

 

There are no adequate and well-controlled studies on heparin use in pregnant women. In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans. Heparin does not cross the  placenta,  based  on  human  and  animal  studies.  Administration  of  heparin  to pregnant animals at doses higher than the maximum human daily dose based on body weight resulted in increased resorptions. Use heparin during pregnancy only if the potential benefit justifies the potential risk to the fetus.

 

If available, preservative-free heparin is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants.

 

In a published study conducted in rats and rabbits, pregnant animals received heparin intravenously during organogenesis at a dose of 10,000 units/kg/day, approximately 10 times the maximum human daily dose based on body weight. The number of early resorptions increased in both species. There was no evidence of teratogenic effects.

 

Nursing Mothers

If available, preservative-free heparin is recommended when heparin therapy is needed during lactation. Due to its large molecular weight, heparin is not likely to be excreted in human milk, and any heparin in milk would not be orally absorbed by a nursing infant. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Exercise caution when administering heparin to a nursing mother.

None stated.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of heparin.  Because  these  reactions  are  reported  voluntarily  from  a  population  of uncertain size, it is not always possible to reliably estimate their frequency.

 

• Hemorrhage – Hemorrhage is the chief complication that may result from heparin therapy. Gastrointestinal or urinary tract bleeding during anticoagulant therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but certain specific hemorrhagic complications may be difficult to detect including:

-     Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred with heparin therapy, including fatal cases.

-     Ovarian  (corpus  luteum)  hemorrhage  developed  in  a  number  of  women  of reproductive age receiving short- or long-term heparin therapy.

-     Retroperitoneal hemorrhage.

• HIT and HITT, including delayed onset cases.
• Local irritation – Local irritation, erythema, mild pain, hematoma, or ulceration have occurred following deep subcutaneous (intrafat) injection of heparin. Because such reactions occur more frequently after intramuscular administration, the IM route is not recommended.
• Histamine-like reactions – Such reactions have been observed at the site of injection. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin, occasionally requiring skin grafting.
• Hypersensitivity – Generalized hypersensitivity reactions have been reported with chills, fever, and urticaria as the most usual manifestations; asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occur less frequently. Itching and burning, especially on the plantar site of the feet, may occur.
• Elevations   of   serum   aminotransferases   –   Significant   elevations   of   aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin.
• Others – Osteoporosis following long-term administration of high doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis,  delayed  transient  alopecia,  priapism,  and  rebound  hyperlipemia  on discontinuation of heparin have been reported.

 

Reporting of suspected adverse reactions

 

• Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC)

Fax: +966-11-205-7662

Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

Toll free phone: 8002490000

E-mail: npc.drug@sfda.gov.sa

Website: www.sfda.gov.sa/npc

 

• Other GCC States: Please contact the relevant competent authority.

Bleeding is the chief sign of heparin overdosage.

 

Neutralization of Heparin Effect When clinical circumstances (bleeding) require reversal of the heparin effect, protamine sulfate (1% solution) by slow infusion will neutralize heparin. No more than 50 mg should be administered, very slowly, in any 10 minute period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 30 minutes after intravenous injection. Because fatal reactions often resembling anaphylaxis have been reported with protamine, it should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information, consult the prescribing information for protamine sulfate injection.

Heparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, possessing anticoagulant properties. It is composed of polymers of alternating derivations of α-D-glucosamido (N-sulfated O-sulfated or N-acetylated) and O-sulfated uronic acid (α-L-iduronic acid or β-D-glucuronic acid).

 

Structure of heparin sodium (representative subunits):

 

Heparin is a sterile preparation of heparin sodium derived from porcine intestinal tissue, standardized for anticoagulant activity, in water for injection. It is intended for intravenous or deep subcutaneous administration. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram.

 

When necessary, the pH of heparin is adjusted with hydrochloric acid and/or sodium hydroxide. The pH range is 5.0 to 7.5.

 

Mechanism of Action

Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system.  Small  amounts  of  heparin  in  combination  with  antithrombin  III  (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of Factor XIII, the fibrin stabilizing factor. Heparin does not have fibrinolytic activity.

 

Pharmacodynamics

Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of heparin.

 

Peak plasma levels of heparin are achieved 2–4 hours following subcutaneous administration, although there are considerable individual variations. Log-linear plots of heparin plasma concentrations with time for a wide range of dose levels are linear which suggests the absence of zero order processes. Liver and the reticulo-endothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t½ = 10 minutes) and, after the age of 40 a slower beta phase, indicate uptake in organs. The absence of a relationship between anticoagulant half- life and concentration half-life may reflect factors such as protein binding of heparin.

 

Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (aPTTs) compared with patients under 60 years of age.

No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin. No studies in animals have been performed addressing mutagenesis or impairment of fertility.

-  Benzyl alcohol

- Sodium chloride

-  HCl solution

-  Sodium hydroxide solution

- Water for injection

Heparin is incompatible with certain substances in solution (e.g., alteplase, amikacin sulfate, atracurium besylate, ciprofloxacin, cytarabine, daunorubicin, droperidol, erythromycin lactobionate, gentamicin sulfate, idarubicin, kanamycin sulfate, mitoxantrone HCl, polymyxin B sulfate, promethazine HCl, streptomycin sulfate, tobramycin sulfate). Consult specialized references to verify with which substances incompatibilities have been noted, as compatibility may depend on concentration, temperature, time, and other variables.

36 months.

Store below 30°C, away from light. Protect from freezing.

Type 1 clear glass vials.

Pack size: 10 vial.

Storage of prepared infusion solution should not exceed 4 hours at room temperature or 24 hours at 2 to 8°C.