Heparin Sodium

Confirm the selection of the correct formulation and strength prior to administration of the drug.

INSTRUCTIONS FOR USE for the freeflex^® Bag

Leave bag in the overwrap until time of use.

The intact port cap provides visual tamper evidence.  Do not use if port cap is prematurely removed.

Maintain strict aseptic technique during handling.

To Open:

1. Always inspect the bag before and after removal from the overwrap.
2. Place the bag on a clean, flat surface. Starting in the bottom corner, peel the overwrap open and remove the bag.
3. Check the bag for leaks by squeezing firmly. If leaks are found, discard the bag.
4. Do not use if the solution is cloudy or a precipitate is present.

To Prepare for Administration:

1. Immediately before connecting the infusion set, firmly grasp the BLUE infusion port cap with the arrow pointing away from the bag between index finger and thumb.  Gently break off the port cap. The membrane of the infusion port is sterile, and disinfection before initial use is not necessary if proper aseptic handling technique is followed.
2. Use a non-vented infusion set or close the air-inlet on a vented set. The BLUE infusion port is compatible with spike systems produced according to ISO 8536-4, with an external spike diameter of 5.5 to 5.7 mm.
3. Close the roller clamp of the infusion set.
4. Hold the base of the BLUE infusion port and insert the spike by rotating your wrist slightly until the spike is fully inserted.
5. The port membrane contains a self-sealing septum that helps prevent leakage after removing the spike.  The infusion port is not intended to be spiked more than once.
6. Hang from the hole at the top of the bag.
7. For Single Use Only.  Discard unused portion.

Do not admix with other drugs.

Do not use flexible container in series connections.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 

Adjust the dosage of heparin sodium according to the patient’s coagulation test results.  When heparin is given by continuous intravenous infusion, determine the coagulation time approximately every 4 hours in the early stages of treatment.  When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the early stages of treatment and at appropriate intervals thereafter.  Dosage is considered adequate when the activated partial thromboplastin time (APTT) is 1.5 to 2 times the normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value.      

Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy.

The dosing recommendations in Table 1 are based on clinical experience.  Although dosage 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

 * Based on 150 lb. (68 kg) patient.

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 (intravenous 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.

Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium 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.

To ensure continuous anticoagulation when converting from Heparin Sodium 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 [see Drug Interactions (7.1)].

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

Follow equipment manufacturer’s 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.

Do not use this product as a “catheter lock flush” product. Heparin is supplied in various strengths. Fatal hemorrhages have occurred due to medication errors.  Carefully examine all heparin products to confirm the correct container choice prior to administration of the drug.

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

Hemorrhage, including fatal events, has occurred in patients receiving Heparin Sodium.  Hemorrhage can occur at virtually any site in patients receiving heparin.  Adrenal hemorrhage (with resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have occurred during anticoagulant therapy with heparin [see Adverse Reactions (6.1)]. A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age [see Clinical Pharmacology (12.3)].  An unexplained fall in hematocrit or fall in blood pressure should lead to serious consideration of a hemorrhagic event.

Use heparin sodium 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 tap 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 and continuous tube drainage of the stomach or small intestine.
• Other  — Menstruation, liver disease with impaired hemostasis.

HIT is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets.  HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. 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, thrombus formation on a prosthetic cardiac valve, 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 or 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 or HITT.

Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of 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/mm ³ or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions (5.3)].

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, heparin sodium should be discontinued promptly [see Overdosage (10)].  Periodic platelet counts, hematocrits are recommended during the entire course of heparin therapy [see Dosage and Administration (2.2)].

Increased 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.

Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations [see Adverse Reactions (6.1)].  Because heparin sodium is derived from animal tissue, monitor for signs and symptoms of hypersensitivity when it is used in patients with a history of allergy.

Heparin Sodium in 5% Dextrose Injection

This product contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people.  The overall prevalence of sulfite sensitivity in the general population is unknown and probably low.  Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

The following adverse reactions have been identified during post-approval use of heparin sodium. 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 [see Warnings and Precautions (5.2)].  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:

                  –  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 anticoagulant 
                      therapy.      

                 –   Retroperitoneal hemorrhage.

• HIT and HITT, including delayed onset cases  [see Warnings and Precautions (5.3 and 5.4)].
• Hypersensitivity –   Generalized hypersensitivity reactions have been reported with chills, fever, and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely.  Itching and burning, especially on the plantar side of the feet, may occur [see Warnings and Precautions (5.7)].
• 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 sodium have also been reported.

Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained.

Drugs such as NSAIDS (including salicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIb/IIIa antagonists (including abciximab, eptifibatide, and tirofiban), and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. To reduce the risk of bleeding, a reduction in the dose of antiplatelet agent or heparin is recommended.

Digitalis, tetracyclines, nicotine, antihistamines, or intravenous nitroglycerin may partially counteract the anticoagulant action of heparin sodium.

Heparin Sodium in 5% Dextrose Injection

Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are recommended during coadministration of heparin and intravenous nitroglycerin.

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).

Risk Summary
There are no available data on heparin sodium use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage.  In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans.  No teratogenicity, but early embryo-fetal death was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 40,000 units/24 hours infusion (see Data).  Consider the benefits and risks of Heparin Sodium in 0.45% Sodium Chloride Injection or Heparin Sodium in 5% Dextrose Injection to a pregnant woman and possible risks to the fetus when prescribing Heparin Sodium in 0.45% Sodium Chloride Injection or Heparin Sodium in 5% Dextrose Injection to a pregnant woman.  
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Human Data
The maternal and fetal outcomes associated with uses of heparin via various dosing methods and administration routes during pregnancy have been investigated in numerous studies.  These studies generally reported normal deliveries with no maternal or fetal bleeding and no other complications.
Animal Data
In a published study conducted in rats and rabbits, pregnant animals received heparin intravenously during organogenesis at a dose of 10,000 USP 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.

Risk Summary

There is no information regarding the presence of Heparin Sodium in 0.45% Sodium Chloride Injection or Heparin Sodium in 5% Dextrose Injection in human milk, the effects on the breastfed infant, or the effects on milk production.  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.  The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Heparin Sodium in 0.45% Sodium Chloride Injection or Heparin Sodium in 5% Dextrose Injection and any potential adverse effects on the breastfed infant from Heparin Sodium in 0.45% Sodium Chloride Injection or Heparin Sodium in 5% Dextrose Injection or from the underlying maternal condition [see Use in Specific Populations (8.4)].

There are no adequate and well-controlled studies on heparin use in pediatric patients.  Pediatric dosing recommendations are based on clinical experience [see Dosage and Administration (2.4)].

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 [see Warnings and Precautions (5.2)].  Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology (12.3)].

Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce a conformational change, which markedly enhances the serine protease activity of Antithrombin III, thereby inhibiting the activated coagulation factors involved in the clotting sequence, particularly Xa and IIa. Small amounts of heparin inhibit Factor Xa, and larger amounts inhibit thrombin (Factor IIa). Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor.  Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

Bleeding time is usually unaffected by heparin. Various times (activated clotting time, activated partial thromboplastin time, prothrombin time, whole blood clotting time) are prolonged by full therapeutic doses of heparin; in most cases it is not measurably affected by low doses of heparin.

Absorption
Heparin is not absorbed through the gastrointestinal tract and therefore administered via parenteral route. Peak plasma concentration and the onset of action are achieved immediately after intravenous administration.
Distribution
Heparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases and lipoproteins. The volume of distribution is 0.07 L/kg.
Elimination
Metabolism
Heparin does not undergo enzymatic degradation.
Excretion
Heparin is mainly cleared from the circulation by liver and reticuloendothelial cells mediated uptake into extravascular space. Heparin undergoes biphasic clearance, a) rapid saturable clearance (zero order process due to binding to proteins, endothelial cells and macrophage) and b) slower first order elimination. The plasma half-life is dose-dependent and it ranges from 0.5 to 2 h.
Specific Population
Geriatric patients
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 [see Use in Specific Populations (8.5)].

No long-term studies in animals have been performed to evaluate the carcinogenic potential of heparin. Also, no studies in animals have been performed concerning mutagenesis or impairment of fertility.