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DOSAGE AND ADMINISTRATION



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DOSAGE AND ADMINISTRATION 

Parenteral drug products should be inspected visually for particulate matter and discoloration 

prior to administration, whenever solution and container permit. Slight discoloration does not 

alter potency. 

Heparin Lock Flush Solution is not recommended for use in neonates (see WARNINGSUse In 



Neonates). 

Maintenance Of Patency Of Intravenous Devices 

To prevent clot formation in a heparin lock set or central venous catheter following its proper insertion, 

Heparin Lock Flush Solution, USP is injected via the injection hub in a quantity sufficient to fill the 

entire device. This solution should be replaced each time the device is used. Aspirate before 

administering any solution via the device in order to confirm patency and location of needle or catheter 

tip. If the drug to be administered is incompatible with heparin, the entire device should be flushed 

with normal saline before and after the medication is administered; following the second saline flush, 

Heparin Lock Flush Solution, USP may be reinstilled into the device. The device manufacturer's 

instructions should be consulted for specifics concerning its use. Usually this dilute heparin solution 

will maintain anticoagulation within the device for up to 4 hours. 

NOTE: Since repeated injections of small doses of heparin can alter tests for activated partial 

thromboplastin time (APTT), a baseline value for APTT should be obtained prior to insertion of an 

intravenous device. 

Withdrawal Of Blood Samples 

Heparin Lock Flush Solution, USP may also be used after each withdrawal of blood for laboratory 

tests. When heparin would interfere with or alter the results of blood tests, the heparin solution should 

be cleared from the device by aspirating and discarding it before withdrawing the blood sample. 



HOW SUPPLIED 

HEP-LOCK (Heparin Lock Flush Solution, USP) 

10 USP units/mL 


NDA 17-037/S-158 

Page 21 


 

 

1 mL DOSETTE vials packaged in 25s (NDC 0641-0392-25) 



 

2 mL DOSETTE vials packaged in 25s (NDC 0641-0393-25) 

 

10 mL Multiple Dose vials packaged in 25s (NDC 0641-2438-45) 



 

30 mL Multiple Dose vials packaged in 25s (NDC 0641-2442-45) 

100 USP units/mL 

 

1 mL DOSETTE vials packaged in 25s (NDC 0641-0389-25) 



 

2 mL DOSETTE vials packaged in 25s (NDC 0641-0387-25) 

 

10 mL Multiple Dose vials packaged in 25s (NDC 0641-2436-45) 



 

30 mL Multiple Dose vials packaged in 25s (NDC 0641-2443-45) 



Storage 

Store at 20

°-25°C (68°-77°F) [see USP Controlled Room Temperature]



REFERENCES 

1.

 



Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin Induced Thrombocytopenia – 

A Case Report – J Jpn Assn Torca Surg.1992;40(3):110-111. 

2.

 

Warkentin T, Kelton J. Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis. Annals of 



Internal Medicine. 2001;135:502-506. 

3.

 



Rice L, Attisha W, Drexler A, Francis J. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of 

Internal Medicine, 2002;136:210-215. 

4.

 



Dieck J., C. Rizo-Patron, et al. (1990). “A New Manifestation and Treatment Alternative for Heparin-

Induced Thrombosis.” Chest 98(1524-26). 

5.

 

Smythe M, Stephens J, Mattson. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Emergency 



Medicine, 2005;45(4):417-419. 

6.

 



Divgi A. (Reprint), Thumma S., Hari P., Friedman K., Delayed Onset Heparin-Induced Thrombocytopenia 

(HIT) Presenting After Undocumented Drug Exposure as Post-Angiography Pulmonary Embolism. Blood

2003;102(11):127b. 

Hep-Lock, Baxter and Dosette are registered trademarks of Baxter International, Inc., or its 

subsidiaries. 

 

Manufactured by 



Baxter Healthcare Corporation 

Deerfield, IL 60015 USA 



NDA 17-037/S-158 

Page 22 


 

For Product Inquiry  1 800 ANA DRUG (1-800-262-3784) 

MLT-00103/3.0

 

 



 

 


NDA 17-037/S-158 

Page 23 


 

HEP-LOCK U/P 

Preservative-Free 

(Heparin Lock Flush Solution, USP) 

R



only 

DESCRIPTION 

Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called 

glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars 

occurring in heparin are: (1) 

α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-α-D-glucose 6-

sulfate, (3) 

β-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose and (5) α-L-iduronic acid. 

These sugars are present in decreasing amounts, usually in the order (2)>(1)>(4)>(3)>(5), and are 

joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of 

its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic 

protons of the sulfate units are partially replaced by sodium ions. 

Structural formula of Heparin Sodium (representative sub-units): 

 

HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution, USP) is a sterile solution for 



intravenous flush only. It is not to be used for anticoagulant therapy. HEP-LOCK U/P is specially 

formulated for use in situations where the use of preservatives is not advisable. Each mL contains 

heparin sodium 10 or 100 USP units, derived from porcine intestines and standardized for use as an 

anticoagulant, sodium chloride 8 mg, monobasic sodium phosphate monohydrate 2.3 mg

,

 

and dibasic 



sodium phosphate anhydrous 0.5 mg in Water for Injection. pH 5.0-7.5. The potency is determined by 

biological assay using a USP reference standard based on units of heparin activity per milligram. 



CLINICAL PHARMACOLOGY 

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 


NDA 17-037/S-158 

Page 24 


 

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 the fibrin stabilizing factor. 

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. Loglinear 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 (t

1/2

 = 10 min), and 



after the age of 40 a slower beta phase, indicates 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. 

Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots. 

INDICATIONS AND USAGE 

HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution, USP) is intended to maintain 

patency of an indwelling venipuncture device designed for intermittent injection or infusion therapy or 

blood sampling. Heparin Lock Flush Solution may be used following initial placement of the device in 

the vein, after each injection of a medication or after withdrawal of blood for laboratory tests. (See 

DOSAGE AND ADMINISTRATIONMaintenance of Patency of Intravenous Devices for 

directions for use.) 



HEP-LOCK U/P is not to be used for anticoagulant therapy. 

CONTRAINDICATIONS 

Heparin sodium should NOT be used in patients with the following conditions: severe 

thrombocytopenia; an uncontrollable active bleeding state (see WARNINGS), except when this is due 

to disseminated intravascular coagulation. 



WARNINGS 

Heparin is not intended for intramuscular use. 



NDA 17-037/S-158 

Page 25 


 

Hypersensitivity 

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

threatening situations. (See ADVERSE REACTIONSHypersensitivity.) 

Hemorrhage 

Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in 

hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious 

consideration of a hemorrhagic event. 

Heparin sodium should be used with extreme caution in infants and in patients with disease states in 

which there is increased danger of hemorrhage. Some of the conditions in which increased danger of 

hemorrhage exists are: 

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. 

Gastrointestinal 

Ulcerative lesions and continuous tube drainage of the stomach or small intestine. 



Other 

Menstruation, liver disease with impaired hemostasis. 



Thrombocytopenia 

Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence 

of 0 to 30%. Platelet counts should be obtained at baseline and periodically during heparin 


NDA 17-037/S-158 

Page 26 


 

administration. Mild thrombocytopenia (count greater than 100,000/mm

3

) may remain stable or reverse 



even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. 

If the count falls below 100,000/mm

3

 or if recurrent thrombosis develops (see Heparin-induced 



Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis), the heparin product 

should be discontinued and, if necessary, an alternative anticoagulant administered.  

 

Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and 

Thrombosis (HITT) 

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 referred to 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.  Thrombocytopenia of any degree 

should be monitored closely.  If the platelet count falls below 100,000/mm

or if recurrent thrombosis 



develops, the heparin product should be promptly discontinued and alternative anticoagulants 

considered if patients require continued anticoagulation.  



Delayed Onset of HIT and HITT 

Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis 

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. 

Use in Neonates and Infants 

 

The 100 unit



/

mL concentration should not be used in neonates or in infants who weigh less than 10 kg 

because of the risk of systemic anticoagulation. Caution is necessary when using the 10 unit/mL 

concentration in premature infants who weigh less than 1 kg who are receiving frequent flushes since a 

therapeutic heparin dose may be given to the infant in a 24-hour period. 

PRECAUTIONS 

General 

Precautions must be exercised when drugs that are incompatible with heparin are administered through 

an indwelling intravenous catheter containing Preservative-Free Heparin Lock Flush Solution. (See 

DOSAGE AND ADMINISTRATIONMaintenance of Patency of Intravenous Devices.) The 

concentration of phosphorus in the heparin solution is 0.63 mg/mL.  



NDA 17-037/S-158 

Page 27 


 

Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced 

Thrombocytopenia and Thrombosis (HITT) 

See WARNINGS



Increased Risk to Older Patients, Especially Women 

A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. 



Laboratory Tests 

Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the 

entire course of heparin use (see DOSAGE AND ADMINISTRATION). 

Drug Interactions 

Platelet Inhibitors 

Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, 

hydroxychloroquine 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. 

Other Interactions 

Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of 

heparin sodium. 

Carcinogenesis, Mutagenesis, Impairment of Fertility 

No long-term studies in animals have been performed to evaluate the carcinogenic potential of heparin 

sodium. Also, no reproduction studies in animals have been performed concerning mutagenesis or 

impairment of fertility. 



Pregnancy 

Teratogenic Effects—Pregnancy Category C 

Animal reproduction studies have not been conducted with heparin sodium. It is also not known 

whether heparin sodium can cause fetal harm when administered to a pregnant woman or can affect 

reproduction capacity. Heparin sodium should be given to a pregnant woman only if clearly needed. 



NDA 17-037/S-158 

Page 28 


 

Nonteratogenic Effects 

Heparin does not cross the placental barrier. 



Nursing Mothers 

Heparin is not excreted in human milk. 



Pediatric Use 

Safety and effectiveness in pediatric patients have not been established (see WARNINGS, Use in 



Neonates and Infants). 

Geriatric Use 

A higher incidence of bleeding has been reported in patients over 60 years of age, especially women 

(see CLINICAL PHARMACOLOGY and PRECAUTIONSGeneral). 

ADVERSE REACTIONS 

Hemorrhage 

Hemorrhage is the chief complication that may result from heparin use (see WARNINGS, 



Hemorrhage). An overly prolonged clotting time or minor bleeding during therapy can usually be 

controlled by withdrawing the drug (see OVERDOSAGE). 



Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced 

Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT 

See WARNINGS



Local Irritation 

Local irritation and erythema have been reported with the use of Heparin Lock Flush Solution



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.  


NDA 17-037/S-158 

Page 29 


 

Thrombocytopenia has been reported to occur in patients receiving heparin, with a reported incidence 

of 0 to 30%. While often mild and of no obvious clinical significance, such thrombocytopenia can be 

accompanied by severe thromboembolic complications such as skin necrosis, gangrene of the 

extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, and 

possibly death. (See WARNINGS and PRECAUTIONS.) 

Certain episodes of painful, ischemic and cyanosed limbs have in the past been attributed to allergic 

vasospastic reactions. Whether these are in fact identical to the thrombocytopenia-associated 

complications remains to be determined.

 

OVERDOSAGE 



Symptoms 

Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be 

noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding.

 

Treatment—Neutralization of Heparin Effect 

When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% 

solution) by slow infusion will neutralize heparin sodium. 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 1/2 hour after intravenous injection. 

Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. 

Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given 

only when resuscitation techniques and treatment of anaphylactoid shock are readily available. 

For additional information consult the labeling of Protamine Sulfate Injection, USP products.

 

DOSAGE AND ADMINISTRATION 

Parenteral drug products should be inspected visually for particulate matter and discoloration 

prior to administration, whenever solution and container permit. Slight discoloration does not 

alter potency.

 

Preservative-Free Heparin Lock Flush Solution in the 100 unit/mL concentration is not recommended 

for use in neonates and infants (see WARNINGS, Use In Neonates and Infants).

 


NDA 17-037/S-158 

Page 30 


 

Maintenance of Patency of Intravenous Devices 

To prevent clot formation in a heparin lock set or central venous catheter following its proper insertion, 

Preservative-Free Heparin Lock Flush Solution, USP is injected via the injection hub in a quantity 

sufficient to fill the entire device. This solution should be replaced each time the device is used. 

Aspirate before administering any solution via the device in order to confirm patency and location of 

needle or catheter tip. If the drug to be administered is incompatible with heparin, the entire device 

should be flushed with normal saline before and after

 

the medication is administered; following the 



second saline flush, Preservative-Free Heparin Lock Flush Solution, USP may be reinstilled into the 

device. The device manufacturer's instructions should be consulted for specifics concerning its use. 

Usually this dilute heparin solution will maintain anticoagulation within the device for up to 4 hours. 

NOTE: Since repeated injections of small doses of heparin can alter tests for activated partial 

thromboplastin time (APTT), a baseline value for APTT should be obtained prior to insertion of an 

intravenous device.

 

Withdrawal of Blood Samples 

Preservative-Free Heparin Lock Flush Solution, USP may also be used after each withdrawal of blood 

for laboratory tests. When heparin would interfere with or alter the results of blood tests, the heparin 

solution should be cleared from the device by aspirating and discarding it before withdrawing the 

blood sample. 

HOW SUPPLIED 

HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution, USP) 

10 USP units/mL 

 

1 mL DOSETTE vials packaged in 25s (NDC 0641-0272-25) 



100 USP units/mL 

 

1 mL DOSETTE vials packaged in 25s (NDC 0641-0273-25) 



Storage 

Store at 20

°-25°C (68°-77°F) [see USP Controlled Room Temperature]



REFERENCES 

7.

 



Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin Induced Thrombocytopenia – 

A Case Report – J Jpn Assn Torca Surg.1992;40(3):110-111. 



NDA 17-037/S-158 

Page 31 


 

8.

 



Warkentin T, Kelton J. Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis. Annals of 

Internal Medicine. 2001;135:502-506. 

9.

 



Rice L, Attisha W, Drexler A, Francis J. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of 

Internal Medicine, 2002;136:210-215. 

10.


 

Dieck J., C. Rizo-Patron, et al. (1990). “A New Manifestation and Treatment Alternative for Heparin-

Induced Thrombosis.” Chest 98(1524-26). 

11.


 

Smythe M, Stephens J, Mattson. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Emergency 



Medicine, 2005;45(4):417-419. 

12.


 

Divgi A. (Reprint), Thumma S., Hari P., Friedman K., Delayed Onset Heparin-Induced Thrombocytopenia 

(HIT) Presenting After Undocumented Drug Exposure as Post-Angiography Pulmonary Embolism. Blood

2003;102(11):127b. 

ESI logo, Hep-Lock and Dosette are registered trademarks of Baxter International, Inc., or its 

subsidiaries. 

 

Manufactured by 



Baxter Healthcare Corporation 

Deerfield, IL 60015 USA 

For Product Inquiry   1 800 ANA DRUG (1-800-262-3784) 

MLT-00090/5.0 



 


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