Description
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 WARNINGS, Use 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.
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
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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.
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.
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 x 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 ,
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
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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.
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
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 REACTIONS, Hypersensitivity.)
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:
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.
Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras.
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
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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) 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 3 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 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
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).
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.
Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium.
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 PRECAUTIONS, General).
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 .
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.
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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.
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.
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.
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).
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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.
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.
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 Yüklə 191,03 Kb. Dostları ilə paylaş:
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