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Pediatric Use Follow recommendations of appropriate pediatric reference texts. In general, the following dosage schedule may be used as a guideline: Initial Dose 50 units/kg (IV, drip) Maintenance Dose 100 units/kg (IV, drip) every 4 hours, or 20,000 units/m 2 /24 hours continuously Geriatric Use Patients over 60 years of age may require lower doses of heparin. Surgery of the Heart and Blood Vessels 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.
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Low-Dose Prophylaxis of Postoperative Thromboembolism A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism. The most widely used dosage has been 5000 units 2 hours before surgery and 5000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25- to 26-gauge) to minimize tissue trauma. A concentrated solution of heparin sodium is recommended. Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery. Patients with bleeding disorders and those having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as should patients receiving oral anticoagulants or platelet-active drugs (see WARNINGS). The value of such prophylaxis in hip surgery has not been established. The possibility of increased bleeding during surgery or postoperatively should be borne in mind. If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable. If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated. All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery. Coagulation test values should be normal or only slightly elevated. There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters. Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. Blood Transfusion Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation. Usually, 7500 USP units of heparin sodium are added to 100 mL of 0.9 % Sodium Chloride Injection, USP (or 75,000 USP units per 1000 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.
Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample. Leukocyte counts should be performed on heparinized blood within 2 hours after addition of the heparin. Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or platelet counts.
Heparin Sodium Injection, USP 1000 USP units/mL 1 mL DOSETTE vial packaged in 25s (NDC 0641-0391-25) 10 mL Multiple Dose vial packaged in 25s (NDC 0641-2440-45) 30 mL Multiple Dose vial packaged in 25s (NDC 0641-2450-45) 5000 USP units/mL 1 mL DOSETTE vial packaged in 25s (NDC 0641-0400-25) 10 mL Multiple Dose vial packaged in 25s (NDC 0641-2460-45) 10,000 USP units/mL 1 mL DOSETTE vial packaged in 25s (NDC 0641-0410-25)
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4 mL Multiple Dose vial packaged in 25s (NDC 0641-2470-45) Also available from Baxter: HEP-LOCK (Heparin Lock Flush Solution, USP) and HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution, USP). Storage Store at 20 °-25°C (68°-77°F) [see USP Controlled Room Temperature]. Baxter, Hep-Lock and Dosette are trademarks of Baxter International, Inc., or its subsidiaries.
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.
6. D
IVGI A.
(R EPRINT
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T HUMMA S.,
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.2003;102(11):127 B .
Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)
MLT-01119/3.0
NDA 17-037/S-158 Page 13
HEP-LOCK (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 (Heparin Lock Flush Solution, USP) is a sterile solution for intravenous flush only. It is not to be used for anticoagulant therapy. Each mL contains heparin sodium 10 or 100 USP units, derived from porcine intestines and standardized for use as an anticoagulant, sodium chloride 9 mg and benzyl alcohol 0.01 mL in Water for Injection. pH 5.0-7.5; sodium hydroxide and/or hydrochloric acid used, if needed, for pH adjustment. The potency is determined by biological assay using a USP reference standard based on units of heparin activity per milligram.
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 NDA 17-037/S-158 Page 14
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 ½
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.
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
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 15
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 anticoagulants administered.
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 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.
This product contains the preservative benzyl alcohol and is not recommended for use in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Preservative-Free Heparin Lock Flush Solution, USP should be used for maintaining the patency of intravenous injection devices in neonates. NDA 17-037/S-158 Page 17
PRECAUTIONS General In infants, the cumulative amounts of heparin and benzyl alcohol received from the frequent administration of Heparin Lock Flush Solution during a 24-hour period must be considered. Where preservative-free heparin lock flush solution is indicated, HEP-LOCK
U/P is available. Precautions must be exercised when drugs that are incompatible with heparin are administered through an indwelling intravenous catheter containing Heparin Lock Flush Solution. (See DOSAGE AND ADMINISTRATION, Maintenance Of Patency Of Intravenous Devices.) 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.
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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. 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. Not for use in neonates (see WARNINGS). 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). NDA 17-037/S-158 Page 19
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. 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.
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 /
hour after intravenous injection. NDA 17-037/S-158 Page 20
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.
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