Prescription Drugs

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 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 after the age of 40 a slower beta phase, indicates (t½ = 10 minutes) and 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 thrombo-plastine times (APTTs) compared with patients under 60 years of age. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

HEPFLUSH® -10 (heparin lock flush solution), USP FOR MAINTENANCE OF PATENCY OF INTRAVENOUS INJECTION DEVICES ONLY. NOT FOR ANTICOAGULANT THERAPY. DERIVED FROM PORCINE INTESTINAL MUCOSA. PRESERVATIVE FREE. 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-glu-curonic 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. Heparin Lock Flush Solution, USP is a sterile preparation of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity, with sufficient sodium chloride to make it isotonic with blood. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Structure of Heparin Sodium (representative subunits): Each mL contains: 10 USP Units Heparin sodium (porcine); 9 mg sodium chloride; Water for Injection q.s. Sodium hydroxide and/or hydrochloric acid for pH adjustment (5.0-7.5).

INDICATIONS 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 ADMINISTRATION, Maintenance of Patency of IV Devices for directions for use). Heparin lock flush solution is not to be used for anticoagulant therapy. DOSAGE AND ADMINISTRATION Parental 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, USP is not recommended for use in the neonate (see WARNINGS). Maintenance of Patency of IV 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, the heparin lock flush solution 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 anti-coagulation 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 a heparin lock set. Withdrawal of Blood Samples Heparin lock flush solution 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 Product No. NDC No. 1710 63323-017-10 HEPFLUSH®-10 (Heparin Lock Flush Solution, USP, Preservative Free), 10 USP Units/mL, in a 10 mL flip-top, single dose vial, in packages of 25. Unused portion of the vial should be discarded. Use only if solution is clear and seal intact. Storage Store at 20°to 25°C (68°to 77°F) [see USP Controlled Room Temperature]. REFERENCES 1. Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin Induced Throm-bocytopenia – 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. APP Pharmaceuticals, LLC, Schaumburg, IL60173. For Product Inquiry: 1-800-551-7176. Revised: January 2008.

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE 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 metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about ½ hour after intravenous injection. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions often resembling anaphy-laxis 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. CONTRAINDICATIONS Heparin sodium should NOTbe 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.

SIDE EFFECTS Hemorrhage Hemorrhage is the chief complication that may result from heparin use (see WARNINGS). An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug (see OVERDOSAGE). Thrombocytopenia, Heparin-induced Throm-bocytopenia (HIT) and Heparin-induced Throm-bocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT See WARNINGS. 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, lacrima-tion, headache, nausea and vomiting, and ana-phylactoid 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, myocar-dial infarction, pulmonary embolism, stroke, and possibly death (see WARNINGS, 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. 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.

WARNINGS Heparin is not intended for intramuscular use. Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations (see ADVERSE REACTIONS, Hypersensitivity). 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, throm-bocytopenia and some vascular purpuras. Gastrointestinal Ulcerative lesions and continuous tubedrainage 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. Mild thrombocytopenia (count greater than 100,000/mm³) 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/mm³or 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. 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 monitered closely. If the platelet count falls below 100,000/mm³or 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 throm-bocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT. Use in Neonates Preservative-Free Heparin Lock Flush Solution, USP should be used for maintaining the patency of intravenous injection devices in neonates. PRECAUTIONS General In infants, the cumulative amounts of heparin received from the frequent administration of Heparin Lock Flush Solution, USP during a 24- hour period should be considered. Precautions must be exercised when drugs which are incompatible with heparin are administered through an indwelling intravenous catheter containing Heparin Lock Flush Solution, USP (see DOSAGE AND ADMINISTRATION, Maintenance of Patency of IV Devices). Thrombocytopenia, Heparin-induced Throm-bocytopenia (HIT) and Heparin-induced Throm-bocytopenia and Thrombosis (HITT) See WARNINGS. Increased Risk to Older Patients, Especially Women A higher incidence of bleeding has been reported in patients, particulary 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). Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate the carcinogenic potential of heparin. 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 PRECAUTIONS, General and CLINICAL PHARMACOLOGY).