Vademecum

Description: Enoxaparin is a low-molecular-weight heparin (LMWH) produced through partial depolymerization of porcine mucosal heparin. While unfractionated heparin contains molecules ranging from 3000—30,000 (mean 15,000) daltons, enoxaparin molecules are 2000—8000 daltons. Enoxaparin and other low molecular weight heparins produce a more predictable anticoagulant response than UFH, reflecting their better bioavailability after subcutaneous injection, longer half-life, and dose-independent clearance. A meta-analysis published in 2000 revealed no significant differences between LMWHs and UFH in effectiveness in the treatment of venous thromboembolism, incidence of major or minor bleeding, or thrombocytopenia.[234] Enoxaparin was the first LMWH to be approved in the US; it was originally approved by the FDA on March 29, 1993 for prevention of DVT in patients undergoing hip or knee replacement surgery. The drug was subsequently approved for DVT prophylaxis in patient undergoing abdominal surgery. In March 1998, enoxaparin was approved for the treatment of unstable angina and non-Q-wave myocardial infarction. In December 1998, enoxaparin received approval for the inpatient treatment of acute pulmonary embolism (PE) and DVT; it also received approval for outpatient treatment of acute DVT not associated with PE when combined with warfarin. Enoxaparin continues to be investigated for thromboembolism prophylaxis in pregnancy. In Europe, the drug has been marketed since 1987 under the trade name Clexane®. Mechanism of Action: Enoxaparin exerts its antithrombotic activity by binding to and accelerating the activity of antithrombin III (AT III). The interaction with antithrombin is mediated by a unique pentasaccharide sequence distributed along the heparin chains. Only 15—25% of the chains of enoxaparin contain this pentasaccharide sequence, compared with about one-third of the chains of unfractionated heparin (UFH). By activating antithrombin, coagulation factor Xa and factor IIa (thrombin) are inhibited. Enoxaparin and other LMWHs are more selective inhibitors of factor Xa than UFH. Although any pentasaccharide chain can inhibit factor Xa, only those at least 18 saccharide units long can inactivate thrombin, since a long chain is required to form a ternary complex between heparin, antithrombin and thrombin. Although most of the chains of UFH are at least 18 saccharide units long, less than 50% of those of enoxaparin and other LMWHs are of adequate length to bind both antithrombin and thrombin (factor IIa). Therefore, the anti-factor Xa:anti-factor IIa inhibitory ratio of enoxaparin is 3—4:1, compared to 1:1 for UFH. Ultimately, thrombin inhibition prevents the formation of fibrin clots. At recommended doses, enoxaparin does not significantly affect platelet activity, prothrombin time (PT) or activated partial thromboplastin time (aPTT). Compared with UFH, low molecular weight heparins (LMWH) have reduced binding to plasma proteins such as vitronectin, lipoproteins, fibronectin, fibrinogen, platelet factor 4 and von Willebrand factor. The reduced nonspecific binding of LMWHs to plasma proteins or cells accounts for many of the differences between LMWHs and UFH. Compared with heparin, LMWHs have the following characteristics: 1) reduced ability to catalyze inactivation of thrombin versus factor Xa (as described above); 2) improved bioavailability at low doses and improved predictability of the anticoagulant response; 3) an increased plasma half-life due to reduced binding to macrophages and endothelial cells; 4) a lower incidence of heparin-induced thrombocytopenia due to reduced binding to platelets and platelet factor 4; and 5) possibly reduced binding to osteoblasts and an associated reduction in bone loss. Pharmacokinetics: Enoxaparin is administered by subcutaneous (SC) injection. The absorption of enoxaparin after SC injection is approximately 92%. Peak plasma anti-factor Xa activity occurs 3—5 hours after SC injection. Mean peak anti-factor Xa activity is 0.16 IU/ml and 0.38 IU/ml after 20 mg and 40 mg doses, respectively. In patients receiving enoxaparin doses of 1 mg/kg SC every 12 hours, mean peak anti-factor Xa activity is 1.1 IU/ml. Enoxaparin has a low affinity for binding to endothelial cells and does not cross the placenta to any significant extent. The primary route of elimination for enoxaparin appears to be renal and is dose-independent, unlike heparin, which has several saturable mechanisms of elimination. The elimination half-life of enoxaparin based on anti-factor Xa activity ranges from 3 to 6 hours (mean: 4.5 hours) after SC administration and can be increased in patients with chronic severe renal failure. Following a 40 mg dose of enoxaparin, significant anti-factor Xa activity persists in plasma for about 12 hours.

Indications...Dosage For the treatment of acute deep venous thrombosis (DVT): •for inpatient treatment of DVT with or without pulmonary embolism: Subcutaneous dosage: Adults: 1 mg/kg SC every 12 hours or 1.5 mg/kg SC every 24 hours. Both regimens were equivalent to continuous IV heparin in clinical trials. Oral warfarin was begun within 72 hours of initiation of enoxaparin; enoxaparin was discontinued when the targeted warfarin INR was achieved and a minimum of 5 days of enoxaparin administration had elapsed. •for the outpatient treatment of acute deep venous thrombosis (DVT) not associated with pulmonary embolism, in conjunction with warfarin: Adults: 1 mg/kg SC every 12 hours. Warfarin therapy should be administered when appropriate (usually within 72 hours of enoxaparin initiation). Enoxaparin should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved. In clinical trials, thromboembolism recurrence with enoxaparin (5.3%) was similar to inpatient treatment with continuous IV heparin. Episodes of major bleeding were also similar. Enoxaparin patients spent an average of 1.1 days in the hospital compared to 6.5 days for the heparin group.[1246] For deep venous thrombosis (DVT) prophylaxis or pulmonary embolism prophylaxis: •following knee replacement surgery: Subcutaneous dosage: Adults: 30 mg SC every 12 hours. The initial dose should be given 12—24 hours post-operatively provided hemostasis has been established. Treatment should be continued throughout the period of post-operative care until the risk of DVT has diminished. Up to 14 days administration has been well tolerated. The average duration of administration is 7—10 days. In a comparison of therapies for preventing DVT following knee arthroplasty, enoxaparin 30 mg SC twice daily was superior to warfarin. In this study, the medications were continued for 14 days or until hospital discharge, whichever occurred first.[1165] •for hip replacement surgery, during and following hospitalization: Subcutaneous dosage: Adults: 30 mg SC every 12 hours. The initial dose should be given 12—24 hours post-operatively provided hemostasis has been established. Treatment should be continued throughout the period of post-operative care until the risk of DVT has diminished. In clinical trials, the average duration of therapy was 7—10 days of the twice daily regimen. Up to 14 days of therapy has been well tolerated. Alternatively, a dose of 40 mg SC once daily, with the initial dose given 12 hours prior to surgery, may be considered. Following the initial inpatient phase of prophylaxis (i.e., 30 mg SC every 12 hours or 40 mg SC once daily), continued prophylaxis with 40 mg SC once daily for 3 weeks is recommended by the manufacturer.[1618] [1292] •in patients undergoing major abdominal surgery who are at risk for thromboembolic complications: Subcutaneous dosage: Adults: 40 mg SC once daily, with the initial dose given 2 hours prior to surgery. The subsequent dose, provided hemostasis has been established, is administered 24 hours after the initial pre-operative dose and continued once daily for 7—10 days. Treatment should be continued throughout the period of post-operative care until the risk of DVT has diminished. Up to 12 days of therapy has been well tolerated. •in patients who are at risk for thromboembolic complications due to severely restrictive mobility during acute illness (e.g., moderate to severe heart failure, respiratory failure, severe infection, back pain, vertebral compression or arthritic episodes): Subcutaneous dosage: Adults: 40 mg SC once daily. In a phase III trial, treatment with enoxaparin resulted in a significantly lower incidence of DVT when compared with placebo (4.4% vs. 11.9%) after 14 days of treatment. The reduced incidence was maintained at 3 months of follow-up. There were no significant differences in adverse reactions between the treatment group and placebo except for ecchymosis at the injection site. •in patients undergoing elective neurosurgery† who are at risk for thrombotic complications, such as those patients with malignancy or motor deficits: Subcutaneous dosage: Adults: 40 mg SC once daily, with the initial dose given 24 hours after surgery, has been used in combination with compression stockings, provided hemostasis has been established and no contraindications to LMWH use exist. Limited study suggests that the combination of LMWH with stockings may be more effective than stockings alone in preventing venous thrombolembolism, however, routine use is not recommended until more is known regarding bleeding risks with LMWH use in neurosurgical patients.[2337] •in patients with major trauma† without intracranial bleeding: Subcutaneous dosage: Adults: In a randomized, double-blind comparison, enoxaparin 30 mg SC every 12 hours, started within 36 hours of injury and continued for up to 14 days, was superior to low-dose heparin.[1293] •in pregnant females† with risk factors for thromboembolism during pregnancy†, including antiphospholipid antibody syndrome†: NOTE: The safety and efficacy of enoxaparin use has not been evaluated for pregnant females with prosthetic valve replacements. Subcutaneous dosage: Pregnant females: A dosage of 40 mg SC once daily has been used. In one study of 61 women at high risk for thromboembolism, enoxaparin was initiated in the first trimester and continued throughout pregnancy. Anti-factor Xa levels were monitored. No increased bleeding risk was observed, and no embolic complications occured during the pregnancies. Fetal and neonatal outcomes were normal. Decreased bone density was reported in 34% of the women after delivery, but could not be directly attributed to the use of enoxaparin from this study.[2338] For the prevention of ischemic complications of unstable angina or non-Q-wave acute myocardial infarction: Subcutaneous dosage: Adults: 1 mg/kg SC every 12 hours, with concurrent aspirin. Treatment should be continued for a minimum of 2 days and until the patient is clinically stable. The usual duration of treatment is 2—8 days.[1457] To minimize the risk of bleeding following vascular instrumentation during the treatment of unstable angina, the vascular access sheath should remain in place for 6—8 hours following a dose of enoxaparin. The next scheduled dose of enoxaparin should be given no sooner than 6—8 hours after sheath removal. For systemic anticoagulation† in patients with combined venous and arterial thromboembolism†: Subcutaneous dosage: Adults: A dose of 1 mg/kg SC twice daily has been used. Patients with renal impairment: CrCl < 30 ml/min: Adjustment of enoxaparin dosage may be considered in these patients. No specific guidelines for dose adjustments are available. Monitoring of anti-Xa activity should be considered during chronic therapy. †non-FDA-approved indication

Administration Subcutaneous Administration •Enoxaparin is administered by subcutaneous injection. Do not administer intramuscularly. •All patients should be evaluated for a bleeding disorder prior to administration of enoxaparin, unless the medication is needed urgently. •Do not mix enoxaparin injection with other injections or parenteral fluids. •If withdrawing enoxaparin from ampules, utilize a tuberculin or equivalent graduated syringe to ensure proper measurement of the required dose. Use filter needles during or after withdrawal of enoxaparin from ampules as required by aseptic technique. •Prefilled syringes for the 30 mg and 40 mg doses of enoxaparin are not graduated. Do not use these syringes to administer partial doses. •Enoxaparin cannot be used interchangeably (unit for unit) with heparin sodium or other low molecular weight heparins. •Visually inspect parenteral products for particulate matter and discoloration prior to administration. Subcutaneous injection: •Patients should be in a supine position and enoxaparin should be administered by deep subcutaneous injection. •Enoxaparin should be injected into the left and right anterolateral or posterolateral abdominal wall. Using the thumb and forefinger, you must lift up a fold of skin while giving the injection. The entire length of the needle should be inserted at a 45 to 90 degree angle. •The injection site should be alternated with each injection. Do not rub the injection site after administration. •To avoid loss of drug when using the 30 mg or 40 mg prefilled syringes, do not expel the air bubble from the syringe before injecting enoxaparin.

Contraindications Bleeding is the major risk associated with use of enoxaparin. Before initiating therapy, coagulopathy should be ruled out. Enoxaparin should not be used in patients with severe bleeding disorders, such as hemophilia or idiopathic thrombocytopenic purpura (ITP). Enoxaparin is contraindicated in patients with active major bleeding, including GI bleeding or hemorrhagic stroke in the acute phase. Enoxaparin should be used with caution in any disease state in which there is an increased risk of hemorrhage, such as acute infective endocarditis, dissecting aneurysm, peptic ulcer disease, recent GI bleeding, non-hemorrhagic stroke, diverticulitis, inflammatory bowel disease, thrombocytopenia, menstruation, threatened abortion or other abnormal vaginal bleeding, severe hepatic disease or renal disease, uncontrolled hypertension, and hypertensive or diabetic retinopathy. Caution should also be used in patients who have undergone recent brain, spinal, or ophthalmological surgery. Patients should be observed closely for bleeding if enoxaparin is administered during or immediately following diagnostic lumbar puncture, epidural anesthesia, spinal anesthesia, or tube drainage of the stomach or small intestine (see Adverse Reactions). In addition, patients should be monitored closely for a fall in hematocrit and/or a fall in blood pressure, hematuria, hematemesis, and other signs or symptoms of bleeding. Periodic complete blood counts and stool occult blood tests are recommended. The risk of enoxaparin-associated bleeding and serious adverse reactions increases with age. The platelet count should be monitored in patients receiving enoxaparin. If thrombocytopenia (platelet count < 100,000/mm3) occurs, enoxaparin therapy should be discontinued due to an increased risk of bleeding. Cases of thrombocytopenia with disseminated thrombosis have been observed in clinical practice with heparins and low-molecular weight heparins. Low molecular weight heparins (LMWH) such as enoxaparin should not be used for the treatment of acute heparin-induced thrombocytopenia (HIT). Although LMWHs are less likely to trigger formation of HIT antibodies than unfractionated heparin (UFH), LMWHs are just as effective as UFH at triggering platelet activation by HIT antibodies (i.e., LMWHs have essentially 100% in vitro cross-reactivity).[1966] Enoxaparin should be used with caution in patients with a history of heparin-induced thrombocytopenia. Enoxaparin is contraindicated in patients with porcine protein hypersensitivity or hypersensitivity to heparin, or who have a positive in vitro test for antiplatelet antibodies in the presence of enoxaparin. Intramuscular injections should not be administered to patients receiving enoxaparin. IM injections may cause bleeding, bruising, or hematoma formation in patients who are anticoagulated. Enoxaparin is classified as FDA pregnancy risk category B. Teratogenic effects have not been demonstrated in animals. No well controlled studies exist in pregnant women. Several reports have described the use of enoxaparin during pregnancy without fetal or maternal complications.[2338] Spontaneous postmarketing fetal deaths have been reported in some enoxaparin-treated patients, primarily in women with lupus anticoagulant or antiphospholipid antibody syndrome who have a history of fetal loss. One event was associated with placental hemorrhage; the case was complicated by the use of IV and SC unfractionated heparin prior to the time of fetal distress. In addition, one case of hyperlipidemia with hypertriglyceridemia has been reported in a diabetic pregnant woman on enoxaparin; causality is uncertain. Compared with unfractionated heparin, low molecular weight heparins (LMWHs) may have advantages in pregnant women because they cause less heparin-induced thrombocytopenia and may be less likely to produce osteoporosis. The safety and efficacy of LMWHs in preventing systemic thromboembolic complications secondary to prosthetic heart valves in pregnancy is unknown. The treatment of acute venous thromboembolism in pregnancy requires weight-adjusted dosing, but optimal dose regimens have not been established. Until comparative clinical trials are available, the American College of Chest Physicians recommends consideration of a LMWH primarily in patients intolerant of unfractionated heparin and in those with osteopenia. It is unknown if enoxaparin is excreted into breast milk. However, because of the relatively high molecular weight of enoxaparin, excretion is expected to be minimal. Also, because of inactivation by the GI tract on oral ingestion, any potential risk to a nursing infant posed by enoxaparin should be negligible. The manufacturer recommends caution when using enoxaparin in women who are breast-feeding. Enoxaparin should be used with caution in patients receiving other anticoagulant therapy (e.g., warfarin), thrombolytic therapy (e.g., alteplase, reteplase, streptokinase), and/or platelet inhibitors (e.g., aspirin, ticlopidine), or NSAIDs, due to the potential increased risk of bleeding. If co-administration of these agents with enoxaparin continues, patients should be closely monitored. Use enoxaparin cautiously in elderly patients, patients with renal impairment (CrCl < 30 ml/min) or renal failure, and patients weighing < 45 kg. These patients may have delayed elimination of enoxaparin. The incidence of bleeding complications is higher in elderly patients as compared to younger adult patients when enoxaparin is given at doses of 1.5 mg/kg once daily or 1 mg/kg every 12 hours. An adjustment of enoxaparin dosage may be considered in these populations. Monitoring of anti-Xa activity should be considered. Safety and efficacy of enoxaparin have not been established in children. Patients who are anticoagulated are at increased the risk of bleeding during dental procedures. Patient should inform health care providers of anticoagulant therapy prior to having dental work performed. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Interactions There have been no documented pharmacokinetic interactions of enoxaparin with other drugs. However, an additive risk of bleeding may be seen in patients receiving other platelet inhibitors (e.g. aspirin, ASA), thrombolytic agents (e.g. alteplase, reteplase, streptokinase), or other anticoagulants (e.g., heparin, warfarin) in combination with enoxaparin. In addition, large doses of salicylates (>= 6 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents, antithymocyte globulin, or strontium-89 chloride in combination with enoxaparin. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with enoxaparin because of their potential to cause GI bleeding or inhibit platelet aggregation. Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of porfimer or verteporfin photodynamic therapy. Additive bleeding may occur if enoxaparin is given in combination with ginger, zingiber officinale, or garlic, allium sativum. Ginger inhibits thromboxane synthetase (platelet aggregation inducer) and is a prostacyclin agonist. Garlic produces clinically significant antiplatelet effects. Ginkgo biloba should be used cautiously in patients taking anticoagulants. Ginkgo can produce clinically-significant antiplatelet effects; a compound found in Ginkgo biloba, ginkgolide-B, may act as a selective antagonist of platelet activating factor (PAF). Although a review of Ginkgo biloba in 1992 stated that no known drug interactions exist,[1705] spontaneous hyphema has been reported in an elderly male who began taking ginkgo while stabilized on daily aspirin. After ginkgo was stopped, no further bleeding was noted despite continuing the aspirin therapy.[1706] Other clinical data exist[1707] that describe spontaneous subdural hematomas associated with chronic Ginkgo biloba ingestion. Horse chestnut, Aesculus hippocastanum may increase the risk of bleeding if co-administered to patients treated with anticoagulant or anti-platelet medications. Aesculin, a saponin in the horse chestnut seed, appears to have antithrombin effects, but the exact mechanism is not clear. Careful monitoring of clinical and/or laboratory parameters is warranted if this herb is coadministered with any of these agents. Theoretically feverfew, Tanacetum parthenium may enhance the effects of the anticoagulants via inhibition of platelet aggregation or via antithrombotic activity. Concurrent use may increase the risk of bleeding. Clinical interactions have not yet been reported; however, avoidance of the use of feverfew during anticoagulant therapy seems prudent. When mifepristone, RU-486 is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the increased risk of serious bleeding.

Adverse Reactions The most serious adverse reaction associated with enoxaparin therapy is bleeding. which can occur from any site. This can involve minor bleeding, such as bleeding from the gums or hematuria (2%), or frank hemorrhage (7%). During initial clinical trials for DVT prophylaxis, major bleeding, which include those requiring a transfusion, a decrease in hemoglobin > 2 mg/dl, bleeding leading to interruption of treatment or death, intracranial bleeding, ocular hemorrhage, or retroperitoneal bleeding, occurred in 2—4% of patients treated with enoxaparin. In patients with unstable angina or non-Q-wave myocardial infarction, the incidence of major bleeding in enoxaparin-treated patients was similar to that of patients treated with heparin (1%). Bleeding events may include epistaxis, hematoma, or GI bleeding (melena, hematochezia, and/or hematemesis). Injection site hematoma occurred in 9% of patients. If bleeding is serious, enoxaparin therapy should be discontinued, and protamine can be administered as an antagonist. One mg of protamine should be given to neutralize 1 mg of enoxaprin. Several cases of bleeding or hematoma within the spinal column have been reported with concurrent use of enoxaparin and epidural/spinal anesthesia or spinal puncture. Many of the epidural or spinal hematomas caused neurologic injury, including long-term or permanent paralysis. The risk of epidural or spinal hematoma is higher with the use of postoperative indwelling epidural catheters, traumatic or repeated spinal or epidural punctures, or in patients treated concomitantly with NSAIDs, platelet inhibitors, or other anticoagulants. During initial clinical trials, adverse events (other than bleeding) occurring more often in enoxaparin-treated patients than in placebo-treated patients were anemia (3%), fever (8%), and peripheral edema (6%). Other adverse reactions reported during post-marketing safety surveillance of enoxaparin included injection site reaction (bleeding, ecchymosis, erythema, skin necrosis, inflammatory nodules), purpura, systemic allergic reaction (ie., pruritus, urticaria), vesicular rash, and thrombocytosis. The incidence of enoxaparin-induced thrombocytopenia is slightly lower than for heparin. Drug-induced thrombocytopenia occurred in 9 of 332 patients receiving heparin compared to none of 333 patients who received enoxaparin for DVT prophylaxis after hip surgery.[1311] Moderate thrombocytopenia (platelet count of 50,000—100,000/mm3) has been reported in 2% of patients receiving the drug. Cases of thrombocytopenia with disseminated thrombosis (disseminated intravascular coagulation (DIC)) has been observed in clinical practice with heparins and low-molecular weight heparins, including enoxaparin. Rare cases of hyperlipidemia have been reported with the use of enoxaparin in clinical practice. One case of hyperlipidemia with marked hypertriglyceridemia was reported in a diabetic, pregnant woman. The precise relationship to enoxaparin has not been established. Elevated hepatic enzymes greater than 3-times the upper limit of normal occur in about 6% of patients treated with enoxaparin. Such elevations are fully reversible and rarely associated with hyperbilirubinemia. There have been a few cases of fetal death reported in pregnant women receiving enoxaparin. Causality has not been determined in these cases. In one case, placental hemorrhages and detachment were found in association with fetal death.

Enoxaparin Lovenox®

234. Dolovich LR, Ginsberg JS, Douketis JD, et al. A meta-analysis comparing low-molecular weight heparins with unfractionated heparin in the treatment of venous thromboembolism. Arch Intern Med 2000;160:181—8.

1246. Levine M, Gent M, Hirsh J et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996;334:677—81.

1165. Leclerc JR, Geerts WH, Desjardins L et al. Prevention of venous thromboembolism after knee arthroplasty. A randomized, double-blind trial comparing enoxaparin with warfarin. Ann Intern Med 1996;124:619—26.

1618. Planes A, Vochelle N, Darmon JY, et al. Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement. Lancet 1996;348:224—8.

1292. Bergqvist D, Benoni G, Bjorgell O et al. Low-molecular weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med 1996;335:696—700.

2337. Agnelli G, Piovella F, Buoncristiani P, et al. Enoxaparin plus compression stockings compared with compresssion stockings alone in the prevention of venous thromboembolism after elective neurosurgery. N Engl J Med 1998;339:80—5.

1293. Geerts WH, Jay RM, Code KI et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996;335:701—7.

2338. Nelson-Piercy C, Letsky EA, de Swiet M. Low-molecular weight heparin for obstetric thromboprophylaxis: experience of sixty-nine pregnancies in sixty-one women at high risk. Am J Obstet Gynecol 1997;176:1062—8.

1457. Cohen M, Demers C, Gurfindel EP et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997;337:447—52.

1966. Hirsh J, Warkentin TE, Raschke R, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1998;114:489S—510S.

1705. Kleijnen J, Knipschild P. Ginkgo biloba. Lancet 1992;340:1136—9.

1706. Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract. N Engl J Med 1997;336:1108.

1707. Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology 1996;46:1775—6.

1311. Warkentin TE, Levine MN, Hirsh J et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330—5.