Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3619
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Innohep (Injection)
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All patients should be evaluated for bleeding disorders before administration of INNOHEP'. Since coagulation parameters are unsuitable for monitoring INNOHEP' activity, routine monitoring of coagulation parameters is not required .<br/>Adult Dosage: The recommended dose of INNOHEP' for the treatment of DVT with or without PE is 175 anti-Xa IU/kg of body weight, administered SC once daily for at least 6 days and until the patient is adequately anticoagulated with warfarin (INR at least 2.0 for two consecutive days). Warfarin sodium therapy should be initiated when appropriate (usuallywithin 1-3 days of INNOHEP' initiation). Pregnancy has little or no influence on the pharmacokinetics of INNOHEP' and no dosing adjustment is needed for pregnancy. As INNOHEP' may theoretically affect the PT/INR, patients receiving both INNOHEP' and warfarin should have blood for PT/INR determination drawn just prior to the next scheduled dose of INNOHEP'. Table 8 provides INNOHEP' doses for the treatment of DVT with or without PE. It is necessary to calculate the appropriate INNOHEP' dose for patient weights not displayed in Table 8. An appropriately calibrated syringe should be used to assure withdrawal of the correct volume of drug from INNOHEP' vials. To calculate the volume (mL) of an INNOHEP' 175 anti-Xa IU per kg SC dose for treatment of deep vein thrombosis:<br/>Administration: INNOHEP' is a clear, colorless to slightly yellow solution, and as with other parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. INNOHEP' is administered by SC injection. It must not be administered by intramuscular or intravenous injection. Subcutaneous Injection Technique: Patients should be lying down (supine) or sitting and INNOHEP' administered by deep SC injection. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. The injection site should be varied daily. The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold should be held throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection.
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INNOHEP' is a sterile solution, containing tinzaparin sodium, a low molecular weight heparin. It is available in a multiple dose 2 mL vial. Each 2 mL vial contains 20,000 anti-Factor Xa IU (anti-Xa) of tinzaparin sodium per mL, for a total of 40,000 IU, and 3.1 mg/mL sodium metabisulfite as a stabilizer. The vial contains 10 mg/mL benzyl alcohol as a preservative. Sodium hydroxide may be added to achieve a pH range of 5.0 to 7.5. Tinzaparin sodium is the sodium salt of a low molecular weight heparin obtained by controlled enzymatic depolymerization of heparin from porcine intestinal mucosa using heparinase from Flavobacterium heparinum. The majority of the components have a 2-O-sulpho-4-enepyranosuronic acid structure at the non-reducing end and a 2-N,6-O-disulpho-D-glucosamine structure at the reducing end of the chain. Potency is determined by means of a biological assay and interpreted by the first International Low Molecular Weight Heparin Standard as units of anti-factor Xa (anti-Xa) activity per milligram. The mean tinzaparin sodium anti-factor Xa activity is approximately 100 IU per milligram. The average molecularweight ranges between 5,500 and 7,500 daltons. The molecular weight distribution is:
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Tinzaparin sodium is a low molecular weight heparin with antithrombotic properties. Tinzaparin sodium inhibits reactions that lead to the clotting of blood including the formation of fibrin clots, both in vitro and in vivo. It acts as a potent co-inhibitor of several activated coagulation factors, especially Factors Xa and IIa (thrombin). The primary inhibitory activity is mediated through the plasma protease inhibitor, antithrombin. Bleeding time is usually unaffected by tinzaparin sodium. Activated partial thromboplastin time (aPTT) is prolonged by therapeutic doses of tinzaparin sodium used in the treatment of deep vein thrombosis (DVT). Prothrombin time (PT) may be slightly prolonged with tinzaparin sodium treatment but usually remains within the normal range. Neither aPTT nor PT can be used for therapeutic monitoring of tinzaparin sodium. Neither unfractionated heparin nor tinzaparin sodium have intrinsic fibrinolytic activity; therefore, they do not lyse existing clots. Tinzaparin sodium induces release of tissue factor pathway inhibitor, which may contribute to the antithrombotic effect. Heparin is also known to have a variety of actions that are independent of its anticoagulant effects. These include interactions with endothelial cell growth factors, inhibition of smooth muscle cell proliferation, activation of lipoprotein lipase, suppression of aldosterone secretion, and induction of platelet aggregation.<br/>Pharmacokinetics/Pharmacodynamics: Anti-Xa and anti-IIa activities are the primary biomarkers for assessing tinzaparin sodium exposure because plasma concentrations of low molecular weight heparins cannot be measured directly. Because of analytical assay limitations, anti-Xa activity is the more widely used biomarker. The measurements of anti-Xa and anti-IIa activities in plasma serve as surrogates for the concentrations of molecules which contain the high-affinity binding site for antithrombin (anti-Xa and anti-IIa activities). Monitoring patients based on anti-Xa activity is generally not advised. The data are provided in Figure 1 and Table 2. below. Studies with tinzaparin sodium in healthy volunteers and patients have been conducted with both fixed- and weight-adjusted dose administration. Recommended therapy with tinzaparin sodium is based on weight-adjusted dosing .<br/>Special Populations:
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INNOHEP' is contraindicated in patients with active major bleeding, in patients with (or history of) heparin-induced thrombocytopenia, or in patients with hypersensitivity to tinzaparin sodium. INNOHEP' is contraindicated in patients aged 90 years or older with creatinine clearance���60 mL/min. Patients with known hypersensitivity to heparin, sulfites, benzyl alcohol, or pork products should not be treated with INNOHEP'.
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INNOHEP' is available in a multiple dose 2 mL vial in the following packages: Store at 25��C (77��F); excursions permitted to 15��-30��C (59��-86��F) [See USP Controlled Room Temperature]. Keep out of the reach of children. MANUFACTURED FOR:Celgene CorporationBoulder, CO 80301 MANUFACTURED BY:LEO Pharmaceutical ProductsDK-2750 Ballerup, Denmark Innohep' is a registered trademark of LEO Pharmaceutical Products.
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SPINAL/EPIDURAL HEMATOMAS: When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture. Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis .
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General: INNOHEP' should not be mixed with other injections or infusions. INNOHEP' should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension, or a history of recent gastrointestinal ulceration, diabetic retinopathy, and hemorrhage. Consistent with expected age-related changes in renal function, elderly patients and patients with renal insufficiency may show reduced elimination of tinzaparin sodium. INNOHEP' should be used with care in these patients . Patients aged 90 years or older with creatinine clearance���60 mL/min should not be treated with INNOHEP' . Laboratory Tests: Periodic complete blood counts including platelet count and hematocrit or hemoglobin, and stool tests for occult blood are recommended during treatment with INNOHEP'. When administered at the recommended doses, routine anticoagulation tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT) are relatively insensitive measures of INNOHEP' activity and, therefore, are unsuitable for monitoring. Drug Interactions: Because of increased risk of bleeding, INNOHEP' should be used with caution in patients receiving oral anticoagulants, platelet inhibitors (e.g., salicylates, dipyridamole, sulfinpyrazone, dextran, NSAIDs including ketorolac tromethamine, ticlopidine, and clopidogrel), and thrombolytics. If coadministration is essential, close clinical and laboratory monitoring of these patients is advised .<br/>Laboratory Test Interactions: Elevation of Serum Transaminases: Asymptomatic reversible increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels have occurred in patients during treatment with INNOHEP' . Similar increases in transaminase levels have also been observed in patients and volunteers treated with heparin and other low molecular weight heparins. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like INNOHEP' should be interpreted with caution. Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of tinzaparin sodium. Tinzaparin sodium displayed no genotoxic potential in an in vitro bacterial cell mutation assay (AMES test), in vitro Chinese hamster ovary cell forward gene mutation test, in vitro human lymphocyte chromosomal aberration assay, and in vivo mouse micronucleus assay. Tinzaparin sodium at SC doses up to1800 IU/kg/day in rats (about 2 times the maximum recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance.<br/>Pregnancy:<br/>Pregnancy: Category B:: All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of INNOHEP' to increase the risk of developmental abnormalities above background risk.<br/>Fetal Risk Summary: INNOHEP' is not predicted to increase the risk of developmental abnormalities. INNOHEP' does not cross the placenta, based on human and animal studies, and shows no evidence of teratogenic effects or fetotoxicity.<br/>Clinical Considerations: Pregnancy alone confers an increased risk for thromboembolism that is even higher for women with preexisting thromboembolic disease, certain high risk pregnancy conditions, and a history of complications during a previous pregnancy. All patients receiving anticoagulants such as tinzaparin, including pregnant women, are at risk for bleeding. Pregnant women receiving tinzaparin should be carefully monitored for evidence of bleeding or excessive anticoagulation. Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women should be apprised of the potential hazard to the fetus and the mother if tinzaparin is administered during pregnancy. Consideration for use of a shorter acting agent should be specifically addressed as delivery approaches.<br/>Data: Nursing Mothers: In studies where tinzaparin sodium was administered subcutaneously to lactating rats, very low levels of tinzaparin sodium were found in breast milk. It is not known whether tinzaparin sodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when INNOHEP' is administered to nursing women. Pediatric Use: Safety and effectiveness of tinzaparin sodium in pediatric patients have not been established. Geriatric Use: In the clinical studies for the treatment of DVT described in the CLINICAL STUDIES section, 58% of patients were 65 or older and 29% were 75 and over. In these studies, no significant overall differences in safety or effectiveness were observed between these subjects and younger subjects. In the interim analysis of an ongoing study (IRIS study) comparing INNOHEP' (175 IU/kg once daily) and unfractionated heparin (UFH) in the initial treatment of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in elderly patients (75 years or older) with creatinine clearance���60 mL/min, a higher mortality was observed in patients aged 90 years or older who were treated with INNOHEP' as compared to those treated with unfractionated heparin. Patients aged 90 years or older with creatinine clearance���60 mL/min should not be treated with INNOHEP'
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Symptoms/Treatment: Accidental overdosage of INNOHEP' (tinzaparin sodium injection) may lead to bleeding complications . Nosebleeds, blood in urine or tarry stools may be noted as the first signs of bleeding. Easy bruising or petechial hemorrhages may precede frank bleeding. In case of minor bleeding, the patient should be monitored for signs of more severe bleeding. Of patients known to have received an overdose of tinzaparin sodium in clinical trials, defined as one or more doses>200 IU/kg for the treatment of DVT or>100 IU/kg for the prevention of DVT, approximately 16% experienced a bleeding complication. Of spontaneous reports of probable overdosing with tinzaparin sodium, approximately 81% were accompanied by bleeding, usually hematoma. Most patients who have bleeding complications while receiving INNOHEP' can be controlled by discontinuing INNOHEP', applying pressure to the site, if possible, and replacing volume and hemostatic blood elements (e.g., red blood cells, fresh frozen plasma, platelets) as required. In the event that this is ineffective, protamine sulfate can be administered. In cases of serious bleeding or large overdose, protamine sulfate (1% solution) can be given by slow IV infusion at a dose of 1 mg protamine for every 100 anti-Xa IU of INNOHEP' given. A second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU of INNOHEP' may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged. Even with the additional dose of protamine, the aPTT may remain more prolonged than would usually be found following administration of protamine to reverse unfractionated heparin. Protamine does not completely neutralize tinzaparin sodium anti-Xa activity (maximum about 60%). Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions have been reported with protamine sulfate, it should be given only when resuscitation facilities are readily available. For additional information consult the labeling of Protamine Sulfate Injection, USP, products. Single SC doses of tinzaparin sodium at 22,000 and 7,700 IU/kg (about 10 and 7 times the maximum recommended human dose, respectively, based upon body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity included hematoma formation and bleeding at the injection site, anemia, decreased motor activity, unsteady gait, piloerection, and ptosis.
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tinzaparin sodium
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Innohep (Injection)
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Bleeding: Bleeding is the most common adverse event associated with INNOHEP' (tinzaparin sodium injection); however, the incidence of major bleeding is low. In clinical trials, the definition of major bleeding included bleeding accompanied by���2 gram/dL decrease in hemoglobin, requiring transfusion of 2 or more units of blood products, or bleeding which was intracranial, retroperitoneal, or into a major prosthetic joint. The data are provided in Table 4. Fatal or nonfatal hemorrhage from any tissue or organ can occur. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as, but are not limited to, paralysis; paresthesia; headache, chest, abdomen, joint, muscle or other pain; dizziness; shortness of breath, difficult breathing or swallowing; swelling; weakness; hypotension, shock, or coma. Therefore, the possibility of hemorrhage shouldbe considered in evaluating the condition of any anticoagulated patient with complaints which do not indicate an obvious diagnosis . Thrombocytopenia: In clinical studies thrombocytopenia was identified in 1% of patients treated with INNOHEP'. Severe thrombocytopenia (platelet count<50,000/mm) occurred in 0.13% . Elevations of Serum Aminotransferases: Asymptomatic increases in aspartate (AST [SGOT]) and/or alanine (ALT [SGPT]) aminotransferase levels greater than 3 times the upper limit of normal of the laboratory reference range have been reported in up to 8.8% and 13% for AST and ALT, respectively, of patients receiving tinzaparin sodium for the treatment of DVT. Similar increases in aminotransferase levels have also been observed in patients and healthy volunteers treated with heparin and other low molecular weight heparins. Such elevations are reversible and are rarely associated with increases in bilirubin . Local Reactions: Mild local irritation, pain, hematoma, and ecchymosis may follow SC injection of INNOHEP'. Injection site hematoma has been reported in approximately 16% of patients treated with INNOHEP'. Hypersensitivity: Anaphylactic/anaphylactoid reactions may occur in association with INNOHEP' use . Adverse Events: Adverse events with INNOHEP' or heparin reported at a frequency of���1% in clinical trials with patients undergoing treatment for proximal DVT with or without PE, are provided in Table 5. Other Adverse Events in Completed or Ongoing Trials: Other adverse events reported at a frequency of���1% in 4,000 patients who received INNOHEP' in completed or ongoing clinical trials are listed by body system: Body as a Whole: injection site hematoma, reaction unclassified. Cardiovascular Disorders, General: hypotension, hypertension. Central and Peripheral Nervous System Disorders: dizziness. Gastrointestinal System Disorders: flatulence, gastrointestinal disorder (not otherwise specified), dyspepsia. Heart Rate and Rhythm Disorders: tachycardia. Myo-, Endo-, Pericardial and Valve Disorders: angina pectoris. Platelet, Bleeding and Clotting Disorders: hematoma, thrombocytopenia. Psychiatric Disorders: insomnia, confusion. Red Blood Cell Disorders: anemia. Resistance Mechanism Disorders: healing impaired, infection. Respiratory System Disorders: pneumonia, respiratory disorder. Skin and Appendages Disorders: rash erythematous, pruritus, bullous eruption, skin disorder. Urinary System Disorders: urinary retention, dysuria. Vascular (Extracardiac) Disorders: thrombophlebitis deep, thrombophlebitis leg deep. Serious adverse events reported in clinical trials or from post-marketing experience are included in Tables 6 and 7, respectively: Ongoing Safety Surveillance: When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanentparalysis . Spinal epidural hematoma with INNOHEP' administered at a therapeutic dose has been reported in at least one patient who had not received neuraxial anesthesia or spinal puncture.
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INNOHEP' is not intended for intramuscular or intravenous administration. INNOHEP' cannot be used interchangeably (unit for unit) with heparin or other low molecular weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage. Each of these medications has its own instructions for use. INNOHEP' should not be used in patients with a history of heparin-induced thrombocytopenia . Hemorrhage: INNOHEP', like other anticoagulants, should be used with extreme caution in conditions with increased risk of hemorrhage, such as bacterial endocarditis; severe uncontrolled hypertension; congenital or acquired bleeding disorders including hepatic failure and amyloidosis; active ulcerative and angiodysplastic gastrointestinal disease; hemorrhagic stroke; shortly after brain, spinal or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors. Bleeding can occur in any tissue or organ of the body during therapy with INNOHEP'. Hemorrhage in some cases has been reported to result in death or permanent disability. A hemorrhagic event should be seriously considered in the presence of an unexplained fall in hematocrit, hemoglobin, or blood pressure. If severe hemorrhage occurs, INNOHEP' should be discontinued. Spinal or epidural hematomas can occur with the associated use of low molecular weight heparins or heparinoids and spinal/epidural anesthesia or spinal puncture which can result in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters or with the concomitant use of additional drugs affecting hemostasis such as NSAIDs . Thrombocytopenia: Thrombocytopenia can occur with the administration of INNOHEP'. In clinical studies, thrombocytopenia (platelet count<100,000/mmif baseline value���150,000/mm,���50% decline if baseline<150,000/mm) was identified in 1% of patients given INNOHEP'; severe thrombocytopenia (platelet count less than 50,000/mm) occurred in 0.13%. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm, INNOHEP' should be discontinued. Cases of thrombocytopenia with disseminated thrombosis also have been observed in clinical practice with heparins, and low molecular weight heparins, including tinzaparin sodium. Some of these cases were complicated by organ infarction with secondary organ dysfunction or limb ischemia, and have resulted in death. Hypersensitivity: INNOHEP' contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown, but is probably low. Sulfite sensitivity is more frequent in asthmatic people than in non-asthmatic people. Priapism: Priapism has been reported from post-marketing surveillance as a rare occurrence. In some cases surgical intervention was required. Miscellaneous: INNOHEP' multiple dose vial contains benzyl alcohol as a preservative. The administration of medications containing benzyl alcohol as a preservative to premature neonates has been associated with a fatal���Gasping Syndrome." Because benzyl alcohol may cross the placenta, INNOHEP' preserved with benzyl alcohol should be used with caution in pregnant women only if clearly needed .
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INNOHEP' is indicated for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered in conjunction with warfarin sodium. The safety and effectiveness of INNOHEP' were established in hospitalized patients.
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Innohep
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