WARNINGS
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 (see CONTRAINDICATIONS).
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 (see boxed WARNING and PRECAUTIONS, Drug Interactions).
Thrombocytopenia: Thrombocytopenia can occur with the administration of INNOHEP®.
In clinical studies, thrombocytopenia (platelet count <100,000/mm3 if baseline value ≥150,000/mm3, ≥50% decline if baseline <150,000/mm3) was identified in 1% of patients given INNOHEP®; severe thrombocytopenia (platelet count less than 50,000/mm3) occurred in 0.13%.
Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3, 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 (see PRECAUTIONS, Pregnancy).
PRECAUTIONS
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 (see CLINICAL PHARMACOLOGY, Special Populations). Patients aged 90 years or older with creatinine clearance ≤ 60 mL/min should not be treated with INNOHEP® (see CONTRAINDICATIONS).
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 (see PRECAUTIONS, Laboratory Tests).
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® (see ADVERSE REACTIONS, Elevations of Serum Aminotransferases). 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 to 1800 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.
Pregnancy
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.
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.
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.
Data
Human Data - Fifty-four women pregnant or planning to become pregnant with conditions requiring anticoagulation received INNOHEP® in an open-label, prospective, pregnancy dose finding study. (See Clinical Pharmacology, Special Populations, Pregnancy.) Patients received 50 to 175 IU/kg/day, with dosing starting as early as prior to conception or as late as 32 weeks gestation. Duration of exposure ranged from 3 to 463 days (median 159 days). From 55 pregnancies, there were 50 live births, 3 first trimester miscarriages, and 2 intrauterine deaths at 17 and 30 weeks. Approximately 6% of pregnancies were complicated by fetal distress.
Approximately 10% of pregnant women receiving INNOHEP® experienced significant vaginal bleeding. A cause and effect relationship for the above observations has not been established.
Animal Data - Teratogenicity studies have been performed in rats at SC doses up to 1800 IU/kg/day (about 2 times the maximum recommended human dose based on body surface area) and in rabbits at SC doses up to 1900 IU/kg/day (about 4 times the maximum recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to tinzaparin sodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. INNOHEP® does not cross the placenta.
Cases of "Gasping Syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99 - 404 mg/kg/day). The 2 mL vial of INNOHEP® contains 20 mg of benzyl alcohol (10 mg of benzyl alcohol per mL) (see WARNINGS, Miscellaneous). If INNOHEP® is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazards to the fetus.
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® (see CLINICAL PHARMACOLOGY, Special Populations and CONTRAINDICATIONS).
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