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

Thrombocytopenia:   Thrombocytopenia can occur with the administration of INNOHEP.

In clinical studies, thrombocytopenia (platelet count <100,000/mm ³ if baseline value ≥150,000/mm ³ , ≥50% decline if baseline <150,000/mm ³ ) was identified in 1% of patients given INNOHEP; severe thrombocytopenia (platelet count less than 50,000/mm ³ ) occurred in 0.13%.

Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm ³ , INNOHEP should be discontinued. Cases of thrombocytopenia with disseminated thrombosis also have been observed in clinical practice with heparin, and low molecular weight heparins, including tinzaparin. 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

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 ).

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, and NSAIDs including ketorolac tromethamine ticlopidine, and clopidogrel), and thrombolytics. If co-administration is essential, close clinical and laboratory monitoring of these patients is advised (see

PRECAUTIONS

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 subcutaneous 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

Teratogenic Effects:   Pregnancy Category B: Teratogenicity studies have been performed in rats at subcutaneous doses up to 1800 IU/kg/day (about 2 times the maximum recommended human dose based on body surface area) and in rabbits at subcutaneous 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.

Cases of teratogenic effects that include cleft palate, optic nerve hypoplasia, and trisomy 21 (Downs) syndrome, and cutis aplasia of the scalp have been reported in infants of women who received INNOHEP during pregnancy. A cause and effect relationship has not been established.

Non-teratogenic Effects:   There have been reports of fetal death/miscarriage in pregnant women receiving INNOHEP who had high risk pregnancies and/or a prior history of spontaneous abortion. Approximately 6% of pregnancies were complicated by fetal distress. There have been spontaneous reports of one case each of pulmonary hypoplasia or muscular hypotonia in infants of women receiving INNOHEP during pregnancy. A cause and effect relationship for the above observations has not been established.

Approximately 10% of pregnant women receiving INNOHEP experienced significant vaginal bleeding. A cause and effect relationship has not been established.

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.

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

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 know 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 clinical studies for the treatment of DVT, 58% of patients were 65 or older and 29% were 75 and over. No significant overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity to tinzaparin sodium of some older individuals cannot be ruled out.

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