Tinzaparin

Pronunciation

(tin ZA pa rin)

U.S. Brand Names

Innohep®

Synonyms

Tinzaparin Sodium

Generic Available

Canadian Brand Names

Innohep®

Use

Treatment of acute symptomatic deep vein thrombosis, with or without pulmonary embolism, in conjunction with warfarin sodium

Pregnancy Risk Factor

Pregnancy Implications

There are no adequate and well-controlled studies in pregnant women. Cases of teratogenic effects and/or fetal death have been reported (relationship to tinzaparin not established). Use during pregnancy only if clearly needed. Pregnant women, or those who become pregnant while receiving tinzaparin, should be informed of the potential risks to the fetus.

Lactation

Excretion in breast milk unknown/use caution

Contraindications

Hypersensitivity to tinzaparin sodium, heparin, sulfites, benzyl alcohol, pork products, or any component of the formulation; active major bleeding; heparin-induced thrombocytopenia (current or history of)

Warnings/Precautions

Patients with recent or anticipated neuraxial anesthesia (epidural or spinal anesthesia) are at risk of spinal or epidural hematoma and subsequent paralysis. Consider risk versus benefit prior to neuraxial anesthesia; risk is increased by concomitant agents which may alter hemostasis, as well as traumatic or repeated epidural or spinal puncture, and indwelling epidural catheters. Patient should be observed closely for signs and symptoms of neurological impairment. Not to be used interchangeably (unit for unit) with heparin or any other low molecular weight heparins.

Monitor patient closely for signs or symptoms of bleeding. Certain patients are at increased risk of bleeding. Risk factors include bacterial endocarditis; congenital or acquired bleeding disorders; active ulcerative or angiodysplastic GI diseases; severe uncontrolled hypertension; hemorrhagic stroke; use shortly after brain, spinal, or ophthalmologic surgery; patients treated concomitantly with platelet inhibitors; recent GI bleeding; thrombocytopenia or platelet defects; severe liver disease; hypertensive or diabetic retinopathy; or in patients undergoing invasive procedures. Monitor platelet count closely. Rare cases of thrombocytopenia have occurred. Manufacturer recommends discontinuation of therapy if platelets are <100,000/mm³ .

Safety and efficacy in pediatric patients has not been established. Use with caution in the elderly (delayed elimination may occur). Heparin can cause hyperkalemia by affecting aldosterone; similar reactions could occur with LMWHs. Monitor for hyperkalemia. For subcutaneous injection only, do not mix with other injections or infusions. Clinical experience is limited in patients with BMI >40 kg.

Adverse Reactions

As with all anticoagulants, bleeding is the major adverse effect of tinzaparin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables.

>10%:

Hepatic: Increased ALT (13%)

Local: Injection site hematoma (16%)

1% to 10%:

Cardiovascular: Angina pectoris, chest pain (2%), hyper-/hypotension, tachycardia

Central nervous system: Confusion, dizziness, fever (2%), headache (2%), insomnia, pain (2%)

Dermatologic: Bullous eruption, pruritus, rash (1%), skin disorder

Gastrointestinal: Constipation (1%), dyspepsia, flatulence, nausea (2%), nonspecified gastrointestinal disorder, vomiting (1%)

Genitourinary: Dysuria, urinary retention, urinary tract infection (4%)

Hematologic: Anemia, hematoma, hemorrhage (2%), thrombocytopenia (1%)

Hepatic: Increased AST (9%)

Local: Deep vein thrombosis, injection site hematoma

Neuromuscular & skeletal: Back pain (2%)

Renal: Hematuria (1%)

Respiratory: Dyspnea (1%), epistaxis (2%), pneumonia, pulmonary embolism (2%), respiratory disorder

Miscellaneous: Impaired healing, infection, unclassified reactions

<1%: Abdominal pain, diarrhea, major bleeding

Additional serious adverse reactions reported in clinical trials and postmarketing experience: Abscess, acute febrile reaction, agranulocytosis, allergic purpura, allergic reaction, angioedema, anorectal bleeding, cardiac arrhythmia, cellulitis, cerebral hemorrhage, cholestatic hepatitis, coronary thrombosis, dependent edema, epidermal necrolysis, erythematous gastrointestinal hemorrhage, granulocytopenia, hemarthrosis, hematemesis, hemoptysis, injection site bleeding, intracranial hemorrhage, ischemic necrosis, melena, MI, necrosis, neoplasm, ocular hemorrhage, pancytopenia, peripheral ischemia, priapism, purpura, rash, retroperitoneal/intra-abdominal bleeding, severe thrombocytopenia, skin necrosis, spinal epidural hematoma, Stevens-Johnson syndrome, thromboembolism, urticaria, vaginal hemorrhage, wound hematoma

Postmarketing and/or case reports: The following adverse effects have been reported in infants of women receiving tinzaparin during pregnancy (relationship has not been established): Cleft palate (one report), optic nerve hypoplasia (one report), trisomy 21 (one report), fetal death/miscarriage, fetal distress, neonatal hypotonia, cutis aplasia of the scalp

Overdosage/Toxicology

Overdose may lead to bleeding; bleeding may occur at any site. In case of overdose, discontinue medication, apply pressure to bleeding site if possible, and replace volume and hemostatic blood elements as required. If these measures are ineffective, or if bleeding is severe, protamine sulfate may be administered at 1 mg per every 100 anti-Xa int. units of tinzaparin.

Drug Interactions

Drugs which affect platelet function (eg, aspirin, NSAIDs, dipyridamole, ticlopidine, clopidogrel, sulfinpyrazone, dextran) may potentiate the risk of hemorrhage.

Thrombolytic agents increase the risk of hemorrhage.

Warfarin: Risk of bleeding may be increased during concurrent therapy. Tinzaparin is commonly continued during the initiation of warfarin therapy to assure anticoagulation and to protect against possible transient hypercoagulability

Stability

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)

Mechanism of Action

Standard heparin consists of components with molecular weights ranging from 4000-30,000 daltons with a mean of 16,000 daltons. Heparin acts as an anticoagulant by enhancing the inhibition rate of clotting proteases by antithrombin III, impairing normal hemostasis and inhibition of factor Xa. Low molecular weight heparins have a small effect on the activated partial thromboplastin time and strongly inhibit factor Xa. The primary inhibitory activity of tinzaparin is through antithrombin. Tinzaparin is derived from porcine heparin that undergoes controlled enzymatic depolymerization. The average molecular weight of tinzaparin ranges between 5500 and 7500 daltons which is distributed as (<10%) 2000 daltons (60% to 72%) 2000-8000 daltons, and (22% to 36%) >8000 daltons. The antifactor Xa activity is approximately 100 int. units/mg.

Pharmacodynamics/Kinetics

Onset of action: 2-3 hours

Distribution: 3-5 L

Half-life elimination: 3-4 hours

Metabolism: Partially metabolized by desulphation and depolymerization

Bioavailability: 87%

Time to peak: 4-5 hours

Excretion: Urine

Dosage

SubQ:

Adults: 175 anti-Xa int. units/kg of body weight once daily. Warfarin sodium should be started when appropriate. Administer tinzaparin for at least 6 days and until patient is adequately anticoagulated with warfarin.

Note: To calculate the volume of solution to administer per dose: Volume to be administered (mL) = patient weight (kg) x 0.00875 mL/kg (may be rounded off to the nearest 0.05 mL)

Elderly: No significant differences in safety or response were seen when used in patients 65 years of age. However, increased sensitivity to tinzaparin in elderly patients may be possible due to a decline in renal function.

Dosage adjustment in renal impairment: Patients with severe renal impairment had a 24% decrease in clearance, use with caution.

Dosage adjustment in hepatic impairment: No specific dosage adjustment has been recommended.

Administration

Patient should be lying down or sitting. Administer by deep SubQ injection, alternating between the left and right anterolateral and left and right posterolateral abdominal wall. Vary site daily. The entire needle should be introduced into the skin fold formed by the thumb and forefinger. Hold the skin fold until injection is complete. To minimize bruising, do not rub the injection site.

Monitoring Parameters

CBC including platelet count and hematocrit or hemoglobin, and stool for occult blood; the monitoring of PT and/or aPTT is not necessary. Patients receiving both warfarin and tinzaparin should have their INR drawn just prior to the next scheduled dose of tinzaparin.

Test Interactions

Asymptomatic increases in AST (SGOT) (8.8%) and ALT (SGPT) (13%) have been reported. Elevations were >3 times the upper limit of normal and were reversible and rarely associated with increases in bilirubin.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This drug can only be administered by injection. Use exactly as directed (if self-administered, follow exact instructions for injection and syringe disposal). Do not alter dosage or discontinue without consulting prescriber. You may have a tendency to bleed easily while taking this drug (brush teeth with soft brush, use waxed dental floss, use electric razor, avoid scissors or sharp knives, and avoid potentially harmful activities). Report immediately any unusual bleeding or bruising (eg, mouth, nose, blood in urine or stool); chest pain or palpitations; confusion, dizziness, or headache; skin rash or itching; GI upset (eg, nausea, vomiting, abdominal pain, acute constipation); warmth, swelling, pain, or redness in calves or other areas; back or muscle pain; respiratory difficulties; or other persistent adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant or intend to become pregnant. Consult prescriber if breast-feeding.

Additional Information

Contains sodium metabisulfite and benzyl alcohol, 10 mg/mL

Cardiovascular Considerations

Low molecular weight heparins (LMWHs) compare favorably to unfractionated heparin (UFH) in the prevention and treatment of venous thromboembolism. LMWHs are associated with less thrombocytopenia, compared to heparin, and do not require routine therapeutic monitoring. The role of tinzaparin in the treatment of acute coronary syndromes is not established.

Obesity/Renal Dysfunction: There is no consensus for adjusting/correcting the weight-based dosage of LMWH for patients who are morbidly obese. Tinzaparin offers weight-based dosing (up to 162 kg) in its package insert. Monitoring of antifactor Xa activity 4 hours after an injection may be warranted. Patients who have a reduction in calculated creatinine clearance are at risk of an accumulated anticoagulant effect when they are treated with certain LMWHs. All LMWHs may not behave the same in patients with renal dysfunction. Some clinicians monitor anti-Xa levels for patients with Clcr<30 mL/minute.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause insomnia, confusion, or dizziness

Mental Health: Effects on Psychiatric Treatment

May rarely cause agranulocytosis; use caution with clozapine and carbamazepine

Dosage Forms

Injection, solution: 20,000 anti-Xa int. units/mL (2 mL) [contains benzyl alcohol and sodium metabisulfite]

References

Hull RD, Raskob GE, Pineo GF, et al, "Subcutaneous Low-Molecular-Weight Heparin Compared With Continuous Intravenous Heparin in the Treatment of Proximal-Vein Thrombosis," N Engl J Med , 1992, 326(15):975-82.

Nagge J, Jackevicius C, Dzavik V, et al, "Acute Profound Thrombocytopenia Associated With Eptifibatide Therapy," Pharmacotherapy , 2003, 23(3):374-9.

Simonneau G, Sors H, Charbonnier B, et al, "A Comparison of Low-Molecular-Weight Heparin With Unfractionated Heparin for Acute Pulmonary Embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire," N Engl J Med , 1997, 337(10):663-9.

International Brand Names

Innohep® (AT, BE, CA, CO, CR); innohep® (DE, DK); Innohep® (DO, ES, FI, FR, GB, GT, HN, IE, IL, LU, NL, NO, NZ, PA, PT, RO, SE, SG, SI, SV, TH)

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