Innohep

Generic Name: Tinzaparin Sodium
Class: Heparins
ATC Class: B01AB10
VA Class: BL110

Warning(s)

Special Alerts:

LEO Pharma Inc. is recalling these lots from the US market as a voluntary measure after a dialogue with the FDA following an inspection at the production facility in Ballerup, Denmark. The dialogue concerned the production process and more specifically, the theoretical risk of presence of particulate matter in the released vials. The recall is not linked to any incidents of adverse events or customer complaints. Based on the limited quantity delivered to the US market, LEO Pharma Inc. has decided to discontinue marketing Innohep 20,000 IU/ml multidose vials in the US effective February 10, 2011.

Warning(s)

  • Spinal/Epidural Hematoma Risk
  • Epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis, associated with concurrent use of low molecular weight (LMW) heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture.1

  • Risk increased by use of indwelling epidural catheters or by concomitant use of drugs affecting hemostasis (e.g., NSAIAs, platelet inhibitors, other anticoagulants).1

  • Risk also increased by traumatic or repeated epidural or spinal puncture.1

  • Monitor frequently for signs and symptoms of neurologic impairment and treat urgently if neurologic compromise noted.1

  • Consider potential benefits versus risks of spinal or epidural anesthesia or spinal puncture in patients receiving or being considered for thromboprophylaxis with anticoagulants.1 (See Neurologic Effects under Cautions.)

Introduction

Anticoagulant; a low molecular weight heparin.1 2 3 4 5 6 7 8

Uses for Innohep

DVT and Pulmonary Embolism

Treatment of acute symptomatic DVT with or without pulmonary embolism when administered in conjunction with warfarin.1 27 Safety and efficacy established in clinical trials in hospitalized patients.1

A low molecular weight (LMW) heparin recommended by the American College of Chest Physicians (ACCP) for the treatment of suspected DVT or acute nonmassive pulmonary embolism while awaiting confirmation of diagnosis, provided no contraindications exist.27

A LMW heparin preferred over unfractionated heparin for the treatment of DVT or acute nonmassive pulmonary embolism.27

A LMW heparin recommended by ACCP as alternative to oral anticoagulation (e.g., with warfarin) for long-term treatment of confirmed DVT or acute nonmassive pulmonary embolism in patients in whom oral anticoagulation is contraindicated or inconvenient.27

ACCP recommends that unfractionated heparin be substituted for LMW heparin in patients with severe renal failure.27

Superficial Thrombophlebitis

A LMW heparin suggested by ACCP as alternative to unfractionated heparin for treatment of superficial thrombophlebitis.27

Systemic Venous Thrombosis in Pediatric Patients

A LMW heparin suggested by ACCP for treatment and prevention of systemic venous thrombosis in neonates and children; data insufficient to make strong recommendations.30

Renal Vein Thrombosis

A LMW heparin suggested by ACCP for the treatment of renal vein thrombosis in neonates; data limited and use of anticoagulant or thrombolytic therapy controversial in such patients.30

Cerebral Venous Sinus Thrombosis

A LMW heparin recommended by ACCP with follow-up oral anticoagulation (e.g., warfarin) in adults with acute cerebral venous sinus thrombosis, even in the presence of hemorrhagic venous infarcts.

Not recommended by some clinicians for use in adults with large hemorrhagic venous infarcts and associated hematomas.

Neonates without large ischemic infarction or intracranial hemorrhage: Initial therapy with a LMW heparin or unfractionated heparin suggested, then administer LMW heparin for 3 months.

Neonates with large infarcts or intracranial hemorrhage: Radiographic monitoring suggested; initiate anticoagulation if extension of thrombus detected.

Children without major intracranial hemorrhage: LMW heparin or unfractionated heparin followed by LMW heparin or oral anticoagulation (e.g., with warfarin).

Spontaneous Aortic Thrombosis

Urgent, aggressive use of thrombolytic or surgical therapy supported by anticoagulation with a LMW heparin or unfractionated heparin suggested by ACCP in neonates experiencing spontaneous aortic thrombosis with evidence of renal ischemia.

Thrombophilia and Other Complications of Pregnancy

A LMW heparin recommended in selected patients for prevention or treatment of thromboembolism during pregnancy.29

Embolism Associated with Atrial Fibrillation/Flutter

A LMW heparin may be initiated at diagnosis to reduce the incidence of embolism in patients undergoing cardioversion for atrial fibrillation/flutter of <48 hours’ duration, provided no contraindications exist.e

A LMW heparin may be substituted for oral anticoagulant (e.g., warfarin) therapy in patients with atrial fibrillation who require a series of diagnostic or surgical procedures that necessitate interruption of oral anticoagulation for >1 week or in selected high-risk patients who require interruption of oral anticoagulant therapy for shorter periods.j

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Thromboembolism Associated with Prosthetic Heart Valves

A LMW heparin recommended in selected patients for prophylaxis of thromboembolism associated with prosthetic heart valves.23 d

Thromboprophylaxis in General Surgery

A LMW heparin recommended by ACCP for prevention of postoperative venous thromboembolism in patients undergoing general (e.g., abdominal) surgery who are at risk for thromboembolic complications.2 6 7 8 28

Early ambulation without specific thromboprophylaxis recommended by ACCP in patients undergoing general surgery who are at low risk for venous thromboembolism (those undergoing minor operations who are <40 years of age and who have no clinical risk factors).23 28

Recommended as alternative to fixed low-dose unfractionated heparin in moderate-risk general surgery patients (those undergoing nonmajor surgery who are 40–60 years of age or who have additional risk factors for thromboembolism, patients <40 years of age undergoing major surgery with no additional risk factors, and patients with risk factors who are undergoing minor surgery).23 28

Recommended as alternative to fixed low-dose unfractionated heparin in patients undergoing general surgery who are at higher risk for thromboembolism (those undergoing major surgery who are >40 years of age or who have additional risk factors and patients undergoing nonmajor surgery who are >60 years of age or who have additional risk factors).23 28

Recommended as alternative to low-dose unfractionated heparin and in combination with intermittent pneumatic compression or graduated-compression stockings in high-risk general surgery patients23 28 (those >40 years of age with multiple risk factors such as a history of previous venous thromboembolism, cancer, or a hypercoagulable state).28 Continue LMW heparin therapy after hospital discharge in selected high-risk general surgery patients, including those undergoing major cancer surgery.23 28

Thromboprophylaxis with low-dose unfractionated heparin, LMW heparin, intermittent pneumatic compression, graduated-compression stockings, or a combination of these therapies suggested in patients undergoing laparoscopic gynecologic procedures who have additional risk factors for venous thromboembolic events (e.g., malignancy, older age, previous thromboembolism, prior pelvic radiation therapy, use of an abdominal surgical approach).28

Thromboprophylaxis with a LMW heparin recommended as alternative to low-dose unfractionated heparin or intermittent pneumatic compression recommended in patients having major gynecologic surgery for benign disease who do not have additional risk factors for thromboembolism.28 Begin just prior to surgery and continue until hospital discharge or patient is ambulatory.28

Routine prophylaxis with LMW heparin or unfractionated heparin recommended in patients undergoing extensive gynecologic procedures for malignancy and those with additional risk factors for venous thromboembolic events.28 Alternative regimens include intermittent pneumatic compression continued until hospital discharge, or the combination of low-dose unfractionated heparin or LMW heparin and intermittent pneumatic compression or graduated-compression stockings.28 Continue prophylaxis for 2–4 weeks following hospital discharge in those who are at particularly high risk for thromboembolism (e.g., previous cancer surgery, >60 years of age, history of thromboembolism).28

Thromboprophylaxis in Hip-Replacement Surgery

A LMW heparin recommended by ACCP for prophylaxis of postoperative deep-vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing hip-replacement surgery.23 28

ACCP suggests extended prophylaxis in patients undergoing hip-replacement surgery who have ongoing risk factors for venous thromboembolism (e.g., obesity, delayed mobilization, cancer, history of venous thromboembolism).28

Thromboprophylaxis in Hip-Fracture Surgery

A LMW heparin recommended by ACCP for prevention of postoperative DVT and pulmonary embolism in patients undergoing hip-fracture surgery.28

ACCP suggests extended prophylaxis in patients who have ongoing risk factors for venous thromboembolism.28

Knee-Replacement Surgery or Knee Arthroscopy

A LMW heparin recommended by ACCP for routine prophylaxis of DVT and pulmonary embolism in patients undergoing knee-replacement surgery.

A LMW heparin suggested by ACCP for prophylaxis of venous thromboembolism in high-risk patients undergoing knee arthroscopy (e.g., those with preexisting thromboembolic risk factors or following a prolonged or complicated procedure); based on limited data.28

Thromboprophylaxis in Neurosurgery

A LMW heparin recommended by ACCP as alternative therapy (e.g., instead of intermittent pneumatic compression with or without graduated-compression stockings) for prophylaxis of thromboembolism in selected patients undergoing intracranial neurologic surgery.28

Combination of a LMW heparin or low-dose unfractionated heparin with graduated-compression stockings and/or intermittent pneumatic compression recommended in patients with multiple risk factors for venous thromboembolism.28

Thromboprophylaxis in Elective Spinal Surgery

A LMW heparin recommended by ACCP for prevention of venous thromboembolism in patients undergoing elective spinal surgery who have additional risk factors (e.g., advanced age, known malignancy, neurologic deficit, previous venous thromboembolic event, anterior surgical approach), as alternative to postoperative low-dose unfractionated heparin or perioperative intermittent pneumatic compression.28

Combine anticoagulant therapy with graduated-compression stockings and/or intermittent pneumatic compression in patients with multiple risk factors for venous thromboembolism.28

Thromboprophylaxis in Trauma

A LMW heparin recommended by ACCP as first-line prophylaxis of thromboembolism in patients with major trauma.23

Initiate prophylaxis as soon as considered safe to do so and continue until hospital discharge, including during inpatient rehabilitation.28

Extended prophylaxis after hospital discharge suggested in patients with major mobility impairment.28

Thromboprophylaxis in Acute Spinal Cord Injury

A LMW heparin recommended by ACCP as first-line prophylaxis of thromboembolism in patients with acute spinal cord injury.28 For prevention of thromboembolism in the rehabilitation phase of acute spinal cord injury, continue therapy or, alternatively, convert to full-dose oral anticoagulation.28

Thromboprophylaxis in Patients with Burns

A LMW heparin recommended by ACCP as alternative therapy to low-dose unfractionated heparin in burn patients who have at least one additional risk factor for venous thromboembolism (e.g., advanced age, morbid obesity, extensive or lower extremity burns, concomitant lower extremity trauma, use of a femoral catheter, or prolonged immobility).28 Initiate prophylaxis as soon as the risk of bleeding is no longer high, provided no contraindications exist.28

Thromboprophylaxis prior to Long-Distance Travel

Single prophylactic dose of a LMW heparin may be considered for thromboprophylaxis prior to travel as alternative to below-knee graduated-compression stockings in those with risk factors for venous thrombosis (e.g., previous DVT, coagulation disorder, limited mobility, current or recent cancer, large varicose veins, severe obesity).28 Data insufficient to support routine use in any group of travelers.28

Thromboprophylaxis in Selected Medical Conditions

A LMW heparin recommended by ACCP for prophylaxis of thromboembolism in medical patients with CHF or severe lung disease or who have severely restricted mobility in conjunction with one or more additional risk factors (e.g., cancer, previous venous thromboembolism, sepsis, acute neurologic disease, inflammatory bowel disease).23 28

Acute Ischemic Stroke

A LMW heparin recommended by ACCP as first-line therapy for prophylaxis of thromboembolism in patients with acute ischemic stroke and impaired mobility who have no contraindications.c

Acute Ischemic Complications of Unstable Angina and Non-ST-Segment Elevation/Non-Q-Wave MI

A LMW heparin recommended for reduction in the risk of acute cardiac ischemic events (death and/or MI) in patients with unstable angina or non-ST-segment elevation/non-Q-wave MI (i.e., non-ST-segment elevation acute coronary syndromes).b f g h i Used concurrently with aspirin and/or other standard therapy (e.g., nitrates, β-adrenergic blockers, clopidogrel, platelet glycoprotein [GP] IIb/IIIa-receptor inhibitors).b f g h i

Considered by ACCP preferable to unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes who have received a GP IIb/IIIa-receptor inhibitor prior to PCI.b

Acute Ischemic Complications of ST-Segment Elevation MI

A LMW heparin suggested by the AHA, ACC, and ACCP as alternative to unfractionated heparin for adjunctive therapy in patients with ST-segment elevation MI receiving thrombolytic therapy.

Additional study and experience recommended before routine use of LMW heparin instead of unfractionated heparin in patients with ST-segment elevation MI.

LMW heparin not recommended in place of unfractionated heparin as adjunctive therapy for patients who are >75 years of age or who have renal dysfunction (Scr >2.5 mg/dL in men or >2 mg/dL in women).

Preferred over unfractionated heparin by ACC and AHA in patients with CHF after ST-segment elevation MI who are hospitalized for prolonged periods, nonambulatory, or are considered at high risk for DVT and are not receiving other anticoagulant therapy.

Also recommended by ACC and AHA in patients surviving ST-segment elevation MI with or without acute ischemic stroke who have cardiac sources of embolism (atrial fibrillation, mural thrombus, akinetic segment) after reperfusion; administer until adequate anticoagulation with warfarin achieved.

ACC and AHA suggest as reasonable therapy in patients with ST-segment elevation MI who are not receiving thrombolytic therapy, provided no contraindications to anticoagulation exist.

Innohep Dosage and Administration

Administration

  • Administer by deep sub-Q injection; must not be given IV or IM.1

  • Vary injection sites daily; alternate injection sites between left and right anterolateral and left and right posterolateral abdominal wall.1 Patient should be sitting or supine during administration.1

  • Do not mix with other injections or infusions.1

Dosage

Dosages for tinzaparin sodium and regular (unfractionated) heparin or other low molecular weight (LMW) heparins cannot be used interchangeably on a unit-for-unit (or mg-for-mg) basis.1

Available as tinzaparin sodium; dosage expressed in anti-factor Xa international units (IU, units).1 Each mg is equivalent to approximately 100 units.1

Adults

Treatment of DVT and Nonmassive Pulmonary Embolism
Sub-Q

175 units/kg once daily for ≥6 days and until adequate anticoagulation with warfarin achieved (INR of 2 for two consecutive days).1 27 Continue oral anticoagulation for at least 3 months.27

ACCP recommends against routine monitoring of anticoagulation (e.g., anti-factor Xa activity) with LMW heparin treatment of acute venous thromboembolism.27

Patients with cancer or in whom oral anticoagulation contraindicated or inconvenient:27 175 units/kg once daily for ≥3–6 months.27 Continue anticoagulation indefinitely or until cancer is resolved.27

Prevention of Venous Thrombosis and Pulmonary Embolism
General Surgery
Sub-Q

Patients at moderate risk for thromboembolic complications: ≤3400 units of a LMW heparin (e.g., tinzaparin) once daily, given 1–2 hours before surgery and continued for 5–10 days.2 6 23 28

Patients at higher risk for thromboembolic complications: >3400 units of a LMW heparin (e.g., tinzaparin) once daily,28 given 1–2 hours before surgery and continued for 5–10 days.2 6 23

Patients at high risk for thromboembolic complications (e.g., those with multiple risk factors such as age >40 years, malignant disease, a history of DVT or PE), >3400 units of a LMW heparin (e.g., tinzaparin) once daily combined with graduated-compression stockings or intermittent pneumatic compression28 given 1–2 hours before surgery and continued for 5–10 days.2 6 23

Hip-replacement Surgery
Sub-Q

Initiate therapy with a LMW heparin (e.g., tinzaparin) either preoperatively or postoperatively; several regimens have been used.28 ACCP recommends initiation 12–24 hours postoperatively following achievement of hemostasis in patients at high risk for bleeding.28

Preoperative start, 12 hours prior to surgery: >3400 units of a LMW heparin (e.g., tinzaparin) once daily for ≥10 days postoperatively recommended by ACCP.28

Postoperative start, day of surgery: Half the usual high-risk dosage (e.g., >1700 units) of a LMW heparin (e.g., tinzaparin) 4–6 hours after surgery or the usual high-risk dosage (e.g., >3400 units) 12–24 hours after surgery, followed by >3400 units daily recommended by ACCP.28

Extended prophylaxis: ACCP recommends continuation of a LMW heparin (e.g., tinzaparin) for up to 28–35 days postoperatively in patients considered at high risk for thromboembolism.28

Hip-fracture Surgery
Sub-Q

ACCP recommends the usual high-risk dosage (>3400 units) of a LMW heparin (e.g., tinzaparin) daily initiated either preoperatively or postoperatively; optimum dosage and regimen not defined.28 If surgery likely to be delayed, initiate preoperatively and reinstitute postoperatively after hemostasis achieved.28

Continue prophylaxis for at least 10 days (i.e., most patients will continue anticoagulation following hospital discharge).28

Extended prophylaxis: ACCP recommends continuation of a LMW heparin (e.g., tinzaparin) for up to 28–35 days postoperatively in patients considered at high risk for thromboembolism.28

Knee-replacement Surgery
Sub-Q

Preoperative or postoperative start: ACCP recommends the usual high-risk dosage (>3400 units) of a LMW heparin (e.g., tinzaparin) daily.28

Continue prophylaxis for at least 10 days (i.e., most patients will continue anticoagulation following hospital discharge).28

Thrombophilia and Other Complications of Pregnancy
Sub-Q

Women with antiphospholipid syndrome and a history of venous thrombosis who require long-term anticoagulation: 175 units/kg daily in conjunction with low-dose aspirin throughout pregnancy followed by postpartum resumption of long-term oral anticoagulation.29

Treatment and secondary prevention of acute venous thromboembolism: 175 units/kg daily for the remainder of pregnancy.29 Continue oral anticoagulation (e.g., with warfarin) for at least 6 weeks postpartum.29

Secondary prevention after >2 episodes of venous thromboembolism in women receiving long-term anticoagulation: 175 units/kg daily throughout pregnancy suggested, followed by postpartum resumption of long-term anticoagulation.29

Adjust LMW heparin dosage for extremes of body weight.29

Discontinue LMW heparin 24 hours prior to elective induction of labor.29

Embolism Associated with Atrial Fibrillation/Flutter
Sub-Q

Patients with atrial fibrillation duration <48 hours undergoing cardioversion who have no contraindications to anticoagulation: 175 units/kg once daily.27 e

ACCP suggests same regimen for anticoagulation in patients undergoing cardioversion for atrial flutter.e

Unstable Angina and Non-ST-Segment Elevation/Non-Q-Wave MI
Sub-Q

175 units/kg once daily for 7 days has been used.b

Special Populations

Pregnancy has little or no influence on tinzaparin pharmacokinetics; no dosage adjustment needed during pregnancy.1

Cautions for Innohep

Contraindications

  • Known hypersensitivity to tinzaparin, heparin, sulfites, benzyl alcohol, or pork products.1

  • Active major bleeding.1

  • Current diagnosis of or history of heparin-induced thrombocytopenia.1

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Renal Impairment

Interim data from the Innohep in Renal Insufficiency Study (IRIS) revealed a higher overall mortality rate in geriatric patients with renal impairment (i.e., ≥70 years of age with estimated Clcr ≤30 mL/minute, or ≥75 years of age with estimated Clcr ≤60 mL/minute) who received tinzaparin compared with those who received unfractionated heparin.1 43 Causes of death not fully elucidated but probably not related to overanticoagulation, underanticoagulation, or manufacturing problem with tinzaparin or unfractionated heparin preparations used in study.43 Pending final review of IRIS study results and detailed analysis of manufacturing data, manufacturer and US FDA state that clinicians should consider alternatives to tinzaparin for treatment of DVT and/or PE in geriatric patients (i.e., >70 years of age) with renal impairment.1 43

Neurologic Effects

Epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis, associated with concurrent use of low molecular weight (LMW) heparins and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures.1 Spinal epidural hematoma reported in patients receiving tinzaparin with or without concurrent neuraxial anesthesia or spinal puncture.1 Frequent monitoring for signs of neurologic improvement recommended.1 (See Boxed Warning.)

Hematologic Effects

Use with extreme caution in patients with increased risk of hemorrhage.1 Such patients include those with bacterial endocarditis; severe uncontrolled hypertension; congenital or acquired bleeding disorders including hepatic failure or amyloidosis; active GI ulceration; angiodysplastic GI disease; hemorrhagic stroke; recent brain, spinal, or ophthalmic surgery; use of concomitant platelet inhibitor therapy.1 Use with caution in patients with a bleeding diathesis, uncontrolled arterial hypertension, history of recent GI ulceration, diabetic retinopathy, and hemorrhage.1 Unexplained decreases in hematocrit, hemoglobin, or BP may indicate hemorrhage.1

Discontinue if severe hemorrhage occurs.1

Thrombocytopenia reported.1 Heparin-induced thrombocytopenia can occur.1

Monitor thrombocytopenia of any degree closely and discontinue if platelet counts are <100,000/mm3.1 1

GU Effects

Priapism reported rarely.1

Sensitivity Reactions

Sulfite Sensitivity

Formulation contains sodium metabisulfite,1 which may cause serious allergic-type reactions in certain susceptible individuals (e.g., asthmatic patients).1 15 16 17 18 19 20 21 22 May result in acute bronchospasm or, less frequently, life-threatening anaphylaxis.1 21

General Precautions

Hepatic Effects

Increases in serum aminotransferase concentrations reported.1

Because serum aminotransferase determinations are important in the differential diagnosis of MI, liver disease, and pulmonary emboli, interpret elevation of these enzymes during therapy with caution.1

Local Effects

Hematoma, mild local irritation, pain, and ecchymosis reported.1

Specific Populations

Pregnancy

Category B.1

Not predicted to increase risk of fetal developmental abnormalities.1 No evidence of teratogenicity or fetotoxicity.1

Pregnancy alone associated with increased risk of thromboembolism; greater risk of thromboembolism in women with a history of thromboembolism and certain high-risk pregnancy conditions (including hereditary or acquired thrombophilias and the presence of a mechanical prosthetic heart valve).1 45 46 47 If used in pregnant women with mechanical prosthetic heart valves, some clinicians recommend frequent monitoring of anti-factor Xa concentrations and adjustment of dosage to ensure consistent anticoagulation.44 48

Substantial maternal hemorrhage can occur.1 Hemorrhage can occur at any site and may lead to death of mother and/or fetus.1 Monitor pregnant women carefully for evidence of bleeding or excessive anticoagulation.1 As delivery approaches, consider use of a shorter-acting anticoagulant.1

Because benzyl alcohol may cross the placenta, tinzaparin injection containing benzyl alcohol should be used in pregnant women only if clearly needed.1 (See Pediatric Use under Cautions.)

Lactation

Use with caution.1

Pediatric Use

Safety and efficacy not established.1 Large amounts (i.e., 100–400 mg/kg daily) of benzyl alcohol have been associated with toxicity in neonates;1 9 10 11 12 13 14 each mL of tinzaparin contains 10 mg of benzyl alcohol.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.1 However, geriatric patients with renal impairment treated with tinzaparin are at increased risk of death compared with those treated with unfractionated heparin;1 therefore, manufacturer and FDA state that clinicians should consider alternatives to tinzaparin for treatment of DVT and/or PE in geriatric patients (i.e., >70 years of age) with renal impairment.1 43 (See Increased Mortality in Geriatric Patients with Renal Impairment under Cautions.)

Renal Impairment

Use with caution in patients with renal impairment.1 (See Special Populations under Pharmacokinetics.) In geriatric patients (i.e., >70 years of age) with renal impairment, consider alternative therapy.1 43 (See Increased Mortality in Geriatric Patients with Renal Impairment under Cautions.) ACCP recommends substitution with unfractionated heparin in patients with severe renal failure.27

Common Adverse Effects

Urinary tract infection, pulmonary embolism, chest pain, epistaxis, headache, nausea, unspecified hemorrhage, back pain, fever, pain, constipation, rash, dyspnea, vomiting, hematuria.1

Interactions for Innohep

Specific Drugs

Drug

Interaction

Comments

Anticoagulants, Oral

Increased risk of bleeding1

If coadministration is essential, monitor closely1

Platelet-aggregation inhibitors

Increased risk of bleeding1

If coadministration is essential, monitor closely1

Thrombolytic agents

Increased risk of bleeding1

If coadministration is essential, monitor closely1

Innohep Pharmacokinetics

Absorption

Bioavailability

86.7% (absolute bioavailability) based on anti-factor Xa activity.1 Has greater bioavailability after sub-Q administration than unfractionated heparin.2 5 6 8

Onset

Following sub-Q administration, plasma levels of anti-factor Xa activity increase in the first 2–3 hours and reach a maximum within 4–5 hours.1

Distribution

Extent

The volume of distribution of tinzaparin sodium is approximately 3.1–5 L, suggesting that the distribution is limited to the central compartment.1 Distributes into milk in rats; not known whether distributed into human milk.1

Elimination

Metabolism

Partially metabolized by desulfation and depolymerization.1

Elimination Route

Excreted mainly in urine.1

Half-life

Approximately 3–4 hours (based on anti-factor Xa activity).1 Has a longer half-life than unfractionated heparin.2 5 6 8

Special Populations

Moderate (Clcr 30–50 mL/minute) to severe (Clcr <30 mL/minute) renal impairment may reduce clearance.1

Drug clearance not affected by age or gender.1

Stability

Storage

Parenteral

Solution for Injection

25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits reactions that lead to clotting of blood and the formation of fibrin clots both in vitro and in vivo.1 2

  • Inhibits several coagulation factors, especially factors Xa and IIa (thrombin).1 Less effect on thrombin than unfractionated heparin at a given level of anti-factor Xa activity.1 2

  • At recommended dosages, prolongs aPTT.1 PT may be slightly prolonged but usually remains within the normal range.1

  • No intrinsic fibrinolytic activity and cannot lyse established thrombi.1

  • Increases the release of tissue factor pathway inhibitor.1

Advice to Patients

  • Importance of reporting any signs of bleeding (e.g., bruising, petechiae, hematuria) to clinicians immediately.1

  • Importance of reporting history of hypersensitivity to heparin, sulfites, or pork products.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Tinzaparin Sodium (Porcine)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use only

20,000 units/mL

Innohep (with benzyl alcohol and sodium metabisulfite)

Pharmion

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions March 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Celgene. Innohep (tinzaparin sodium) injection prescribing information. Summit, NJ; 2008 Dec.

2. Friedel HA, Balfour JA. Tinzaparin: A review of its pharmacology and clinical potential in the prevention and treatment of thromboembolic disorders. Drugs. 1994; 48:638-60. [PubMed 7528134]

3. 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; 326:975-82. [IDIS 294264] [PubMed 1545850]

4. Simonneau G, Sors H, Charbonnier B et al for the THESEE Study Group. A comparison of low molecular weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med. 1997; 337:663-9. [IDIS 390614] [PubMed 9278462]

5. Hull RD, Raskob GE, Brant RF et al for the American-Canadian Thrombosis Study Group. Low molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. Arch Intern Med. 2000; 160:229-36. [IDIS 442247] [PubMed 10647762]

6. Anon. Low molecular weight heparins for venous thromboembolism. Drug Ther Bull. 1998; 36:25-9. [PubMed 9684414]

7. Hull R, Raskob G, Pineo G et al. A comparison of subcutaneous low molecular weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med. 1993; 329:1370-6. [IDIS 322164] [PubMed 8413432]

8. Planes A, Samama MM, Lensing AWA et al. Prevention of deep vein thrombosis after hip replacement: Comparison between two low molecular weight heparins, tinzaparin and enoxaparin. Thromb Haemost. 1999; 81:22-5. [IDIS 421679] [PubMed 10348714]

9. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356-8. [IDIS 175725] [PubMed 6889041]

10. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12(2):10-11. [PubMed 7188569]

11. Centers for Disease Control. Neonatal deaths associated with use of benzyl alcohol. MMWR Morb Mortal Wkly Rep. 1982; 31:290-1. [IDIS 150868] [PubMed 6810084]

12. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982; 307:1384-8. [IDIS 160823] [PubMed 7133084]

13. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol. 1984; 1:288-92. [PubMed 6440575]

14. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol. 1984; 148:344-6. [IDIS 181207] [PubMed 6695984]

15. Food and Drug Administration. Sulfites in foods and drugs. FDA Drug Bull. 1983; 13:12. [PubMed 6604672]

16. Sogn D. The ubiquitous sulfites. JAMA. 1984; 251:2986-7. [IDIS 185969] [PubMed 6716628]

17. Koepke JW, Christopher KL, Chai H et al. Dose-dependent bronchospasm from sulfites in isoetharine. JAMA. 1984; 251:2982-3. [IDIS 185966] [PubMed 6716626]

18. Twarog FJ, Leung DYM. Anaphylaxis to a component of isoetharine (sodium bisulfite). JAMA. 1982; 248:2030-1. [IDIS 158261] [PubMed 7120631]

19. Baker GJ, Collett P, Allen DH. Bronchospasm induced by metabisulphite-containing foods and drugs. Med J Aust. 1981; 2:614-7. [IDIS 146240] [PubMed 7334982]

20. Koepke JW, Selner JC, Dunhill AL. Presence of sulfur dioxide in commonly used bronchodilator solutions. J Allergy Clin Immunol. 1983; 72:504-8. [IDIS 178793] [PubMed 6630799]

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