Tinzaparin

Pharmacologic Category

Anticoagulant; Anticoagulant, Low Molecular Weight Heparin

Dosing: Adult

Mechanical prosthetic heart valve (aortic or mitral position) to bridge anticoagulation (off-label use):

Note: Bridging during intervals of subtherapeutic anticoagulation should be considered for patients with mechanical mitral or tricuspid valve replacement; however, for patients with mechanical aortic valve replacement, bridging is not required unless an additional thromboembolic risk factor is present or patient has an older generation mechanical aortic valve (AHA/ACC [Nishimura 2017]).

SubQ: 175 anti-Xa units/kg once daily (ACCP [Douketis 2012]).

Venous thromboembolism prophylaxis:

Bariatric surgery, moderate to high venous thromboembolism risk (off-label use): Based on limited evidence: SubQ: Initial: 75 anti-Xa units/kg once daily starting on postoperative day 1 (minimum dose: 4,500 anti-Xa units once daily and maximum dose: 14,000 anti-Xa units once daily); round dose to the closest possible syringe size; duration of therapy is typically 10 days postoperatively (Pai 2018; Tseng 2018). Note: Optimal duration of prophylaxis is unknown, but is usually continued until hospital discharge and may be extended for up to 6 weeks postoperatively depending upon venous thromboembolism (VTE) risk. There is no consensus on indications for extended prophylaxis following bariatric surgery (Lim 2018).

Hip replacement surgery: Note: Initiation of LMWH ≥12 hours preoperatively or ≥12 hours postoperatively is recommended; extended duration up to 35 days suggested (ACCP [Guyatt 2012]).

Preoperative regimen: SubQ: 50 anti-Xa units/kg given 2 hours preoperatively followed by 50 anti-Xa units/kg once daily for 7 to 10 days

Postoperative regimen: SubQ: 75 anti-Xa units/kg once daily, with initial dose given postoperatively and continued for 7 to 10 days

Knee replacement surgery: SubQ: 75 anti-Xa units/kg once daily, with initial dose given postoperatively and continued for 7 to 10 days. Note: Initiation of LMWH ≥12 hours preoperatively or ≥12 hours postoperatively is recommended; extended duration of up to 35 days suggested (ACCP [Guyatt 2012]). Body weight dosing using prefilled syringes may also be considered. Refer to manufacturer labeling for detailed dosing recommendations.

General surgery: SubQ: 3,500 anti-Xa units once daily, with initial dose given 2 hours prior to surgery and then continued postoperatively for 7 to 10 days

Anticoagulant in extracorporeal circuit during hemodialysis (recommendations apply to stable patients with chronic renal failure): IV:

Dialysis session ≤4 hours (no hemorrhage risk): Initial bolus (via arterial side of circuit or IV): 4,500 anti-Xa units at beginning of dialysis; typically achieves plasma concentrations of 0.5 to 1 anti-Xa units/mL; may give larger bolus for dialysis sessions >4 hours. For subsequent dialysis sessions, may adjust dose as necessary in increments of 500 anti-Xa units based on previous outcome.

Dialysis session >4 hours (hemorrhage risk): Initial bolus (IV only): 2,250 anti-Xa units at beginning of dialysis (do not add to dialysis circuit). A smaller second IV dose may be administered during dialysis sessions >4 hours. For subsequent dialysis sessions, adjust dose as necessary to achieve plasma concentrations of 0.2 to 0.4 anti-Xa units/mL.

Venous thromboembolism treatment:

Note: For timing of initiating oral anticoagulant, see Transitioning between anticoagulants.

Deep vein thrombosis and/or pulmonary embolism treatment: Inpatient treatment: SubQ: 175 anti-Xa units/kg once daily; maximum dose: 18,000 anti-Xa units/day. Note: In select low-risk patients, may consider outpatient treatment for the remainder of the course after first dose administered in hospital or urgent care center (ACCP [Kearon 2016]; Erkens 2010; Hull 2019b).

Duration of therapeutic anticoagulation (first episode, general recommendations): Optimal duration of therapy is unknown and depends on many factors, such as whether provoking events were present, patient risk factors for recurrence and bleeding, and individual preference.

Provoked VTE: 3 months (provided the provoking risk factor is no longer present) (ACCP [Kearon 2016])

Unprovoked PE or DVT (proximal or isolated distal): ≥3 months depending on risk of VTE recurrence and bleeding (ACCP [Kearon 2012]; ACCP [Kearon 2016]; ISTH [Baglin 2012]).

Note: All patients receiving indefinite therapeutic anticoagulation with no specified stop date should be reassessed at periodic intervals.

Venous thromboembolism treatment in patients with active cancer:

Months 1 to 6: SubQ: Initial: 175 anti-Xa units/kg once daily for 5 to 10 days followed by long-term anticoagulation for a total duration of 3 to 6 months (ASCO [Key 2020]; Bauer 2019).

Maintenance beyond 6 months: ACCP and ASCO guidelines for VTE prophylaxis/treatment recommend considering continuing anticoagulation beyond 6 months in select patients due to the persistent high risk of recurrence in those with active cancer; consider risk vs benefit of bleeding and recurrence (ACCP [Kearon 2012]; ACCP [Kearon 2016]; ASCO [Key 2020]).

Transitioning between anticoagulants: Note: This provides general guidance on transitioning between anticoagulants; also refer to local protocol for additional detail:

Transitioning from another anticoagulant to tinzaparin:

Transitioning from therapeutic IV UFH infusion to therapeutic-dose tinzaparin: Discontinue UFH and begin tinzaparin within 1 hour. Note: If aPTT is not in therapeutic range at the time UFH is discontinued, consult local protocol (Nutescu 2007).

Transitioning from tinzaparin to another anticoagulant:

Transitioning from therapeutic-dose tinzaparin to therapeutic IV UFH infusion: Start IV UFH (rate based on indication) 1 to 2 hours before the next dose of tinzaparin would have been due. Note: Omit IV UFH loading dose (Nutescu 2007).

Transitioning from prophylactic tinzaparin to therapeutic IV UFH: UFH should be started without delay. A UFH bolus/loading dose may be used if indicated.

Transitioning from therapeutic-dose tinzaparin to warfarin: Start warfarin and continue tinzaparin until INR is within therapeutic range (Hull 2019a; Wittkowsky 2018). Note: For the treatment of VTE, overlap tinzaparin with warfarin until INR is ≥2 for at least 2 measurements taken ~24 hours apart (duration of overlap is usually 4 to 5 days) (ACCP [Ageno 2012]; Hull 2019b).

Transitioning from therapeutic-dose tinzaparin to a direct oral anticoagulant (DOAC): Note: In treatment of VTE, some DOACs (dabigatran, edoxaban) require 5 days of parenteral anticoagulation prior to transitioning.

General transition recommendation: Start DOAC within 2 hours prior to the next scheduled dose of tinzaparin.

VTE initial treatment transition (alternative recommendation): For acute VTE, some experts start DOAC within 12 to 24 hours after a once-daily LMWH regimen (Hull 2019b).

Dosing: Geriatric

Refer to adult dosing; elimination of tinzaparin may be reduced in elderly patients. Increased sensitivity to tinzaparin in elderly patients may be possible due to a decline in renal function. Avoid use in patients >70 years of age with renal impairment (Leizorovicz 2011).

Dosing: Renal Impairment: Adult

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, primarily undergoes renal elimination and clearance is decreased in renal impairment; use with caution.

CrCl <30 mL/minute: Evidence suggests no accumulation in patients with CrCl down to 20 mL/minute, but there are limited data available in patients with a CrCl <20 mL/minute. While the manufacturer recommends that a dose reduction be considered in patients with CrCl <30 mL/minute, there are no specific dosage adjustments provided in the manufacturer's labeling; use with caution.

Hemodialysis: Not dialyzable (NCS/SCCM [Frontera 2016])

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling. Does not undergo hepatic metabolism; however, has been associated with transient increases in transaminase levels; use with caution.

Dosing: Obesity: Adult

Note: Specific dosing recommendations may not be available for all indications.

Venous thromboembolism prophylaxis:

BMI 30 to 39 kg/m2: Use standard prophylaxis dosing.

BMI ≥40 kg/m2: Increase standard prophylaxis dose by 30% (Nutescu 2009); however, the ideal dose is unknown.

Venous thromboembolism treatment: Use actual body weight to calculate dose; a fixed upper dose limit is not recommended; however, increased monitoring and dosage adjustment based on anti-Xa levels may be considered (Nutescu 2009).

Dosing: Pediatric

Note: 1 mg of tinzaparin equals 70 to 120 units of anti-Xa activity

DVT and/or PE treatment (off-label dose) (Monagle 2012): SubQ: Infants, Children, and Adolescents: Note: May initiate a vitamin K antagonist on day 1 of tinzaparin therapy; discontinue tinzaparin on day 6 or later if INR is not >2.

Birth to 2 months: 275 anti-Xa units/kg once daily

2 to 12 months: 250 anti-Xa units/kg once daily

1 to 5 years: 240 anti-Xa units/kg once daily

5 to 10 years: 200 anti-Xa units/kg once daily

10 to 16 years: 175 anti-Xa units/kg once daily

Dosing: Renal Impairment: Pediatric

There are no pediatric specific recommendations; based on experience in adult patients, use with caution; tinzaparin primarily undergoes renal elimination and clearance is decreased in renal impairment.

Dosing: Hepatic Impairment: Pediatric

There are no pediatric specific recommendations; based on experience in adult patients, use with caution; does not undergo hepatic metabolism; however, has been associated with transient increases in transaminase levels.

Calculations

• 4T score
• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)
• Modified Wells Score for DVT
• Pulmonary Embolism Wells Score

Use: Labeled Indications

Note: Not available in the United States.

Anticoagulation in extracorporeal circuit during hemodialysis: Prevention of clotting in indwelling intravenous lines and extracorporeal circuit during hemodialysis (in patients without high bleeding risk).

Deep vein thrombosis/pulmonary embolus (treatment): Treatment of deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Note: In patients with venous thromboembolism (VTE) (ie, DVT or PE) and without cancer, oral anticoagulants are preferred over low molecular weight heparin (LMWH) (unless LMWH is used as initial parenteral anticoagulation prior to dabigatran, edoxaban, or while initiating warfarin). In patients with venous thromboembolism (VTE) (ie, DVT or PE) and cancer, ACCP recommends LMWH over oral anticoagulants for initial and long-term treatment (Kearon 2012; Kearon 2016).

Postoperative thromboprophylaxis: Prevention of VTE following orthopedic surgery or following general surgery in patients at high risk of VTE.

Use: Off-Label: Adult

Mechanical prosthetic heart valve (aortic or mitral position) to bridge anticoagulationLevel of Evidence [G]

Based on the 2017 American Heart Association/American College of Cardiology (AHA/ACC) focused update of the 2014 guideline for the management of patients with valvular heart disease, a low molecular weight heparin is reasonable to decrease the risk of thrombotic events in patients who require temporary interruption of oral anticoagulation and have a mechanical mitral heart valve, mechanical aortic heart valve plus additional risk factors for thromboembolism (eg, atrial fibrillation, previous thromboembolism, left ventricular dysfunction, or hypercoagulable condition), or older-generation mechanical valves (ball-cage or tilting disc).

Venous thromboembolism prophylaxis in patients undergoing bariatric surgery (moderate to high venous thromboembolism risk)Level of Evidence [C, G]

Data from a single center, retrospective study of consecutive patients with a body mass index ≥30 kg/m2 undergoing bariatric surgery (Roux-en-Y, gastric bypass, sleeve gastrectomy, biliopancreatic diversion or duodenal switch) demonstrated that an extended tinzaparin dosing regimen provided effective venous thromboembolism (VTE) prophylaxis Ref.

The 2013 American Association of Clinical Endocrinologists/Obesity Society/American Association of Metabolic and Bariatric Surgery (AACE/TOS/ASMBS) bariatric surgery guidelines recommend early ambulation along with both sequential compression devices and subcutaneous LMWH or unfractionated heparin administered within 24 hours after surgery, with consideration of extended prophylaxis for those at high risk for VTE (eg, history of DVT).

Level of Evidence Definitions

Level of Evidence Scale

Clinical Practice Guidelines

Atrial Fibrillation:

Canadian Cardiovascular Society, "2016 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation," 2016

Critical Care:

“Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016,” March 2017

Oncology Venous Thromboembolism:

American Society of Clinical Oncology Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer, Clinical Practice Guideline Update, 2013

American Society of Clinical Oncology Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer, Clinical Practice Guideline Update, 2014

Pulmonary Embolism:

“British Thoracic Society Guideline for the Initial Management of Pulmonary Embolism" June 2018

Valvular Heart Disease:

AHA/ACC, “2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease,” March 2014

AHA/ACC, "2017 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease," 2017

Venous Thromboembolism:

ACCP, "Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report,” February 2016

AHA, "The Postthrombotic Syndrome: Evidence-Based Prevention, Diagnosis, and Treatment Strategies,” October 2014

AHA/ASA, "Diagnosis and Management of Cerebral Venous Thrombosis," April 2011

ASCO, “Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update,” August 2019

ASH, “American Society of Hematology 2018 Guidelines for Management of Venous Thromboembolism,” December 2018

Administration: Subcutaneous

Patient should be lying down or sitting. Administer by deep SubQ injection into the lower abdomen (avoiding navel area), outer thigh, lower back, or upper arm. Do not administer IM. Injection site should be varied daily. To minimize bruising, do not rub the injection site.

Administration: Other

Hemodialysis: During hemodialysis, may be administered into the arterial side of the dialyzer circuit or IV in patients with no hemorrhage risk. In patients at risk of hemorrhage, administer IV only (do not add to the dialyzer circuit).

Administration: Pediatric

SubQ: For SubQ administration; do not administer IM. Administer by deep SubQ injection; in adults, it is recommended to alternate between the lower abdomen (avoiding navel area), outer thigh, lower back, or upper arm. Injection site should be varied daily. To minimize bruising, do not rub the injection site.

Storage/Stability

Store at 15°C to 25°C (59°F to 77°F).

Medication Safety Issues

High alert medication:

International issues:

Contraindications

Hypersensitivity to tinzaparin, heparin, or other low molecular weight heparins (LMWH), or any component of the formulation; active bleeding from a local lesion such as an acute ulcer (eg, gastric, duodenal) or ulcerating carcinoma; history of confirmed or suspected immunologically mediated heparin-induced thrombocytopenia (HIT) or positive in vitro platelet-aggregation test in the presence of tinzaparin; acute or subacute septic endocarditis; active major hemorrhage or conditions/diseases involving increased risk of hemorrhage (eg, severe hepatic insufficiency, imminent abortion); hemophilia or major blood clotting disorders; acute cerebral insult or hemorrhagic cerebrovascular accidents without systemic emboli; uncontrolled severe hypertension; diabetic or hemorrhagic retinopathy; injury or surgery involving the brain, spinal cord, eyes or ears; spinal/epidural anesthesia in patients requiring treatment dosages of tinzaparin; use of multi-dose vials containing benzyl alcohol in children <3 years of age, premature infants, and neonates.

Note: Use of tinzaparin in patients with current HIT or HIT with thrombosis is not recommended and considered contraindicated due to high cross-reactivity to heparin-platelet factor-4 antibody (ACCP [Guyatt 2012]; Warkentin 1999).

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: Monitor patient closely for signs or symptoms of bleeding, which may occur at any site. 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; history of hemorrhagic stroke; or use shortly after brain, spinal, or ophthalmology surgery; those concomitantly treated with drugs that increase the risk of bleeding (eg, antiplatelet agents, anticoagulants); recent GI bleeding; thrombocytopenia or platelet defects; severe liver disease; hypertensive or diabetic retinopathy; or in patients undergoing invasive procedures. Withhold or discontinue for minor bleeding. Protamine infusion may be necessary for serious bleeding (consult Protamine monograph for dosing recommendations).

• Hyperkalemia: Monitor for hyperkalemia. Heparin can cause hyperkalemia by suppressing aldosterone production; similar reactions could occur with LMWHs. Most commonly occurs in patients with risk factors for the development of hyperkalemia (eg, diabetes, renal dysfunction, preexisting metabolic acidosis, concomitant use of potassium-sparing diuretics or potassium supplements, long-term use of tinzaparin, and hematoma in body tissues).

• Thrombocytopenia: Cases of thrombocytopenia including thrombocytopenia with thrombosis have occurred. Use with caution in patients with history of thrombocytopenia (drug-induced or congenital) or platelet defects; monitor platelet count closely. Use is contraindicated in patients with history of confirmed or suspected heparin-induced thrombocytopenia (HIT) or positive in vitro test for antiplatelet antibodies in the presence of tinzaparin. Discontinue therapy and consider alternative treatment if platelets are <100,000/mm3 and/or thrombosis develops.

• Thrombocytosis: Asymptomatic thrombocytosis has been observed with use, particularly in patients undergoing orthopedic surgery or with concurrent inflammatory process; discontinue use with increased platelet counts and evaluate the risks/necessity of further therapy.

Disease-related concerns:

• GI ulceration: Use with caution in patients with history of GI ulcer.

• Hepatic impairment: Use with caution in hepatic impairment; associated with transient, dose-dependent increases in AST/ALT/GGT which typically resolve within 2 to 4 weeks of therapy discontinuation.

• Prosthetic heart valves: Prosthetic valve thrombosis has been reported in patients receiving thromboprophylaxis therapy with LMWHs. Pregnant women may be at increased risk.

• Renal impairment: Use with caution in severe renal impairment; clearance is decreased in patients with CrCl ≤50 mL/minute; consider dosage reduction in patients with CrCl <30 mL/minute.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution due to increased bleeding risks. Avoid use in patients >70 years of age with renal impairment. In a trial terminated early, an increase in all-cause mortality has been observed in patients ≥70 years (mean age: >82 years) with CrCl ≤60 mL/minute treated with tinzaparin compared to unfractionated heparin for acute DVT and/or PE (Leizorovicz 2011).

• Extreme body weights: Use with caution in patients <45 kg or >120 kg; limited experience in these patients. Individualized clinical and laboratory monitoring are recommended.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol and should not be used in pregnant women. In neonates, large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”); the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

• Porcine intestinal mucosa: This product is derived from porcine intestinal mucosa and should not be used in patients allergic to pork products.

• Sodium metabisulfite: Some dosage forms contain sodium metabisulfite which may cause allergic-type reactions, including anaphylactic symptoms and life-threatening asthmatic episodes in susceptible people; this is observed more frequently in asthmatics.

Other warnings/precautions:

• Administration: For subcutaneous use only (except in hemodialysis patients); do not administer IM and avoid IM administration of other medications due to the risk of hematoma formation.

• Conversion to other products: Not to be used interchangeably (unit for unit) with heparin or any other low molecular weight heparins.

• Neuraxial anesthesia: Spinal or epidural hematomas, including subsequent paralysis, may occur with recent or anticipated neuraxial anesthesia (epidural or spinal) or spinal puncture in patients anticoagulated with LMWH or heparinoids. Consider risk versus benefit prior to spinal procedures; risk is increased by the use of concomitant agents which may alter hemostasis, the use of indwelling epidural catheters for analgesia, a history of spinal deformity or spinal surgery, as well as traumatic or repeated epidural or spinal punctures. Optimal timing between neuraxial procedures and tinzaparin administration is not known. Delay placement or removal of catheter for at least 12 hours after administration of the last prophylactic dose and at least 24 hours after the last treatment dose of tinzaparin; consider doubling these times in patients with creatinine clearance <30 mL/minute. Risk of neuraxial hematoma may still exist since antifactor Xa levels are still detectable at these time points. Consider holding the next tinzaparin dose for 24 hours if the spinal puncture caused trauma. Patient should be observed closely for bleeding and signs and symptoms of neurological impairment if therapy is administered during or immediately following diagnostic lumbar puncture, epidural anesthesia, or spinal anesthesia. If neurological compromise is noted, urgent treatment is necessary. If spinal hematoma is suspected, diagnose and treat immediately; spinal cord decompression may be considered although it may not prevent or reverse neurological sequelae.

Geriatric Considerations

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. Results from the Innohep in Renal Insufficiency Study (IRIS) study showed an increase in all-cause mortality in elderly patients receiving tinzaparin compared to unfractionated heparin for treatment of DVT and/or PE. The at-risk population has defined as patients ≥70 years of age with CrCl ≤30 mL/minute or ≥75 years of age and CrCl ≤60 mL/minute.

Pregnancy Considerations

Use is contraindicated in conditions involving increased risks of hemorrhage, including women with imminent abortion.

Tinzaparin does not cross the human placenta; increased risks of fetal bleeding or teratogenic effects have not been reported (Bates 2012). Low molecular weight heparin (LMWH) is recommended over unfractionated heparin for the treatment of acute venous thromboembolism (VTE) in pregnant women. LMWH is also recommended over unfractionated heparin for VTE prophylaxis in pregnant women with certain risk factors. LMWH should be discontinued prior to induction of labor or a planned cesarean delivery. For women undergoing cesarean section and who have additional risk factors for developing VTE, the prophylactic use of LMWH may be considered (Bates 2012). When choosing therapy, fetal outcomes (ie, pregnancy loss, malformations), maternal outcomes (ie, VTE, hemorrhage), burden of therapy, and maternal preference should be considered (Bates 2012).

Multiple-dose vials contain benzyl alcohol (avoid use in pregnant women due to association with gasping syndrome in premature infants); use of preservative-free formulation is recommended.

Breast-Feeding Considerations

Small amounts of LMWH have been detected in breast milk; however, because it has a low oral bioavailability, it is unlikely to cause adverse events in a breastfeeding infant. Use of LMWH may be continued in breastfeeding women (Bates 2012).

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 serum ALT (≤13%)

Local: Hematoma at injection site

1% to 10%:

Cardiovascular: Chest pain (2%), angina pectoris (≥1%), cardiac arrhythmia (≥1%), coronary thrombosis (≥1%), myocardial infarction (≥1%), thromboembolism (≥1%)

Central nervous system: Headache (2%), pain (2%)

Dermatologic: Bullous rash (≥1%), erythematous rash (≥1%), maculopapular rash (≥1%), skin necrosis (≥1%)

Endocrine & metabolic: Dependent edema (≥1%)

Gastrointestinal: Nausea (2%), abdominal pain (1%), constipation (1%), diarrhea (1%), vomiting (1%)

Genitourinary: Urinary tract infection (4%)

Hematologic & oncologic: Granulocytopenia (≥1%), hemorrhage (≥1%, including anorectal bleeding, gastrointestinal hemorrhage, hemarthrosis, hematemesis, hematuria, hemopericardium, injection site bleeding, melena, purpura, intra-abdominal bleeding, vaginal bleeding, wound hemorrhage; major: ≤3%, including intracranial, retroperitoneal, or bleeding into a major prosthetic joint), neoplasm (≥1%), thrombocytopenia (≥1%)

Hepatic: Increased serum AST (9%)

Hypersensitivity: Hypersensitivity reaction (≥1%)

Local: Cellulitis at injection site (≥1%)

Neuromuscular & skeletal: Back pain (2%)

Respiratory: Epistaxis (2%), dyspnea (1%)

Miscellaneous: Fever (2%)

<1%, postmarketing, and/or case reports: Agranulocytosis, angioedema, anaphylactoid reaction, epidural hematoma (spinal), hemophthalmos, hemoptysis, hyperkalemia, increased gamma-glutamyl transferase, increased, lactate dehydrogenase, increased serum lipase, metabolic acidosis, osteoporosis, priapism, pruritus, skin rash, Stevens-Johnson syndrome, suppression of aldosterone synthesis, thrombocythemia, toxic epidermal necrolysis, urticaria

Allergy and Idiosyncratic Reactions

• Low Molecular Weight Heparin Allergy

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

5-Aminosalicylic Acid Derivatives: May enhance the adverse/toxic effect of Heparins (Low Molecular Weight). Specifically, the risk for bleeding/bruising may be increased. Risk C: Monitor therapy

Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Aliskiren: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Aliskiren. Risk C: Monitor therapy

Angiotensin II Receptor Blockers: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy

Antithrombin: May enhance the anticoagulant effect of Heparins (Low Molecular Weight). Risk C: Monitor therapy

Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination

Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy

Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Risk D: Consider therapy modification

Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Risk X: Avoid combination

Eplerenone: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Eplerenone. Risk C: Monitor therapy

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Risk D: Consider therapy modification

Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Risk C: Monitor therapy

Fat Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Hemin: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Management: Avoid such combinations when possible. If used concomitantly, increase diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds). Risk D: Consider therapy modification

Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Risk C: Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Inotersen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Risk C: Monitor therapy

Mesoglycan: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Risk X: Avoid combination

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy

Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Risk X: Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Palifermin: Heparins (Low Molecular Weight) may increase the serum concentration of Palifermin. Risk C: Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Pentoxifylline: May enhance the anticoagulant effect of Heparins (Low Molecular Weight). Risk C: Monitor therapy

Potassium Salts: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Potassium Salts. Risk C: Monitor therapy

Potassium-Sparing Diuretics: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Management: Monitor serum potassium concentrations closely. The spironolactone Canadian product monograph lists its combination with heparin or low molecular weight heparins as contraindicated. Risk C: Monitor therapy

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Risk D: Consider therapy modification

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapy

Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Risk C: Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Risk X: Avoid combination

Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Monitoring Parameters

CBC with platelet count (at baseline then periodically throughout therapy); renal function (use Cockcroft-Gault formula); hepatic function; potassium (baseline and regularly thereafter in patients at risk for hyperkalemia); stool for occult blood. Routine monitoring of anti-Xa levels is generally not recommended; however, anti-Xa levels may be beneficial in certain patients (eg, children, obese patients, patients with severe renal insufficiency receiving therapeutic doses, and possibly pregnant women receiving therapeutic doses) (ACCP [Guyatt 2012]). Peak anti-Xa levels are measured 4 to 6 hours after administration. Monitoring of PT and/or aPTT is not of clinical benefit.

Reference Range

Anti-Xa level (measured 4 hours after administration): Fixed-dose (3,500 units): 0.15 anti-Xa units/mL; weight-based (75 to 175 units/kg): 0.34 to 0.70 anti-Xa units/mL; in treatment of venous thromboembolism, a target of 0.85 anti-Xa units/mL has been recommended (Garcia 2012)

Children: Target anti-Xa level: 0.5 to 1 anti-Xa units/mL 4 to 6 hours after administration or 0.5 to 0.8 anti-Xa units/mL 2 to 6 hours after administration (Monagle 2012)

Advanced Practitioners Physical Assessment/Monitoring

Obtain CBC including platelets, potassium, liver function tests, and renal function tests. Obtain stool for occult blood periodically. Screen for known allergy to pork products. Screen for known or suspected history of heparin-induced thrombocytopenia (HIT). Monitor patient’s weight prior to treatment and periodically throughout. Evaluate risk vs benefit in elderly patients, especially those with renal impairment. Assess for signs and symptoms of bleeding, neurological impairment, and thrombocytopenia with/without thrombosis. Consider protamine administration in patients that experience serious bleeding. Evaluate risk vs benefit of continuing/discontinuing therapy in patients who may require neuraxial anesthesia, indwelling epidural catheter or spinal tap. Allow sufficient time between discontinuation/restarting of medication and beginning/finishing neuraxial anesthesia, spinal tap, and cesarean section, and/or delivery. Instruct patients that premature discontinuation increases the risk of thrombotic events.

Nursing Physical Assessment/Monitoring

Verify no known allergy to pork products. Check ordered labs and report any abnormalities. Obtain weight; dosing is weight based. Monitor patient for signs and symptoms of bleeding (bruising or bleeding that is not normal, changes in menstrual periods like lots of bleeding, spotting, or bleeding between cycles, nosebleeds that won’t stop, bowel movements that are red or black like tar, throwing up blood or liquid that looks like coffee grounds) and neurological impairment (midline back pain, sensory defects, motor defects, bowel dysfunction, and bladder dysfunction). Educate patients on bleeding precautions including avoiding invasive procedures, activities that could cause injuries, and how to handle bleeding emergencies. Monitor for signs and symptoms of thrombocytopenia after therapy initiation. Instruct patient on proper subcutaneous self-injection technique if applicable. Advise patient to tell all doctors and dentists about use of an anticoagulant.

Dosage Forms Considerations

Innohep is manufactured from products derived from porcine intestinal mucosa.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injectable, Subcutaneous:

Innohep: 10000 units/mL (0.25 mL, 0.35 mL, 0.45 mL)

Innohep: 10000 units/mL (2 mL); 20000 units/mL (2 mL) [contains benzyl alcohol, sodium metabisulfite]

Innohep: 20000 units/mL (0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL) [contains sodium metabisulfite]

Anatomic Therapeutic Chemical (ATC) Classification

• B01AB10

Generic Available (US)

Yes

Mechanism of Action

Tinzaparin is a low molecular weight heparin (average molecular weight ranges between 5,500 and 7,500 daltons, distributed as <2,000 daltons [<10%], 2,000 to 8,000 daltons [60% to 72%], and >8,000 daltons [22% to 36%]) that binds antithrombin III, enhancing the inhibition of several clotting factors, particularly factor Xa. Tinzaparin anti-Xa activity (70 to 120 units/mg) is greater than anti-IIa activity (~55 units/mg) and it has a higher ratio of antifactor Xa to antifactor IIa activity compared to unfractionated heparin. Low molecular weight heparins have a small effect on the activated partial thromboplastin time.

Pharmacodynamics/Kinetics

Note: Values reflective of anti-Xa activity.

Duration: Detectable anti-Xa activity persists for 24 hours

Absorption: Slow; absorption half-life ~3 hours after subcutaneous administration

Distribution: 4 L

Metabolism: Does not undergo hepatic metabolism

Bioavailability: SubQ: ~90%

Half-life elimination: 82 minutes; prolonged in renal impairment

Time to peak: 4 to 6 hours

Excretion: Urine

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Bleeding is the major adverse effect of tinzaparin. See Effects on Bleeding.

Effects on Bleeding

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 including the intensity of anticoagulation and patient susceptibility. At the recommended doses, LMWHS do not significantly influence platelet aggregation or affect global clotting time (ie, PT or aPTT). Medical consult is suggested.

Index Terms

Tinzaparin Sodium

References

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Brand Names: International

Innohep (AE, BE, BH, DE, DK, ES, FI, FR, GB, GR, HK, IE, JO, KW, LB, LK, LU, NL, NZ, PH, PK, PT, QA, RO, SA, SE, SG, TH, TR, TW); Innohep-PFS (CR, DO, GT, HN, NI, PA, SV); Logiparin (IN)

Last Updated 4/11/20