Tinzaparin

Tinzaparin
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

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Black Box Warning

SPINAL/EPIDURAL HEMATOMAS See full prescribing information for complete Boxed Warning. Spinal/Epidural Hematomas: Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants. A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis

Overview

Tinzaparin is a low molecular weight heparin that is FDA approved for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism. There is a Black Box Warning for this drug as shown here. Common adverse reactions include bleeding, erythema, increase liver function tests, neurologic pain.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Deep Venous Thrombosis

• Dosage Information

• 175 anti-Xa IU/kg SC once daily for at least 6 days (INR at least 2.0 for two consecutive days)
• Warfarin therapy should be initiated within 1-3 days of tinzaparin initiation.
• (100 anti-Xa IU equals 1 mg tinzaparin sodium.)

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Prophylaxis in Deep Venous Thrombosis

• Developed by: ACCP
• Class of Recommendation: Class IIa
• Strength of Evidence: Category B
• Dosing Information/Recommendation

• 3500 anti-Xa IU once daily SC for 5 to 10 days

Pulmonary thromboembolism

• Developed by: ACCP
• Class of Recommendation: Class I
• Strength of Evidence: Category B
• Dosing Information/Recommendation

• 175 anti-Xa IU/kg SC once daily (until INR is 2.0 for two consecutive days)
• co-administered with oral anticoagulation

Non–Guideline-Supported Use

Hemodialysis

• Dosage Information

• 3500 anti-Xa IU once daily SC

Venous thromboembolism

• Dosage Information

• 175 anti-Xa IU/kg SC once daily

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Tinzaparin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Tinzaparin in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Tinzaparin in pediatric patients.

Contraindications

• Tinzaparin is contraindicated in patients with active major bleeding, in patients with (or history of) heparin-induced thrombocytopenia, or in patients with hypersensitivity to tinzaparin sodium.
• Patients with known hypersensitivity to heparin, sulfites, benzyl alcohol, or pork products should not be treated with tinzaparin.

Warnings

SPINAL/EPIDURAL HEMATOMAS See full prescribing information for complete Boxed Warning. Spinal/Epidural Hematomas: Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants. A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis

• Tinzaparin is not intended for intramuscular or intravenous administration.
• Tinzaparin 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.
• Tinzaparin should not be used in patients with a history of heparin-induced thrombocytopenia.

Increased Risk for Death in Elderly Patients with Renal Insufficiency

• Tinzaparin may increase the risk for death, compared to UFH, when administered to elderly patients with renal insufficiency.
• A clinical study compared tinzaparin (175 IU/kg once daily; N = 269) and UFH (N = 268) in the initial treatment of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in elderly patients with renal insufficiency (i.e., patients aged 70 years or older with estimated creatinine clearance of ≤ 30 mL/min or patients aged 75 years or older with estimated creatinine clearance of ≤ 60 mL/min).
• Oral anticoagulants were co-administered beginning on Days 1-3 and study treatment was continued for at least five days until the international normalized ratio (INR) was between 2-3 on two successive days; oral anticoagulants were then continued alone and patients were followed until 90 days after the start of treatment.
• Overall mortality rates were 6.3% in patients treated with UFH and 11.5% in patients treated with tinzaparin. Consider the use of alternatives to tinzaparin in elderly patients with renal insufficiency.

Hemorrhage

• Tinzaparin, 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 tinzaparin. 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, tinzaparin 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.

Thrombocytopenia

• Thrombocytopenia can occur with the administration of tinzaparin.
• In clinical studies, thrombocytopenia (platelet count <100,000/mm3 if baseline value ≥150,000/mm3, ≥50% decline if baseline <150,000/mm3) was identified in 1% of patients given tinzaparin; severe thrombocytopenia (platelet count less than 50,000/mm3) occurred in 0.13%.
• Thrombocytopenia of any degree should be monitored closely.
• If the platelet count falls below 100,000/mm3, tinzaparin should be discontinued. Cases of thrombocytopenia with disseminated thrombosis also have been observed in clinical practice with heparins, and low molecular weight heparins, including tinzaparin sodium. Some of these cases were complicated by organ infarction with secondary organ dysfunction or limb ischemia, and have resulted in death.

Hypersensitivity

• Tinzaparin 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

• Tinzaparin 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, tinzaparin preserved with benzyl alcohol should be used with caution in pregnant women only if clearly needed

Adverse Reactions

Clinical Trials Experience

Bleeding

Bleeding is the most common adverse event associated with tinzaparin; however, the incidence of major bleeding is low. In clinical trials, the definition of major bleeding included bleeding accompanied by ≥2 gram/dL decrease in hemoglobin, requiring transfusion of 2 or more units of blood products, or bleeding which was intracranial, retroperitoneal, or into a major prosthetic joint. The data are provided in Table 4.

Fatal or nonfatal hemorrhage from any tissue or organ can occur. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as, but are not limited to, paralysis; paresthesia; headache, chest, abdomen, joint, muscle or other pain; dizziness; shortness of breath, difficult breathing or swallowing; swelling; weakness; hypotension, shock, or coma. Therefore, the possibility of hemorrhage should be considered in evaluating the condition of any anticoagulated patient with complaints which do not indicate an obvious diagnosis.

Thrombocytopenia

In clinical studies thrombocytopenia was identified in 1% of patients treated with tinzaparin. Severe thrombocytopenia (platelet count <50,000/mm3) occurred in 0.13%.

Elevations of Serum Aminotransferases

Asymptomatic increases in aspartate (AST [SGOT]) and/or alanine (ALT [SGPT]) aminotransferase levels greater than 3 times the upper limit of normal of the laboratory reference range have been reported in up to 8.8% and 13% for AST and ALT, respectively, of patients receiving tinzaparin sodium for the treatment of DVT. Similar increases in aminotransferase levels have also been observed in patients and healthy volunteers treated with heparin and other low molecular weight heparins. Such elevations are reversible and are rarely associated with increases in bilirubin.

Local Reactions

Mild local irritation, pain, hematoma, and ecchymosis may follow SC injection of tinzaparin. Injection site hematoma has been reported in approximately 16% of patients treated with tinzaparin.

Hypersensitivity

Anaphylactic/anaphylactoid reactions may occur in association with tinzaparin use.

Adverse Events

Adverse events with tinzaparin or heparin reported at a frequency of ≥1% in clinical trials with patients undergoing treatment for proximal DVT with or without PE, are provided in Table 5.

Other Adverse Events in Completed or Ongoing Trials

Other adverse events reported at a frequency of ≥1% in 4,000 patients who received tinzaparin in completed or ongoing clinical trials are listed by body system:

• Body as a Whole: injection site hematoma, reaction unclassified.

• Cardiovascular: hypotension, hypertension, tachycardia, angina pectoris.

• Central and Peripheral Nervous System: dizziness.

• Gastrointestinal: flatulence, gastrointestinal disorder (not otherwise specified), dyspepsia.

• Platelet, Bleeding and Clotting Disorders: hematoma, thrombocytopenia.

• Psychiatric: insomnia, confusion.

• Red Blood Cell Disorders: anemia.

• Resistance Mechanism Disorders: healing impaired, infection.

• Respiratory System: pneumonia, respiratory disorder.

• Dermatology: rash erythematous, pruritus, bullous eruption, skin disorder.

• Urinary System: urinary retention, dysuria.

• Vascular (Extracardiac) Disorders: thrombophlebitis.

Postmarketing Experience

Drug Interactions

• Because of increased risk of bleeding, tinzaparin should be used with caution in patients receiving oral anticoagulants, platelet inhibitors (e.g., salicylates, dipyridamole, sulfinpyrazone, dextran, NSAIDs including ketorolac tromethamine, ticlopidine, and clopidogrel), and thrombolytics.
• If coadministration is essential, close clinical and laboratory monitoring of these patients is advised

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): B All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of tinzaparin to increase the risk of developmental abnormalities above background risk.

Fetal Risk Summary

Tinzaparin is not predicted to increase the risk of developmental abnormalities. Tinzaparin does not cross the placenta, based on human and animal studies, and shows no evidence of teratogenic effects or fetotoxicity.

Clinical Considerations

Pregnancy alone confers an increased risk for thromboembolism that is even higher for women with preexisting thromboembolic disease, certain high risk pregnancy conditions, and a history of complications during a previous pregnancy. All patients receiving anticoagulants such as tinzaparin, including pregnant women, are at risk for bleeding. Pregnant women receiving tinzaparin should be carefully monitored for evidence of bleeding or excessive anticoagulation. Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women should be apprised of the potential hazard to the fetus and the mother if tinzaparin is administered during pregnancy. Consideration for use of a shorter acting agent should be specifically addressed as delivery approaches.

Data

Human Data

Fifty-four women pregnant or planning to become pregnant with conditions requiring anticoagulation received tinzaparin in an open-label, prospective, pregnancy dose finding study. Patients received 50 to 175 IU/kg/day, with dosing starting as early as prior to conception or as late as 32 weeks gestation. Duration of exposure ranged from 3 to 463 days (median 159 days). From 55 pregnancies, there were 50 live births, 3 first trimester miscarriages, and 2 intrauterine deaths at 17 and 30 weeks. Approximately 6% of pregnancies were complicated by fetal distress. Approximately 10% of pregnant women receiving tinzaparin experienced significant vaginal bleeding. A cause and effect relationship for the above observations has not been established.

Animal Data

Teratogenicity studies have been performed in rats at SC doses up to 1800 IU/kg/day (about 2 times the maximum recommended human dose based on body surface area) and in rabbits at SC doses up to 1900 IU/kg/day (about 4 times the maximum recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to tinzaparin sodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. tinzaparin does not cross the placenta.

Cases of "Gasping Syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99 - 404 mg/kg/day). The 2 mL vial of tinzaparin contains 20 mg of benzyl alcohol (10 mg of benzyl alcohol per mL). If tinzaparin 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.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tinzaparin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Tinzaparin during labor and delivery.

Nursing Mothers

In studies where tinzaparin sodium was administered subcutaneously to lactating rats, very low levels of tinzaparin sodium were found in breast milk. It is not known whether tinzaparin sodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tinzaparin is administered to nursing women.

Pediatric Use

Safety and effectiveness of tinzaparin sodium in pediatric patients have not been established.

Geriatic Use

tinzaparin may increase the risk for death, compared to UFH, when administered to elderly patients with renal insufficiency. In the clinical studies for the treatment of DVT described in the clinical studies section, 58% of patients were 65 or older and 29% were 75 and over. In these studies, no significant overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Gender

There is no FDA guidance on the use of Tinzaparin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Tinzaparin with respect to specific racial populations.

Renal Impairment

Population Pharmacokinetics

In patients being treated with tinzaparin sodium (175 IU/kg) for DVT, a population pharmacokinetic (PK) analysis determined that tinzaparin sodium clearance based on anti-Xa activity was related to creatinine clearance calculated by the Cockroft Gault equation. In this PK analysis, a reduction in tinzaparin sodium clearance in moderate (30-50 mL/min) and severe (<30 mL/min) renal impairment was observed. Patients with severe renal impairment exhibited a 24% reduction in tinzaparin sodium clearance relative to patients with normal renal function (>80 mL/min).

Hemodialysis Studies

In a study of 12 chronic renal failure patients undergoing hemodialysis, anti-Xa clearance was reduced 28%, consistent with estimates from the population PK analyses. In another study of 6 patients undergoing hemodialysis, the half-life of anti-Xa activity following a single IV dose of 75 IU/kg of tinzaparin sodium on an off-dialysis day was prolonged relative to that for healthy volunteers (5.2 versus 1.6 hours).

Tinzaparin may increase the risk for death, compared to unfractionated heparin (UFH), when administered to elderly patients with renal insufficiency.

Hepatic Impairment

No prospective studies have assessed tinzaparin sodium pharmacokinetics or pharmacodynamics in hepatically-impaired patients. However, the hepatic route is not a major route of elimination of low molecular weight heparins.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Tinzaparin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Tinzaparin in patients who are immunocompromised.

Obesity

Based on the results of a prospective clinical study and the population PK analyses, weight-based dosing is appropriate for heavy/obese patients. Tinzaparin sodium PK parameters based on anti-Xa activity are independent of body weight and body mass index (BMI) when tinzaparin sodium is dosed on a weight basis at 175 IU/kg or 75 IU/kg. In a prospective study of heavy/obese subjects (101 to 165 kg; BMI 26‑61 kg/m2), anti-Xa activity time profiles were similar to those in normal-weight volunteer studies. Data at the 175 IU/kg dose are shown in Figure 2. Clinical trial experience is limited in patients with a BMI >40 kg/m2.

Figure 2 Mean and Standard Deviation of Anti-Xa Activity Following a Single SC Administration of 175 IU/kg Tinzaparin Sodium to Obese Subjects and Normal-Weight Volunteers

Administration and Monitoring

Administration

Tinzaparin is a clear, colorless to slightly yellow solution, and as with other parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Tinzaparin is administered by SC injection. It must not be administered by intramuscular or intravenous injection.

Subcutaneous Injection Technique

Patients should be lying down (supine) or sitting and tinzaparin administered by deep SC injection. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. The injection site should be varied daily. The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold should be held throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection.

Monitoring

Periodic complete blood counts including platelet count and hematocrit or hemoglobin, and stool tests for occult blood are recommended during treatment with tinzaparin. 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 tinzaparin activity and, therefore, are unsuitable for monitoring.

IV Compatibility

There is limited information regarding the compatibility of Tinzaparin and IV administrations.

Overdosage

Accidental overdosage of tinzaparin may lead to bleeding complications. Nosebleeds, blood in urine or tarry stools may be noted as the first signs of bleeding. Easy bruising or petechial hemorrhages may precede frank bleeding. In case of minor bleeding, the patient should be monitored for signs of more severe bleeding.

Of patients known to have received an overdose of tinzaparin sodium in clinical trials, defined as one or more doses >200 IU/kg for the treatment of DVT or >100 IU/kg for the prevention of DVT, approximately 16% experienced a bleeding complication.

Of spontaneous reports of probable overdosing with tinzaparin sodium, approximately 81% were accompanied by bleeding, usually hematoma. Most patients who have bleeding complications while receiving tinzaparin can be controlled by discontinuing tinzaparin, applying pressure to the site, if possible, and replacing volume and hemostatic blood elements (e.g., red blood cells, fresh frozen plasma, platelets) as required. In the event that this is ineffective, protamine sulfate can be administered.

In cases of serious bleeding or large overdose, protamine sulfate (1% solution) can be given by slow IV infusion at a dose of 1 mg protamine for every 100 anti-Xa IU of tinzaparin given. A second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU of tinzaparin may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged. Even with the additional dose of protamine, the aPTT may remain more prolonged than would usually be found following administration of protamine to reverse unfractionated heparin. Protamine does not completely neutralize tinzaparin sodium anti-Xa activity (maximum about 60%).

Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions have been reported with protamine sulfate, it should be given only when resuscitation facilities are readily available. For additional information consult the labeling of Protamine Sulfate Injection, USP, products.

Single SC doses of tinzaparin sodium at 22,000 and 7,700 IU/kg (about 10 and 7 times the maximum recommended human dose, respectively, based upon body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity included hematoma formation and bleeding at the injection site, anemia, decreased motor activity, unsteady gait, piloerection, and ptosis.

Pharmacology

There is limited information regarding Tinzaparin Pharmacology in the drug label.

Mechanism of Action

Tinzaparin sodium is a low molecular weight heparin with antithrombotic properties. Tinzaparin sodium inhibits reactions that lead to the clotting of blood including the formation of fibrin clots, both in vitro and in vivo. It acts as a potent co-inhibitor of several activated coagulation factors, especially Factor Xa and IIa (thrombin). The primary inhibitory activity is mediated through the plasma protease inhibitor, antithrombin.

Bleeding time is usually unaffected by tinzaparin sodium. Activated partial thromboplastin time (aPTT) is prolonged by therapeutic doses of tinzaparin sodium used in the treatment of deep vein thrombosis (DVT). Prothrombin time (PT) may be slightly prolonged with tinzaparin sodium treatment but usually remains within the normal range. Neither aPTT nor PT can be used for therapeutic monitoring of tinzaparin sodium.

Neither unfractionated heparin nor tinzaparin sodium have intrinsic fibrinolytic activity; therefore, they do not lyse existing clots. Tinzaparin sodium induces release of tissue factor pathway inhibitor, which may contribute to the antithrombotic effect. Heparin is also known to have a variety of actions that are independent of its anticoagulant effects. These include interactions with endothelial cell growth factors, inhibition of smooth muscle cell proliferation, activation of lipoprotein lipase, suppression of aldosterone secretion, and induction of platelet aggregation.

Structure

Tinzaparin sodium is the sodium salt of a low molecular weight heparin obtained by controlled enzymatic depolymerization of heparin from porcine intestinal mucosa using heparinase from Flavobacterium heparinum. The majority of the components have a 2-O-sulpho-4-enepyranosuronic acid structure at the non-reducing end and a 2-N,6-O-disulpho-D-glucosamine structure at the reducing end of the chain.

Potency is determined by means of a biological assay and interpreted by the first International Low Molecular Weight Heparin Standard as units of anti-factor Xa (anti-Xa) activity per milligram. The mean tinzaparin sodium anti-factor Xa activity is approximately 100 IU per milligram. The average molecular weight ranges between 5,500 and 7,500 daltons. The molecular weight distribution is:

Pharmacodynamics

Anti-Xa and anti-IIa activities are the primary biomarkers for assessing tinzaparin sodium exposure because plasma concentrations of low molecular weight heparins cannot be measured directly. Because of analytical assay limitations, anti-Xa activity is the more widely used biomarker. The measurements of anti-Xa and anti-IIa activities in plasma serve as surrogates for the concentrations of molecules which contain the high-affinity binding site for antithrombin (anti-Xa and anti-IIa activities). Monitoring patients based on anti-Xa activity is generally not advised.

Studies with tinzaparin sodium in healthy volunteers and patients have been conducted with both fixed- and weight-adjusted dose administration. Recommended therapy with tinzaparin sodium is based on weight-adjusted dosing

Figure 1. Mean and Standard Deviation of Anti-Xa Activity Following SC Administration of a Single 4,500 IU* dose and Once Daily Multiple SC Dose of 175 IU/kg Tinzaparin Sodium to Healthy Volunteers

Pharmacokinetics

Absorption

Plasma levels of anti-Xa activity increase in the first 2 to 3 hours following SC injection of tinzaparin sodium and reach a maximum within 4 to 5 hours. Maximum concentrations (Cmax) of 0.25 and 0.87 IU/mL are achieved following a single SC fixed dose of 4,500 IU (approximately 64.3 IU/kg) and weight-adjusted dose of 175 IU/kg of tinzaparin sodium, respectively. Based on the extent of absorption (AUC0‑∞), a comparison of 4,500 IU and 12,250 IU single doses indicates that increases in anti-Xa activity are greater than dose proportional relative to the increase in dose. Following a single SC injection of tinzaparin sodium, the mean anti-Xa to anti-IIa activity ratio, based on the area under the anti-Xa and anti-IIa time profiles, is 2.8 and is higher than that of unfractionated heparin (approximately 1.2). The absolute bioavailability (following 4,500 IU SC and intravenous [IV] administrations) is 86.7% based on anti-Xa activity.

Distribution

The volume of distribution of tinzaparin sodium ranges from 3.1 L to 5.0 L. These values are similar in magnitude to blood volume, suggesting that the distribution of anti-Xa activity is limited to the central compartment.

Metabolism

Low molecular weight heparins are partially metabolized by desulphation and depolymerization.

Elimination

In healthy volunteers, the elimination half-life following SC administration of 4,500 IU or 175 IU/kg tinzaparin sodium is approximately 3-4 hours based on anti-Xa activity. Clearance following IV administration of 4,500 IU tinzaparin sodium is approximately 1.7 L/hr. The primary route of elimination is renal. Anti-Xa activity did not accumulate with once daily dosing of 175 IU/kg for five days in healthy volunteers.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of tinzaparin sodium. Tinzaparin sodium displayed no genotoxic potential in an in vitro bacterial cell mutation assay (AMES test), in vitro Chinese hamster ovary cell forward gene mutation test, in vitro human lymphocyte chromosomal aberration assay, and in vivo mouse micronucleus assay. Tinzaparin sodium at SC doses up to 1800 IU/kg/day in rats (about 2 times the maximum recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance.

Clinical Studies

Treatment of Acute Deep Vein Thrombosis (DVT) With or Without Pulmonary Embolism (PE)

In a randomized, multicenter, double-blind trial tinzaparin (tinzaparin sodium injection) was compared to unfractionated heparin in 435 hospitalized patients with symptomatic, proximal DVT. Six percent of the enrolled patients had symptomatic pulmonary embolism confirmed by segmental or greater lung scan defect. The study patients ranged in age from 19 to 92 years (mean 61 ± 17 years), 55% were male, 88% were white and 8% black. Patients received either tinzaparin SC once daily according to body weight (175 IU/kg) and a placebo IV bolus followed by continuous placebo IV infusion, or unfractionated heparin as an initial IV bolus dose (5,000 IU) followed by continuous IV infusion of unfractionated heparin with the rate adjusted according to the aPTT (1.5 to 2.5 times control value) and a once daily SC placebo injection. Treatment continued for approximately 6 days, and both treatment groups also received oral warfarin sodium starting on Day 2 which continued to Day 90 with doses titrated to a target INR of 2.0 to 3.0.

The 90-day cumulative thromboembolic (TE) rate [recurrent DVT or PE] with tinzaparin was not significantly different than the rate with unfractionated heparin. The data are provided in Table 3.

Mortality with tinzaparin was 4.6% (10 patients) and with heparin 9.6% (21 patients). The 95% confidence interval (CI) for the mortality difference was 0.16%, 9.76%.

In a multicenter, open-label, randomized clinical trial tinzaparin was compared to unfractionated heparin as initial treatment for hospitalized patients with symptomatic PE not requiring thrombolytic therapy, embolectomy, or vena cava interruption. Patients were excluded if they carried an unusually high risk for thromboembolic and/or bleeding events or other complications. Of the 608 patients treated, 422 had documented DVT. Prior to determination of study eligibility and randomization, patients were allowed to receive unfractionated heparin; 78% of the patients received unfractionated heparin at therapeutic doses for up to 24 hours, and an additional 4% received heparin at therapeutic doses for greater than 24 hours. After randomization, tinzaparin was administered SC once daily, 175 IU/kg body weight; heparin as an initial IV bolus (50 IU/kg) followed by continuous IV infusion with the rate adjusted according to the aPTT (2 to 3 times control value). For both groups, treatment continued for approximately 8 days. All patients also received oral anticoagulant treatment starting in the first 3 days which continued to Day 90.

Thromboembolic events were infrequent for both treatment groups. No difference was observed between the two treatment groups for incidence of recurrence of thromboembolic events.

How Supplied

tinzaparin is available in a multiple dose 2 mL vial in the following packages:

• Box of 1: 2 mL vial (20,000 anti-Xa IU per mL); NDC 50222-342-08
• Box of 10: 2 mL vials (20,000 anti-Xa IU per mL); NDC 50222-342-53

Storage

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

Images

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of tinzaparin in the drug label.

Precautions with Alcohol

Alcohol-Tinzaparin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Innohep®

Look-Alike Drug Names

There is limited information regarding Tinzaparin Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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