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 Factors 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
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. The data are provided in Figure 1 and Table 2 below.
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 (see DOSAGE
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
*Dosing based on single dose of 4,500 IU. Mean dose administered was 64.3 IU/kg.
Table 2 : Summary of Pharmacokinetic Parameters (Mean and
Standard Deviation) Based on Anti-Xa Activity Following Single and Once Daily
Multiple Dose SC Administration of Tinzaparin Sodium to Healthy Volunteers
||Single Dose (N=23)
||Multiple Dose (N=14)
|*Dosing based on single dose of 4,500 IU.
Mean dose administered was 64.3 IU/kg.
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.
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.
Low molecular weight heparins are partially metabolized by desulphation and
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. (See Figure 1 and Table 2.)
Anti-Xa concentrations from approximately 180 patients receiving SC tinzaparin
sodium once daily (175 IU/kg body weight) as the treatment of proximal DVT and
approximately 240 patients undergoing elective hip replacement surgery receiving
SC tinzaparin sodium once daily (~65 IU/kg body weight) were analyzed by population
pharmacokinetic methods. The results indicate that neither age nor gender significantly
alter tinzaparin sodium clearance based on anti-Xa activity (see PRECAUTIONS,
General). However, a reduction in tinzaparin sodium clearance was observed
in patients with impaired renal function (reduced calculated creatinine clearance)
(see Special Populations, Renal Impairment). Weight is also an important
factor for the prediction of tinzaparin sodium clearance, consistent with the
recommendation that INNOHEP® (tinzaparin) therapy be based on weight-adjusted dosing
(see DOSAGE AND ADMINISTRATION).
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 Cockcroft
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).
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).
INNOHEP (tinzaparin) ® may increase the risk for death, compared to unfractionated heparin
(UFH), when administered to elderly patients with renal insufficiency (see WARNINGS and PRECAUTIONS).
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 (see WARNINGS,
In a controlled clinical study of elderly patients with renal insufficiency,
more patients died after INNOHEP (tinzaparin) ® therapy, compared to patients who received
therapy with UFH (see WARNINGS and PRECAUTIONS).
Since renal function declines with age, elimination of tinzaparin sodium may
be reduced in elderly patients. In a prospective study of 30 elderly patients
[6 men, 24 women; aged 87.0±5.9 years; mean body weight 62.7±14.6
kg; creatinine clearance 40.6±15.3 mL/min (range 20-72)] treated with
tinzaparin sodium 175 IU/kg once daily for ten days for acute venous thromboembolism,
there was no accumulation of anti-Xa activity based on peak anti-Xa activity
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
The disposition of INNOHEP® (tinzaparin) was studied in 54 pregnant patients in any
trimester. In this open-label, prospective, dose finding study, those treated
with an INNOHEP® (tinzaparin) dose of 175 IU/kg had similar 24-hour anti-Xa curves at
28 (n=17) and 36 (n=20) weeks gestation. The 175 IU/kg dose resulted in a mean
anti-Xa level of 0.3 to 1.0 IU/mL 4 hours after administration. Mean anti-Xa
levels 4 hours post dose suggest that as pregnancy advances there is no clinically
significant decrease in anti-Xa levels. Pregnancy has little or no influence
on the pharmacokinetics of INNOHEP® (tinzaparin) and no dosing adjustment is needed for
pregnancy. (See DOSAGE AND ADMINISTRATION.)
Treatment of Acute Deep Vein Thrombosis (DVT) With or Without Pulmonary Embolism
In a randomized, multicenter, double-blind trial INNOHEP® (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 INNOHEP® (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
The 90-day cumulative thromboembolic (TE) rate [recurrent DVT or PE] with INNOHEP® (tinzaparin)
was not significantly different than the rate with unfractionated heparin. The
data are provided in Table 3.
Table 3 : Efficacy of Once Daily INNOHEP® (tinzaparin) in the Treatment
of Acute Deep Vein Thrombosis
|Treatment of Acute DVT
||INNOHEP (tinzaparin) 1® 175 IU/kg
|Heparin1 5,000 IU Bolus
then aPTT Adjusted
|Intent to Treat Population2
|Patient Outcome at 90 Days
| Total TE3 Events
|1 Patients were also treated with warfarin
sodium commencing within 24-48 hours of tinzaparin sodium or standard
2 All randomized patients who received at least one dose of active study
3 TE = thromboembolic events (DVT and/or PE).
4 The 95% Confidence Interval (CI) for the total TE event rate difference
(4.0%) was 0.07%, 8.07%.
Mortality with INNOHEP® (tinzaparin) was 4.6% (10 patients) and with heparin 9.6% (21
patients). The 95% confidence interval (CI) for the mortality difference was
In a multicenter, open-label, randomized clinical trial INNOHEP® (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, INNOHEP® (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