Innohep

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Also seek emergency medical attention if you have symptoms of a spinal blood clot: back pain, numbness or muscle weakness in your lower body, or loss of bladder or bowel control.

Stop using tinzaparin and call your doctor at once if you have:

• unusual bleeding (nose, mouth, vagina, or rectum), bleeding from wounds or needle injections, any bleeding that will not stop;
• easy bruising, purple or red pinpoint spots under your skin;
• pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;
• black or bloody stools, coughing up blood or vomit that looks like coffee grounds;
• sudden weakness, severe headache, confusion, or problems with speech, vision, or balance;
• chest pain; or
• pain or burning when you urinate.

Common side effects may include:

• mild headache;
• fever;
• pain;
• nausea, vomiting, stomach pain, indigestion; or
• diarrhea, constipation.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

INNOHEP® is a sterile solution, containing tinzaparin sodium, a low molecular weight heparin. It is available in a multiple dose 2 mL vial.

Each 2 mL vial contains 20,000 anti-Factor Xa IU (anti-Xa) of tinzaparin sodium per mL, for a total of 40,000 IU, and 3.1 mg/mL sodium metabisulfite as a stabilizer. The vial contains 10 mg/mL benzyl alcohol as a preservative. Sodium hydroxide may be added to achieve a pH range of 5.0 to 7.5.

Table 1 Composition of 20,000 anti-Xa IU/mL INNOHEP® (tinzaparin sodium injection)

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:

< 2,000 Daltons < 10%
2,000 to 8,000 Daltons 60% to 72%
> 8,000 Daltons 22% to 36%

Structural Formula:

INNOHEP® (tinzaparin) is indicated for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered in conjunction with warfarin sodium. The safety and effectiveness of INNOHEP® (tinzaparin) were established in hospitalized patients.

Innohep is a prescription medication used with warfarin to treat a condition known as deep vein thrombosis (DVT) with or without a pulmonary embolism. 

Innohep belongs to a group of drugs called low molecular weight heparins or "blood thinners". These work by blocking the function of enzymes involved in making blood clots. 

This medication comes in an injectable form to be given directly under the skin (subcutaneously) by a heathcare professional and is typically injected once daily for at least 6 days. 

Common side effects of Innohep include bleeding, pain at the injection site, and upset stomach.

Innohep can also cause dizziness. Do not drive or operate heavy machinery until you know how Innohep affects you.

Serious side effects have been reported with Innohep. See the "Innohep Precautions" section.

The most common side effect of Innohep is bleeding. 

This is not a complete list of Innohep side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tinzaparin is an anticoagulant that helps prevent the formation of blood clots.

Tinzaparin is used together with warfarin (Coumadin) to treat a type of blood clot called deep vein thrombosis (DVT), which can lead to blood clots in the lungs (pulmonary embolism).

Tinzaparin may also be used for purposes not listed in this medication guide.

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 aggregation.

Pharmacokinetics/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. 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 AND ADMINISTRATION).

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

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. (See Figure 1 and Table 2.)

Population Pharmacokinetics

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® therapy be based on weight-adjusted dosing (see DOSAGE AND ADMINISTRATION).

Renal Impairment

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).

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® may increase the risk for death, compared to unfractionated heparin (UFH), when administered to elderly patients with renal insufficiency (see WARNINGS and PRECAUTIONS).

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 (see WARNINGS, Hemorrhage).

Elderly

In a controlled clinical study of elderly patients with renal insufficiency, more patients died after Innohep® 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 levels.

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

Pregnancy

The disposition of Innohep® was studied in 54 pregnant patients in any trimester. In this open-label, prospective, dose finding study, those treated with an Innohep® 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® and no dosing adjustment is needed for pregnancy. (See Dosage And Administration.)

Bleeding: Bleeding is the most common adverse event associated with Innohep® (tinzaparin sodium injection); 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 (see WARNINGS, Hemorrhage).

Thrombocytopenia: In clinical studies thrombocytopenia was identified in 1% of patients treated with Innohep®. Severe thrombocytopenia (platelet count <50,000/mm3) occurred in 0.13% (see WARNINGS, Thrombocytopenia).

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 (see PRECAUTIONS, Laboratory Tests).

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

Hypersensitivity: Anaphylactic/anaphylactoid reactions may occur in association with Innohep® use (see CONTRAINDICATIONS and WARNINGS).

Adverse Events: Adverse events with Innohep® 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 Innohep® in completed or ongoing clinical trials are listed by body system:

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

Cardiovascular Disorders, General: hypotension, hypertension.

Central and Peripheral Nervous System Disorders: dizziness.

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

Heart Rate and Rhythm Disorders: tachycardia.

Myo-, Endo-, Pericardial and Valve Disorders: angina pectoris.

Platelet, Bleeding and Clotting Disorders: hematoma, thrombocytopenia.

Psychiatric Disorders: insomnia, confusion.

Red Blood Cell Disorders: anemia.

Resistance Mechanism Disorders: healing impaired, infection.

Respiratory System Disorders: pneumonia, respiratory disorder.

Skin and Appendages Disorders: rash erythematous, pruritus, bullous eruption, skin disorder.

Urinary System Disorders: urinary retention, dysuria.

Vascular (Extracardiac) Disorders: thrombophlebitis deep, thrombophlebitis leg deep.

Serious adverse events reported in clinical trials or from post-marketing experience are included in Tables 6 and 7, respectively:

Ongoing Safety Surveillance: When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis (see boxed WARNING).

Spinal epidural hematoma in association with neuraxial anesthesia or spinal puncture with Innohep® has been reported.

Spinal epidural hematoma with Innohep® administered at a therapeutic dose has been reported in at least one patient who had not received neuraxial anesthesia or spinal puncture.

All patients should be evaluated for bleeding disorders before administration of Innohep®. Since coagulation parameters are unsuitable for monitoring Innohep® activity, routine monitoring of coagulation parameters is not required (see PRECAUTIONS, Laboratory Tests).

Adult Dosage

The recommended dose of Innohep® for the treatment of DVT with or without PE is 175 anti-Xa IU/kg of body weight, administered SC once daily for at least 6 days and until the patient is adequately anticoagulated with warfarin (INR at least 2.0 for two consecutive days). Warfarin sodium therapy should be initiated when appropriate (usually within 1-3 days of Innohep® initiation). Pregnancy has little or no influence on the pharmacokinetics of Innohep® and no dosing adjustment is needed for pregnancy.

As Innohep® may theoretically affect the PT/INR, patients receiving both Innohep® and warfarin should have blood for PT/INR determination drawn just prior to the next scheduled dose of Innohep®.

Table 8 provides Innohep® doses for the treatment of DVT with or without PE. It is necessary to calculate the appropriate Innohep® dose for patient weights not displayed in Table 8.

An appropriately calibrated syringe should be used to assure withdrawal of the correct volume of drug from Innohep® vials.

To calculate the volume (mL) of an Innohep® 175 anti-Xa IU per kg SC dose for treatment of deep vein thrombosis:

Administration

Innohep® 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.

Innohep® 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 Innohep® 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.

Very low levels of tinzaparin have been reported in the breast milk of lactating animals.

There are no data on the excretion of tinzaparin into human milk. The manufacturer recommends that caution be used when administering tinzaparin to nursing women.

Summary of Use during Lactation

Although tinzaparin has not been studied, other low molecular weight heparins (e.g., dalteparin, enoxaparin) are not excreted into breastmilk in clinically relevant amounts. Because there is no published experience with tinzaparin during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

Drug Levels

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

References