Tinzaparin (Systemic)


VA CLASSIFICATION
Primary: BL111

Commonly used brand name(s): Innohep.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anticoagulant—

antithrombotic—
Note: Tinzaparin is one of a group of substances known as low molecular weight heparins (LMWHs).



Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

[Thromboembolism, (prophylaxis)]——Tinzaparin is indicated for the prevention of postoperative venous thromboembolism in patients undergoing orthopedic surgery and in patients undergoing general surgery who are at high risk of developing postoperative venous thromboembolism {02}.

Thromboembolism, pulmonary (treatment adjunct); and1
Thrombosis, deep venous (treatment adjunct)1——Tinzaparin is indicated for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered in conjunction with warfarin sodium {01}.

[Thromboembolism, pulmonary (treatment); and]
[Thrombosis, deep venous (treatment)]——Tinzaparin is indicated for the treatment of deep vein thrombosis and pulmonary embolism {02}

[Thrombosis of the extracorporeal system during hemodialysis (prophylaxis)]——Tinzaparin is indicated for the prevention of clotting in indwelling intravenous lines for hemodialysis and extracorporeal circulation in patients without high bleeding risk {02}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Tinzaparin is obtained by enzymatic depolymerization of unfractionated heparin from porcine intestinal mucosa using heparinase from Flavobacterium heparinum{01}{02}.
Molecular weight—
    Averages between 5500 and 7500 daltons {01}{02}


pH
    5.0 to 7.5 {03}{04}

Mechanism of action/Effect:

Tinzaparin's antithrombotic properties are achieved by enhancing the inhibition of coagulation factor Xa and thrombin (factor IIa) by binding to the plasma protease inhibitor, antithrombin III (ATIII). However, other mechanisms may also be involved since tinzaparin potentiates the inhibition of several activated coagulation factors{01}{02}.

Tinzaparin has high anti-Xa activity, but a relatively low inhibitory effect on factor IIa activity compared to unfractionated heparin. The ratio of anti-Xa to anti-IIa activity for tinzaparin is 2 ± 0.5, whereas it is 1 for unfractionated heparin. The higher ratio of anti-Xa to anti-IIa has the potential of providing equivalent antithrombotic effect with reduced hemorrhagic complications{02}.

Bleeding time is usually unaffected by tinzaparin. Activated partial thromboplastin time (aPTT) occasionally may be prolonged by therapeutic doses of tinzaparin.{05} Prothrombin time (PT) may be slightly prolonged with tinzaparin, but usually remains within the normal range. However, neither aPTT nor PT can be used for therapeutic monitoring of tinzaparin {01}.


Other actions/effects:

Tinzaparin does not have intrinsic fibrinolytic activity; therefore it does not lyse existing clots {01}. Tinzaparin induces release of tissue factor pathway inhibitor, which may contribute to the antithrombotic effect{01}.

Absorption:

Based on anti-Xa activity, absolute bioavailability is 86.7% following subcutaneous injection {01}. Based on anti-IIa activity, bioavailability following subcutaneous injection is 67% {02}.

Distribution:

Volume of distribution (Vol D)—3.1 L to 5.0 L {01}.

VolD of anti-Xa activity is 4 L {02}.

VolD of anti-IIa activity is 10.9 L {02}.

Tinzaparin does not appear to cross the placenta {02}.

Biotransformation:

Low molecular weight heparins are partially metabolized by desulphation and depolymerization {01}.

Half-life:

Absorption—   • Anti-Xa activity—200 minutes {02}.
   • Anti-IIa activity—257 minutes {02}.


Elimination— approximately 3 to 4 hours following subcutaneous injection, based on anti-Xa activity {01}.
   • Anti-Xa activity—82 minutes {04}
   • Anti-IIa activity—71 minutes {04}

The elimination half-life of anti-Xa activity for low molecular weight heparins (including tinzaparin) is prolonged in patients with impaired renal function relative to people with normal function {01}{02}.

Onset of action:

Plasma levels of anti-Xa activity increase in the first 2 to 3 hours following subcutaneous injection {01}.

Time to peak concentration:

Peak plasma anti-Xa activity occurs approximately 4 to 6 hours following subcutaneous injection {01}{02}.

Peak plasma concentration:

Plasma anti-Xa activity can be measured as an indication of serum tinzaparin levels; however, clinical trials have not demonstrated a linear correlation between anti-Xa activity and antithrombotic effect {02}.

Following single subcutaneous doses of 4500 International Units (IU) (approximately 64.3 IU/kg) and 175 IU/kg, peak concentrations of plasma anti-Xa activity were 0.25 and 0.87 IU/mL, respectively {01}.



Dose (anti-Xa IU)   Peak Plasma Anti-Xa Activity (Units/mL)  Peak Plasma Anti-IIa Activity (Units/mL) 
2500  0.12  0.02 
5000  0.28  0.03 
10000  0.54  0.08 
{02}

Time to peak effect:

Peak plasma anti-Xa activity occurs approximately 4 to 6 hours following subcutaneous injection {01}{02}.

Duration of action:

Detectable anti-Xa activity persists for 24 hours after subcutaneous injection {02}.

Elimination:
    The primary route of elimination is renal {01}.
    Hepatic elimination is not involved {02}.
    Clearance following intravenous administration of 4500 IU tinzaparin is approximately 1.7 L/hr {01}.
    Neither age nor gender significantly alter tinzaparin clearance based on anti-Xa activity; however, weight is an important factor for the prediction of tinzaparin clearance{01}.
    In patients receiving tinzaparin (175 IU/kg), clearance based on anti-Xa activity was related to creatinine clearance (calculated by Cockroft Gault equation). In patients with moderate (30 to 50 mL/min) and severe renal impairment (<30 mL/min), tinzaparin clearance was reduced. Patients with severe renal impairment exhibited a 24% reduction in tinzaparin clearance {01}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients with known hypersensitivity to heparin, low molecular weight (LMW) heparins, sulfites, benzyl alcohol, or to pork products may be sensitive to tinzaparin also {01}{04}.

Carcinogenicity

No long-term animal studies have been performed with tinzaparin to determine its carcinogenic potential {01}{02}.

Mutagenicity

Tinzaparin was not mutagenic in the in vitro Ames test, the in vitro chinese hamster ovary cell forward gene mutation test, the in vitro human lymphocyte chromosomal aberration test, and the in vivomouse micronucleus test {01}{02}.

Pregnancy/Reproduction
Fertility—
In rats, subcutaneous doses up to 1800 International Units per kg of body weight per day (IU/kg/day) (about 2 times the maximum recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance {01}{02}.

Pregnancy—
Tinzaparin does not appear to cross the placenta {02}.

Adequate and well-controlled studies in humans have not been done {01}{02}.

There have been cases of cleft palate, optic nerve hypoplasia, pulmonary hypoplasia, muscular hypotonia, trisomy 21 (Down's) syndrome, and cutis aplasia of the scalp reported in infants of women who received tinzaparin during pregnancy. However, a cause and effect relationship has not been established. In addition, there have been reports of fetal death/miscarriage in pregnant women receiving tinzaparin who had high risk pregnancies and/or a prior history of spontaneous abortion. Approximately 6% of pregnancies were complicated by fetal distress.{01}.{03}

Approximately 10% of pregnant women receiving tinzaparin experienced significant vaginal bleeding. A cause and effect relationship has not been established. {01}

Studies in pregnant rats and rabbits given subcutaneous doses of tinzaparin up to 1800 IU/kg/day (about 2 times the maximum recommended human dose based on body surface area) and 1900 IU/kg/day (about 4 times the maximum recommended human dose based on body surface area), respectively, showed no evidence of embryotoxic or teratogenic effects {01}{02}.

Tinzaparin should not be used to prevent thromboembolism in pregnant women with prosthetic heart valves. Safety, effectiveness or dosage in pregnant women with prosthetic heart valves can not be determined. {04}

FDA Pregnancy Category B {01}.

Note: The multi-dose vial contains 10 mg of benzyl alcohol per mL, which is not recommended for use during pregnancy since benzyl alcohol may cross the placenta. {01} {04}


Breast-feeding

It is not known whether tinzaparin is distributed into breast milk. {01} {02}Breast-feeding is not recommended for women receiving tinzaparin. {02}

In lactating rats, very low levels of tinzaparin were found in breast milk following subcutaneous administration {01}.

Pediatrics

No information is available on the relationship of age to the effects of tinzaparin in pediatric patients. Safety and efficacy have not been established. {01}{02}

Note: The multi-dose vial contains 10 mg of benzyl alcohol per mL, which is not recommended for use in neonates. {01} {04} Cases of “Gasping Syndrome” have occurred in premature infants when large amounts of benzyl alcohol have been administered (99-404 mg/kg/day). {03}



Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of tinzaparin in the elderly.

No increased bleeding tendency has been observed in the clinical studies with tinzaparin in elderly patients with normal kidney and liver function {02}. However, since renal function is known to decline with age, elderly patients may show reduced elimination of tinzaparin {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Spinal or epidural hematomas have occurred with concurrent use of LMWHs and spinal/epidural anesthesia, resulting in long-term or permanent paralysis. There may be an increased risk with the use of post-operative epidural catheters or with the concomitant use of NSAIDs, platelet aggregation inhibitors, or other drugs affecting coagulation. {02} {03} {04}

Anticoagulants, coumarin- or indandione-derivative, or
Platelet aggregation inhibitors (see Appendix II ) such as:
» Anti-inflammatory drugs, nonsteroidal (NSAIDs), including ketorolac, ticlopidine, and clopidogrel
» Aspirin
Dextran
Dipyridamole
Sulfinpyrazone    (increased risk of bleeding must be considered {01} {02} {03})


Thrombolytic agents, such as:
Alteplase (rt-PA)
Anistreplase (APSAC)
Streptokinase
Urokinase    (concurrent or sequential use may increase the risk of bleeding {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT])    (asymptomatic reversible increases in serum values may occur during tinzaparin therapy; the usefulness of these enzymes in the differential diagnosis of myocardial infarction, pulmonary embolism, or liver disease may, therefore, be decreased; similar increases in transaminase levels have also been observed in patients and healthy volunteers treated with heparin and other low molecular weight heparins {01}{02})

    (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; elevated levels are rarely associated with increases in bilirubin {01})

    (transaminase increases are dose-dependent and have been observed at doses as low as 50 IU/kg/day; no consistent irreversible liver damage has been observed; transaminase increases occurred after more than 3 days of treatment in clinical studies; normalization of transaminase levels can be expected within 2 to 4 weeks of the last dose of tinzaparin {02})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Cerebrovascular accidents, hemorrhagic or acute cerebral insults    (increased risk of bleeding {01} {02})


» Bleeding, major, active    (may be exacerbated {01}{02})


» Hypertension, severe, uncontrolled    (increased risk of cerebral hemorrhage {01}{02})


» Patients with prosthetic heart valves    (cases of thrombosis among patients treated with low molecular weight heparin; safety not established with tinzaparin {04})


Sensitivity to tinzaparin, low molecular weight (LMW) heparins, heparin, sulfites, benzyl alcohol, or pork products {04}
» Thrombocytopenia associated with positive in vitro tests for antiplatelet antibody in the presence of tinzaparin or
» Thrombocytopenia, tinzaparin- or heparin-induced, with disseminated thrombosis, history of or    (risk of recurrence; may result in complications of organ infarction with secondary organ dysfunction or limb ischemia and in some cases death {01} {02} {03})


Risk-benefit should be considered when the following medical problems exist
Any medical procedure or condition in which the risk of bleeding or hemorrhage is present, such as:
» Abortion, threatened{02}
» Anesthesia, epidural or spinal (risk of epidural or spinal hematoma, which can result in long-term or permanent paralysis; this risk is increased with the use of indwelling epidural catheters or by the concomitant use of medications that affect hemostasis, such as nonsteroidal anti-inflammatory drugs, platelet inhibitors, or other anticoagulants; the risk also may be increased by traumatic or repeated epidural or spinal puncture; see General Dosing Information for guidelines regarding the use of regional anesthesia in patients receiving perioperative tinzaparin {01} {04})
» Bleeding disorders, congenital or acquired (e.g., hemophilia) {01} {02}
» Endocarditis, bacterial, acute or subacute {01} {02}
» Hepatic function impairment, severe {01} {02}
» Platelet defects {01} {02}
» Renal function impairment, severe {01} {02}
» Retinopathy, diabetic, hypertensive or hemorrhagic{01} {02}
» Surgery, brain, ophthalmic, otic, or spinal, recent {01} {02}
» Ulcers, other lesions, or recent bleeding of the gastrointestinal tract, active {01} {02}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


Note: Routine anticoagulation tests such as prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin clotting time (TT) are relatively insensitive measures of tinzaparin's anticoagulant activity and, therefore, are unsuitable for monitoring. {01}{02} However, prolongation of aPTT can be used as a criteria of overdose. Dose increases aimed at prolonging aPTT to the same extent as with unfractionated heparin could cause overdose and bleeding. {02}

Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT])    (asymptomatic reversible increases in serum values may occur during tinzaparin therapy {01}{02})


» Anti-factor Xa activity    (plasma anti-Xa activity can be measured as an indication of serum tinzaparin levels; however, clinical trials have not demonstrated a linear correlation between anti-Xa activity and antithrombotic effect; {01}{02} patients receiving tinzaparin are at risk for major bleeding complications when plasma anti-Xa levels approach 2.0 IU/mL {02})


Blood counts, complete (CBC), including:
Hematocrit
Hemoglobin    (recommended periodically during therapy; an unexplained fall in hematocrit or hemoglobin may indicate a hemorrhagic event; some cases of hemorrhage have been reported to result in death or permanent disability {01} {03})


Blood pressure measurement    (recommended periodically during therapy; an unexplained drop in blood pressure may signal occult bleeding; some cases of hemorrhage have been reported to result in death or permanent disability {02}{03})


» Neurologic status     (monitor for signs and symptoms of neurological impairment such as paresthesias, leg weakness, sensory loss, motor deficit, or bowel/bladder dysfunction, which may indicate a potential epidural or spinal hematoma {01})


» Platelet aggregation test    (recommended prior to the initiation of therapy in patients who have congenital, or a history of drug-induced, thrombocytopenia or platelet defects; if the result is negative, tinzaparin therapy may be instituted, with daily monitoring of the platelet count; however, if the result is positive, tinzaparin should not be given {02})


» Platelet count    (recommended prior to the initiation of therapy, then twice weekly for the duration of therapy to detect occult bleeding or any degree of thrombocytopenia {02}{01})


Stool tests for occult blood    (recommended periodically during therapy {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hematoma at injection site {01}{02}{03}(deep, dark purple bruise, pain, or swelling at place of injection)

Incidence less frequent
    
Anemia {01}(pale skin; troubled breathing, exertional; unusual bleeding or bruising; unusual tiredness or weakness), thrombocytopenia {01}{02}(black, tarry stools; chest pain; chills; cough; fever ; painful or difficult urination; shortness of breath; sore throat; sores, ulcers, or white spots on lips or in mouth; swollen glands; unusual bleeding or bruising; unusual tiredness or weakness)
    
angina pectoris {01}(chest pain; chest tightness ; fast or irregular heartbeat; shortness of breath), hypertension {01}(blurred vision; dizziness; severe or continuing dull nervousness ; headache; pounding in the ears; slow or fast heartbeat), hypotension {01}( blurred vision; confusion; dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly ; sweating; unusual tiredness or weakness ), tachycardia {01}(fainting; fast, pounding, or irregular heartbeat or pulse; palpitations )
    
hematuria {01}( blood in urine; lower back pain; pain or burning while urinating), hemorrhage {01}{02}{03}(bleeding gums; coughing up blood; difficulty in breathing or swallowing ; dizziness; headache; increased menstrual flow or vaginal bleeding; nosebleeds ; paralysis; prolonged bleeding from cuts ; red or dark brown urine; red or black, tarry stools; shortness of breath; unexplained pain, swelling, or discomfort, especially in the chest, abdomen, joints, or muscles; unusual bruising; vomiting of blood or coffee ground–like material; weakness)
    
pulmonary embolism {01}(chest pain; cough; fainting; fast heartbeat; sudden shortness of breath or troubled breathing; dizziness or lightheadedness)
    
skin rash {01}{02}
    
urinary tract infection {01}(bladder pain; bloody or cloudy urine; difficult, burning, or painful urination; frequent urge to urinate; lower back or side pain )

Note: In addition to the symptoms listed for hemorrhage , the possibility of hemorrhage should be considered in evaluating the condition of any anticoagulated patient with complaints which do not indicate an obvious diagnosis. {03}


Incidence rare
    
Allergic reaction {01}{02}(fever ; skin rash, hives, or itching)
    
anaphylactoid reaction {01}{02}(cough; difficulty swallowing; dizziness; fast heartbeat; hives; itching; puffiness or swelling of the eyelids or around the eyes, face, lips or tongue; shortness of breath ; skin rash; tightness in chest; unusual tiredness or weakness; wheezing)
    
epidural or spinal hematoma {01}{02}(back pain; bowel/bladder dysfunction; leg weakness; numbness; paralysis; paresthesias)—back pain is not a typical presentation but some patients may experience this symptom{02}
    
skin necrosis {02}( blue-green to black skin discoloration; pain, redness, or sloughing of skin at place of injection)

Incidence not determined
—Observed during clinical practice, estimates of frequency can not be determined    
Abscess {03}(accumulation of pus; swollen, red, tender area of infection; fever)
    
acute febrile reaction {03}(chills or sudden fever; fatigue; headache; malaise; muscle cramps; excessive thirst; weakness)
    
agranulocytosis {03}(cough or hoarseness; fever with or without chills; general feeling of tiredness or weakness; lower back or side pain; painful or difficult urination; sore throat; sores, ulcers, or white spots on lips or in mouth; unusual bleeding or bruising)
    
allergic purpura {03}(raised red swellings on the skin, the buttocks, legs or ankles; large, flat, blue or purplish patches in the skin; painful knees and ankles; fever ; stomach pain; bloody or black, tarry stools ; blood in urine)
    
angioedema {03}(large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, sex organs)
    
cholestatic hepatitis {03}(abdominal or stomach pain; chills; clay-colored stools ; dark urine; diarrhea; dizziness; fever; headache; itching; loss of appetite; nausea; rash; unpleasant breath odor; unusual tiredness or weakness; vomiting of blood; yellow eyes or skin)
    
epidermal necrolysis {03}(redness, tenderness, itching, burning, or peeling of skin; red or irritated eyes; sore throat; fever; chills)
    
hemoptysis {03}( coughing or spitting up blood)
    
increased hepatic enzymes {03}(dark urine; light-colored stools; loss of appetite; nausea and vomiting; unusual tiredness; yellow eyes or skin; fever with or without chills; stomach pain)
    
ischemic necrosis or necrosis {03}(break in the skin, especially associated with blue-black discoloration, swelling, or drainage of fluid)
    
hematoma (collection of blood under the skin; dark, purple bruise; pain, redness, or swelling)
    
ocular hemorrhage {03}(red or bloodshot eye; change in vision; seeing floating spots before the eyes)
    
pancytopenia {03}(high fever; chills; unexplained bleeding or bruising; bloody, black, or tarry stools; pale skin; unusual tiredness or weakness; cough; shortness of breath; sores, ulcers, or white spots on lips or in mouth; swollen glands )
    
peripheral ischemia {03}(itching of skin; numbness and tingling of face, fingers, or toes; pain in arms legs, or lower back, especially pain in calves and/or heels upon exertion; pale, bluish-colored, or cold hands or feet ; weak or absent pulses in legs)
    
rectal bleeding {03}(black, tarry stools; blood in stools)
    
Steven-Johnson syndrome {03}(redness, tenderness, burning, blistering or peeling of skin (usually on the backs of arms and the fronts of legs, mouth, eyes or hands and feet); fever; chills; headache; unusual tiredness or weakness)
    
thrombocythemia {03}(pain, warmth, or burning in fingers, toes and legs; headache; dizziness; problems with vision or hearing)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Back pain {01}
    
headache {01}
    
confusion {01}
    
constipation {01}
    
dizziness {01}
    
insomnia ( trouble in sleeping){01}
    
nausea and vomiting {01}
    
pain at injection site {01}

Incidence rare
    
Priapism {01}(prolonged, painful, inappropriate erection of the penis)

Incidence not determined
—Observed during clinical practice, estimates of frequency can not be determined    
Urticaria {03}(hives or welts; itching; redness of skin; skin rash)





Overdose
For specific information on the agents used in the management of tinzaparin overdose, see the Protamine (Systemic) monograph.

For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Bleeding complications or hemorrhage {01}{02}(bleeding gums; coughing up blood; difficulty in breathing or swallowing; dizziness; headache; increased menstrual flow or vaginal bleeding ; nosebleeds; paralysis; prolonged bleeding from cuts; red or dark brown urine; red or black, tarry stools; shortness of breath ; unexplained pain, swelling, or discomfort, especially in the chest, abdomen, joints, or muscles; unusual bruising ; vomiting of blood or coffee ground–like material ; weakness)


Treatment of overdose


Specific treatment:
Specific treatment—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 {01}.

Administration of protamine, a heparin antagonist, may be required. One mg of protamine sulfate (1% solution) per 100 anti-factor Xa International Units (IU) of tinzaparin is given as a slow intravenous injection. If the activated partial thromboplastin time (aPTT) measured 2 to 4 hours after the first injection remains prolonged, a second injection of 0.5 mg protamine sulfate per 100 anti-factor Xa IU of tinzaparin may be administered. However, the aPTT may remain more prolonged with tinzaparin than with conventional heparin, despite the additional dosing of protamine. Protamine only partially neutralizes tinzaparin anti-Xa activity (approximately 60%) {01}{02}.

Protamine sulfate should be administered with great care to avoid an overdose. Severe hypotensive and anaphylactoid reactions, possibly fatal, may occur with protamine sulfate. In order to avoid these reactions the rate of administration of protamine should not exceed 20 mg/minute. Protamine should be administered only when resuscitation techniques and treatment of anaphylactic shock are readily available.{01}{02}.

See the package insert or Protamine (Systemic) for specific dosing guidelines for use of this product.



Monitoring:
Monitor platelet count and other coagulation parameters {02}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tinzaparin (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to tinzaparin, low molecular weight (LMW) heparins, heparin, sulfites, benzyl alcohol, or to pork products

Pregnancy—Multi-dose vials contain benzyl alcohol, which is not recommended for use during pregnancy since benzyl alcohol may cross the placenta

Not for use in pregnant women with prosthetic heart valves





Breast-feeding—Unknown if distributed into human breast milk; use is not recommended




Use in children——Multi-dose vials contain benzyl alcohol, which is not recommended for use in neonates

Other medications, especially platelet aggregation inhibitors, such as aspirin and nonsteroidal anti-inflammatory drugs including ketorolac,
Other medical problems, especially abortion, threatened; anesthesia, epidural or spinal; cerebrovascular accidents, hemorrhagic or acute cerebral insults; bleeding, major, active; bleeding disorders; endocarditis, bacterial, acute or subacute; hepatic function impairment; hypertension, severe, uncontrolled; patients with prosthetic heart valves; platelet defects; renal function impairment; retinopathy, diabetic, hypertensive or hemorrhagic; surgery, recent; thrombocytopenia; and ulcers, other lesions, or recent bleeding of the gastrointestinal tract

Proper use of this medication
» Proper injection technique

» Safe handling and disposal of syringe

» Proper dosing
Discuss with physician

Proper storage

Precautions while using this medication
» Need to inform all physicians and dentists that this medicine is being used

» Notifying physician immediately if signs and symptoms of bleeding or epidural/spinal hematoma occur


Side/adverse effects
Signs of potential side effects, especially hematoma at injection site, anemia, thrombocytopenia, angina pectoris, hypertension, hypotension, tachycardia, hematuria, hemorrhage, pulmonary embolism, skin rash, urinary tract infection, allergic reaction, anaphylactoid reaction, epidural or spinal hematoma, skin necrosis, abscess, acute febrile reaction, agranulocytosis, allergic purpura, angioedema, cholestatic hepatitis, epidermal necrolysis, increased hepatic enzymes, ischemic necrosis or necrosis, hematoma, ocular hemorrhage, pancytopenia, peripheral ischemia, rectal bleeding, Steven-Johnson syndrome, thrombocythemia


General Dosing Information
Tinzaparin cannot be used interchangeably (unit for unit) with unfractionated heparin or other low molecular weight heparins. {01}{02}

Tinzaparin should not be mixed with other injections or infusions. {03} Due to the risk of hematoma, intramuscular injection of other medications should be avoided during anticoagulant treatment with tinzaparin. {04}

All patients should be evaluated for bleeding disorders prior to administration of tinzaparin. {01}

Tinzaparin is administered by deep subcutaneous injection. It must not be administered by intramuscular or intravenous injection. {01} {02}

Injection technique: Proper subcutaneous administration is necessary to prevent pain and bruising at the site of injection. The patient should be sitting or lying down during the injection. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. Alternatively, tinzaparin can be injected into the side of the thigh, provided care is taken not to inject into muscle tissue. The site should be varied daily. The entire length of the needle should be inserted 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. {01} {02}

For treatment of adverse effects
If bleeding complications or hemorrhage occurs during tinzaparin therapy, tinzaparin should be discontinued. In most cases bleeding complications can be controlled by applying pressure to the site, if possible, and replacing volume and hemostatic blood elements as required. However, in some cases administration of protamine may be required. One mg of protamine sulfate (1% solution) per 100 anti-factor Xa International Units (IU) of tinzaparin is given as a slow intravenous injection. If the activated partial thromboplastin time (aPTT) measured 2 to 4 hours after the first injection remains prolonged, a second injection of 0.5 mg protamine sulfate per 100 anti-factor Xa IU of tinzaparin may be administered. {01}{02}


Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.


TINZAPARIN SODIUM INJECTION

Usual Adult Dose
[Thromboembolism (prophylaxis)]

For prevention of postoperative venous thromboembolism in orthopedic surgery
   • Hip Surgery—Subcutaneous, 50 anti-Xa International Units (IU) per kg of body weight 2 hours prior to surgery followed by 50 anti-Xa IU per kg of body weight once daily for 7 to 10 days {02} or 75 anti-Xa IU per kg of body weight given postoperatively once daily for 7 to 10 days {02}.
   • Knee Surgery—Subcutaneous, 75 anti-Xa International Units (IU) per kg of body weight given postoperatively once daily for 7 to 10 days {02}.

For prevention of postoperative venous thromboembolism in general surgery
Subcutaneous, 3500 anti-Xa International Units (IU) 2 hours prior to surgery followed by 3500 anti-Xa IU once daily for 7 to 10 days {02}.

Thromboembolism, pulmonary (treatment adjunct); and 1
Thrombosis, deep venous (treatment adjunct)1
Subcutaneous, 175 anti-Xa International Units (IU) per kg of body weight 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 therapy is usually initiated within 1 to 3 days of tinzaparin initiation {01}.

Note: To calculate the volume (mL) of an tinzaparin 175 anti-Xa IU per kg subcutaneous dose for treatment of deep vein thrombosis the following equation may be used:

• Patient weight (kg) × 0.00875 mL/kg = volume to be administered (mL) subcutaneously {01}.



[Thromboembolism, pulmonary (treatment) and ]
[ Thrombosis, deep venous (treatment)]
Subcutaneous, 175 anti-Xa International Units (IU) per kg of body weight once daily at the same time every day{02}.

Note: Treatment with vitamin K antagonists is usually initiated immediately. Treatment with tinzaparin should be continued until a therapeutic oral anticoagulant effect has been achieved (INR 2.0 to 3.0), usually within 5 days. The average duration of tinzaparin therapy is 7 days {02}.


[Thrombosis of the extracorporeal system during hemodialysis (prophylaxis)]


Chronic renal failure patients with a low risk of bleeding:
Dialysis lasting up to four hours—Intravenous or as a single injection into the arterial dialyser, 4500 International Units (IU), at the start of dialysis. Optimization of dosage is required for each individual patient. Dosage adjustments should consider the outcome of the previous dialysis session and should be made by increasing or decreasing the dose in steps of 500 IU until an adequate dose is obtained {02}.

Dialysis lasting longer than 4 hours—A larger starting dose may be given. Doses in subsequent dialysis sessions should be adjusted as required {02}.



Chronic renal failure patients with a risk of bleeding:
Dialysis sessions may be carried out using halved doses. An additional smaller dose may be given during dialysis for sessions lasting longer than 4 hours. The dose in subsequent dialysis sessions should be adjusted as required to achieve plasma levels within the range of 0.2 to 0.4 IU anti-Xa/mL. No anticoagulant should be added to the dialyser circuit when using this regimen {02}.



Usual adult prescribing limits
The maximum daily dose has not been clearly established; however, maximum daily doses ranging from 18,000 to 21,000 have been cited by the manufacturer {01}{02}.

Usual Pediatric Dose
Safety and efficacy have not been established {01}{02}.

Usual Geriatric Dose
See Usual adult dose.

Usual geriatric prescribing limits
See Usual adult prescribing limits.

Strength(s) usually available
U.S.—


20,000 anti–Xa IU per mL (Rx) [Innohep (in 2 mL multiple-dose vials) (3.1 mg/mL sodium metabisulfite) (10 mg/mL benzyl alcohol ) (and sodium hydroxide)]{01}

Canada—


3500 anti-Xa IU per 0.35 mL (Rx) [Innohep (in single pre-filled unit-dose syringes) ( 1.75 mg sodium acetate) (sodium hydroxide) (water for injection)]{02}


4500 anti-Xa IU per 0.45 mL (Rx) [Innohep ( in single pre-filled unit-dose syringes) (2.25 mg sodium acetate) (sodium hydroxide) (water for injection )]{02}


10,000 anti-Xa IU per 0.5 mL (Rx) [Innohep ( in single unit-dose graduated syringes) (0.92 mg sodium metabisulphite) (sodium hydroxide) (water for injection )]{02}


14,000 anti-Xa IU per 0.7 mL (Rx) [Innohep ( in single unit-dose graduated syringes) (1.27 mg sodium metabisulphite) (sodium hydroxide) (water for injection )]{02}


18,000 anti-Xa IU per 0.9 mL (Rx) [Innohep ( in single unit-dose graduated syringes) (1.65 mg sodium metabisulphite) (sodium hydroxide) (water for injection )]{02}


10,000 anti-Xa IU per mL (Rx) [Innohep ( in 1 mL multiple-dose vials) (1.8 mg sodium metabisulphite ) (10 mg benzyl alcohol) ( sodium hydroxide) (water for injection )]{02}


20,000 anti-Xa IU per mL (Rx) [Innohep ( in 1 mL multiple-dose vials) (3.1 mg sodium metabisulphite ) (10 mg benzyl alcohol) ( sodium hydroxide) (water for injection )]{02}

Packaging and storage:
Store between 15°C and 25 °C (59°F and 77 °F). Protect from light.{02}

Stability:
Because the unit-dose syringes contain no preservative {02}, each syringe should be used to administer a single dose only.

Auxiliary labeling:
   • Keep out of the reach of children.

Additional information:
The multiple-dose vials contain benzyl alcohol, which is not recommended for use in neonates. A fatal syndrome consisting of metabolic acidosis, central nervous system depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhage has been associated with the administration of benzyl alcohol to neonates.

Because benzyl alcohol may cross the placenta, tinzaparin preserved with benzyl alcohol should be used with caution in pregnant women.



Developed: 08/11/2000
Revised: 12/12/2002



References
  1. Product Information: Innohep®, tinzaparin. DuPont Pharma, Wilmington, DE, USA, (PI revised 7/2000) reviewed 8/2000.
  1. Product Information: Innohep®, tinzaparin. Leo Pharma, Ajax, Ontario, Canada, (PI revised 5/2000) reviewed 8/2000.
  1. Product Information: Innohep®, tinzaparin. DuPont Pharma, Wilmington, DE, USA, (PI revised 5/2001) reviewed 6/2002.
  1. Product Information: Innohep®, tinzaparin. Leo Pharma, Ajax, Ontario, Canada, (PI revised 6/2001) reviewed 6/2002.
  1. Expert Committee comment, 10/2002.
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