Novastan

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Novastan uses


1 INDICATIONS AND USAGE

Novastan Injection is a direct thrombin inhibitor indicated:

  • For prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (1.1)
  • As an anticoagulant in adult patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI) (1.2)

1.1 Heparin-Induced Thrombocytopenia

Novastan Injection is indicated for prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT).

1.2 Percutaneous Coronary Intervention

Novastan Injection is indicated as an anticoagulant in adult patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI).

2 DOSAGE AND ADMINISTRATION

Each 250 mL polyolefin bag contains 250 mg of Novastan ; and, as supplied, is ready for intravenous infusion. Dilution is not required.

Novastan Injection is a clear, colorless to pale yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution is cloudy, contains precipitates, or if the flip-off seal is not intact.

  • Novastan Injection 250 mg in 250 mL aqueous sodium chloride solution (1 mg/mL) is intended for administration to adult patients (2.1)
  • Discontinue all parenteral anticoagulants before administering Novastan Injection (2.1)
  • Adjust dosing in patients with HIT who have moderate or severe hepatic impairment (2.3)

Heparin-Induced Thrombocytopenia (2.1)

The dose for heparin-induced thrombocytopenia without hepatic impairment is 2 mcg/kg/min administered as a continuous infusion (2.1)

  • Discontinue heparin therapy and obtain a baseline aPTT before administering Novastan Injection (2.1)
  • After the initial dose of Novastan Injection, the dose can be adjusted as clinically indicated (2.1)

Percutaneous Coronary Intervention (2.2)

The dose for patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention is started at 25 mcg/kg/min and a bolus of 350 mcg/kg administered via a large bore intravenous line over 3 to 5 minutes (2.2)

  • Activated clotting time (ACT) should be checked 5 to 10 minutes after the bolus dose is completed. The procedure may proceed if the ACT is greater than 300 seconds (2.2)
  • Monitoring therapy and dosage adjustments recommendations should be followed (2.2)
  • See special dosing recommendations for hepatic and renal impaired patients (2.3)

2.1 Dosing in Patients with Heparin-Induced Thrombocytopenia

Initial Dosage

Before administering Novastan Injection, discontinue heparin therapy and obtain a baseline aPTT. The recommended initial dose of Novastan Injection for adult patients without hepatic impairment is 2 mcg/kg/min, administered as a continuous infusion (see Table 1).


Body Weight

(kg)


Dose

(mcg/min)


Infusion Rate

(mL/hr)


50


100


6


60


120


7


70


140


8


80


160


10


90


180


11


100


200


12


110


220


13


120


240


14


130


260


16


140


280


17


a with or without thrombosis

Monitoring Therapy

For use in HIT, therapy with Novastan Injection is monitored using the aPTT with a target range of 1.5 to 3 times the initial baseline value (not to exceed 100 seconds). Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within 1 to 3 hours following initiation of Novastan Injection. Check the aPTT 2 hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.

Dosage Adjustment

After the initiation of Novastan Injection, adjust the dose (not to exceed 10 mcg/kg/min) as necessary to obtain a steady-state aPTT in the target range [see Clinical Studies (14.1)].

2.2 Dosing in Patients Undergoing Percutaneous Coronary Intervention

Initial Dosage

Initiate an infusion of Novastan Injection at 25 mcg/kg/min and administer a bolus of 350 mcg/kg via a large bore intravenous line over 3 to 5 minutes. Check an activated clotting time (ACT) 5 to 10 minutes after the bolus dose is completed. The PCI procedure may proceed if the ACT is greater than 300 seconds.

Dosage Adjustment

If the ACT is less than 300 seconds, an additional intravenous bolus dose of 150 mcg/kg should be administered, the infusion dose increased to 30 mcg/kg/min, and the ACT checked 5 to 10 minutes later (see Table 2).

If the ACT is greater than 450 seconds, decrease the infusion rate to 15 mcg/kg/min, and check the ACT 5 to 10 minutes later (Table 3).

Continue titrating the dose until a therapeutic ACT (between 300 and 450 seconds) has been achieved; continue the same infusion rate for the duration of the PCI procedure.

In case of dissection, impending abrupt closure, thrombus formation during the procedure, or inability to achieve or maintain an ACT over 300 seconds, additional bolus doses of 150 mcg/kg may be administered and the infusion dose increased to 40 mcg/kg/min. Check the ACT after each additional bolus or change in the rate of infusion.

NOTE: 1 mg = 1000 mcg; 1 kg = 2.2 lbs

Body Weight

(kg)


Starting Bolus Dose

(350 mcg/kg)


Starting and Maintenance Continuous Infusion Dosing

For ACT 300 to 450 seconds

25 mcg/kg/min


Bolus Dose (mcg)


Bolus Volume (mL)


Continuous Infusion Dose (mcg/min)


Continuous Infusion Rate (mL/hr)


50


17500


18


1250


75


60


21000


21


1500


90


70


24500


25


1750


105


80


28000


28


2000


120


90


31500


32


2250


135


100


35000


35


2500


150


110


38500


39


2750


165


120


42000


42


3000


180


130


45500


46


3250


195


140


49000


49


3500


210


Body Weight (kg)


If ACT

Less than 300 seconds

Dosage Adjustment†

30 mcg/kg/min


If ACT

Greater than 450 seconds Dosage Adjustment*

15 mcg/kg/min


Additional Bolus

Dose (mcg)


Bolus Volume (mL)


Continuous Infusion Dose (mcg/min)


Continuous Infusion Rate (mL/hr)


Continuous Infusion Dose (mcg/min)


Continuous Infusion Rate (mL/hr)


50


7500


8


1500


90


750


45


60


9000


9


1800


108


900


54


70


10500


11


2100


126


1050


63


80


12000


12


2400


144


1200


72


90


13500


14


2700


162


1350


81


100


15000


15


3000


180


1500


90


110


16500


17


3300


198


1650


99


120


18000


18


3600


216


1800


108


130


19500


20


3900


234


1950


117


140


21000


21


4200


252


2100


126

  • NOTE: 1 mg = 1000 mcg; 1 kg = 2.2 lbs

    Additional intravenous bolus dose of 150 mcg/kg should be administered if ACT less than 300 seconds.

  • * No bolus dose is given if ACT greater than 450 seconds

Monitoring Therapy

For use in PCI, therapy with Novastan Injection is monitored using ACT. Obtain ACTs before dosing, 5 to 10 minutes after bolus dosing, following adjustments in the infusion rate, and at the end of the PCI procedure. Obtain additional ACTs every 20 to 30 minutes during a prolonged procedure.

Continued Anticoagulation after PCI

If a patient requires anticoagulation after the procedure, Novastan Injection may be continued, but at a rate of 2 mcg/kg/min and adjusted as needed to maintain the aPTT in the desired range [see Dosage and Administration (2.1)].

2.3 Dosing in Patients with Hepatic Impairment

For adult patients with HIT and moderate or severe hepatic impairment (based on Child-Pugh classification), an initial dose of 0.5 mcg/kg/min is recommended, based on the approximately 4-fold decrease in Novastan clearance relative to those with normal hepatic function. Monitor the aPTT closely, and adjust the dosage as clinically indicated.

Monitoring Therapy

Achievement of steady-state aPTT levels may take longer and require more dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function.

For patients with hepatic impairment undergoing PCI and who have HIT or are at risk for HIT, carefully titrate Novastan Injection until the desired level of anticoagulation is achieved. Use of Novastan Injection in PCI patients with clinically significant hepatic disease or AST/ALT levels greater than or equal to 3 times the upper limit of normal should be avoided [see Warnings and Precautions (5.2)].

2.4 Dosing in Pediatric Patients with Heparin-Induced Thrombocytopenia/Heparin-Induced Thrombocytopenia and Thrombosis Syndrome

Initial Dosage

Initial Novastan infusion doses are lower for seriously ill pediatric patients compared to adults with normal hepatic function [see Use in Specific Populations ].

Monitoring Therapy

In general, therapy with Novastan is monitored using the aPTT. Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within one to three hours following initiation of Novastan in patients without hepatic impairment [see Warnings and Precautions (5.2)]. Dose adjustment may be required to attain the target aPTT. Check the aPTT two hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.

Dosage Adjustment:

2.5 Conversion to Oral Anticoagulant Therapy

Initiating Oral Anticoagulant Therapy

When converting patients from Novastan to oral anticoagulant therapy, consider the potential for combined effects on International Normalized Ratio (INR). To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, overlap Novastan Injection and warfarin therapy. There are insufficient data available to recommend the duration of the overlap. Initiate therapy using the expected daily dose of warfarin. A loading dose of warfarin should not be used.

The relationship between INR and bleeding risk is altered when Novastan and warfarin are coadministered. The combination of Novastan and warfarin does not cause further reduction in the vitamin K–dependent factor Xa activity than that which is seen with warfarin alone. The relationship between INR obtained on combined therapy and INR obtained on warfarin alone is dependent on both the dose of Novastan and the thromboplastin reagent used. The INR value on warfarin alone (INRW) can be calculated from the INR value on combination Novastan and warfarin therapy [see Drug Interactions (7.2) and Clinical Pharmacology (12.2)].

Coadministration of Warfarin and Novastan Injection at Doses Up to 2 mcg/kg/min

Measure INR daily while Novastan Injection and warfarin are coadministered. In general, with doses of Novastan Injection up to 2 mcg/kg/min, Novastan Injection can be discontinued when the INR is greater than 4 on combined therapy. After Novastan Injection is discontinued, repeat the INR measurement in 4 to 6 hours. If the repeat INR is below the desired therapeutic range, resume the infusion of Novastan Injection and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.

Coadministration of Warfarin and Novastan Injection at Doses Greater than 2 mcg/kg/min

For doses greater than 2 mcg/kg/min, the relationship of INR between warfarin alone to the INR on warfarin plus Novastan is less predictable. In this case, in order to predict the INR on warfarin alone, temporarily reduce the dose of Novastan Injection to a dose of 2 mcg/kg/min. Repeat the INR on Novastan Injection and warfarin 4 to 6 hours after reduction of the Novastan Injection dose and follow the process outlined above for administering Novastan Injection at doses up to 2 mcg/kg/min.

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3 DOSAGE FORMS AND STRENGTHS

Novastan Injection is supplied in a single use polyolefin bag containing 250 mg Novastan in 250 mL aqueous sodium chloride solution (1 mg/mL). The solution is ready for intravenous infusion.

Novastan Injection is supplied as a single use polyolefin bag containing 250 mg Novastan in 250 mL aqueous sodium chloride solution (1 mg/mL) (3)

4 CONTRAINDICATIONS

Novastan is contraindicated in:

  • Patients with major bleeding,
  • Patients with a history of hypersensitivity to Novastan. Airway, skin, and generalized hypersensitivity reactions have been reported [see Adverse Reactions (6.4) ].
  • Major bleeding (4)
  • History of hypersensitivity to this product (4)

5 WARNINGS AND PRECAUTIONS

  • Risk of hemorrhage: Hemorrhage at any site can occur. Use with caution in patients at risk, including those receiving antiplatelet agents, thrombolytics, or other anticoagulants (5.1)
  • Use in hepatic impairment: Adjust starting dose and titrate carefully in patients with HIT who have moderate or severe hepatic impairment. Avoid use in PCI in patients with clinically significant hepatic impairment (5.2)

5.1 Risk of Hemorrhage

Hemorrhage can occur at any site in the body in patients receiving Novastan. An unexplained fall in hematocrit or hemoglobin or a fall in blood pressure should lead to consideration of a hemorrhagic event. Novastan Injection should be used with extreme caution in disease states and other circumstances in which there is an increased danger of hemorrhage. These include severe hypertension; immediately following lumbar puncture; spinal anesthesia; major surgery, especially involving the brain, spinal cord, or eye; hematologic conditions associated with increased bleeding tendencies such as congenital or acquired bleeding disorders and gastrointestinal lesions such as ulcerations.

Concomitant use of Novastan with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding.

5.2 Use in Hepatic Impairment

Use caution when administering Novastan to patients with hepatic impairment by starting with a lower dose and carefully titrating until the desired level of anticoagulation is achieved. Upon cessation of Novastan infusion in the hepatically impaired patient, full reversal of anticoagulant effects may require longer than 4 hours due to decreased clearance and increased elimination half-life of Novastan . Use of Novastan in PCI patients with clinically significant hepatic disease or AST/ALT levels ≥ 3 times the upper limit of normal should be avoided.

5.3 Laboratory Tests

Anticoagulation effects associated with Novastan infusion at doses up to 40 mcg/kg/min correlate with increases of the activated partial thromboplastin time (aPTT). Although other global clot-based tests including prothrombin time (PT), the International Normalized Ratio (INR), and thrombin time (TT) are affected by Novastan, the therapeutic ranges for these tests have not been identified for Novastan therapy. In clinical trials in PCI, the activated clotting time (ACT) was used for monitoring Novastan anticoagulant activity during the procedure. The concomitant use of Novastan and warfarin results in prolongation of the PT and INR beyond that produced by warfarin alone .

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6 ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

  • HIT patients: The most common adverse reactions were dyspnea, hypotension, fever, diarrhea, sepsis, and cardiac arrest (6.1)
  • PCI patients: The most common (> 5%) adverse reactions were chest pain, hypotension, back pain, nausea, vomiting and headache (6.2)

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safetyNovastantevapharm.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Events in Patients with HIT (With or Without Thrombosis)

The following safety information is based on all 568 patients treated with Novastan in Study 1 and Study 2. The safety profile of the patients from these studies is compared with that of 193 historical controls in which the adverse events were collected retrospectively. Adverse events are separated into hemorrhagic and non-hemorrhagic events.

Major bleeding was defined as bleeding that was overt and associated with a hemoglobin decrease ≥ 2 g/dL, that led to a transfusion of ≥ 2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint. Minor bleeding was overt bleeding that did not meet the criteria for major bleeding.

Table 4 gives an overview of the most frequently observed hemorrhagic events, presented separately by major and minor bleeding, sorted by decreasing occurrence among argatroban-treated patients with HIT (with or without thrombosis).

*with or without thrombosis
DIC = disseminated intravascular coagulation.
BKA = below-the-knee amputation.

Major Hemorrhagic EventsPatients may have experienced more than 1 adverse event.


Argatroban-Treated Patients

(Study 1 and Study 2)

(n = 568)

%


Historical ControlThe historical control group consisted of patients with a clinical diagnosis of HIT (with or without thrombosis) that were considered eligible by an independent medical panel.

(n = 193)

%


Overall bleeding


5.3


6.7


Gastrointestinal


2.3


1.6


Genitourinary and hematuria


0.9


0.5


Decrease in hemoglobin and hematocrit


0.7


0


Multisystem hemorrhage and DIC


0.5


1


Limb and BKA stump


0.5


0


Intracranial hemorrhage


0 One patient experienced intracranial hemorrhage 4 days after discontinuation of Novastan and following therapy with urokinase and oral anticoagulation.


0.5


Minor Hemorrhagic Events


Argatroban-Treated Patients

(Study 1 and Study 2)

(n = 568)

%


Historical Control

(n = 193)

%


Gastrointestinal


14.4


18.1


Genitourinary and hematuria


11.6


0.8


Decrease in hemoglobin and hematocrit


10.4


0


Groin


5.4


3.1


Hemoptysis


2.9


0.8


Brachial


2.4


0.8


Table 5 gives an overview of the most frequently observed non-hemorrhagic events sorted by decreasing frequency of occurrence (≥ 2%) among argatroban-treated HIT/HITTS patients.


Argatroban-Treated Patients

(Study 1 and Study 2)

(n = 568)

%


Historical Control The historical control group consisted of patients with a clinical diagnosis of HIT (with or without thrombosis) that were considered eligible by an independent medical panel.

(n = 193)

%


Dyspnea


8.1


8.8


Hypotension


7.2


2.6


Fever


6.9


2.1


Diarrhea


6.2


1.6


Sepsis


6.0


12.4


Cardiac arrest


5.8


3.1


Nausea


4.8


0.5


Ventricular tachycardia


4.8


3.1


Pain


4.6


3.1


Urinary tract infection


4.6


5.2


Vomiting


4.2


0


Infection


3.7


3.6


Pneumonia


3.3


9.3


Atrial fibrillation


3.0


11.4


Coughing


2.8


1.6


Abnormal renal function


2.8


4.7


Abdominal pain


2.6


1.6


Cerebrovascular disorder


2.3


4.1

6.2 Adverse Events in Patients with or at Risk for HIT Patients Undergoing PCI

The following safety information is based on 91 patients initially treated with Novastan and 21 patients subsequently re-exposed to Novastan for a total of 112 PCIs with Novastan anticoagulation. Adverse events are separated into hemorrhagic and non-hemorrhagic (Table 7) events.

Major bleeding was defined as bleeding that was overt and associated with a hemoglobin decrease ≥ 5 g/dL, that led to a transfusion of ≥ 2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint. The rate of major bleeding events in patients treated with Novastan in the PCI trials was 1.8%.

CABG = coronary artery bypass graft.

Major Hemorrhagic EventsPatients may have experienced more than 1 adverse event.


Argatroban-Treated Patients

(n = 112)91 patients who underwent 112 interventions.

%


Retroperitoneal


0.9


Gastrointestinal


0.9


Intracranial


0


Minor Hemorrhagic Events


Argatroban-Treated Patients

(n = 112)

%


Groin (bleeding or hematoma)


3.6


Gastrointestinal (includes hematemesis)


2.6


Genitourinary (includes hematuria)


1.8


Decrease in hemoglobin and/or hematocrit


1.8


CABG (coronary arteries)


1.8


Access site


0.9


Hemoptysis


0.9


Other


0.9


Table 7 gives an overview of the most frequently observed non-hemorrhagic events (> 2%), sorted by decreasing frequency of occurrence among argatroban-treated PCI patients.


Novastan Procedures

(n = 112) 91 patients who underwent 112 interventions.

%


Chest pain


15.2


Hypotension


10.7


Back pain


8.0


Nausea


7.1


Vomiting


6.3


Headache


5.4


Bradycardia


4.5


Abdominal pain


3.6


Fever


3.6


Myocardial infarction


3.6


There were 22 serious adverse events in 17 PCI patients (19.6% in 112 interventions). Table 8 lists the serious adverse events occurring in argatroban-treated patients with or at risk for HIT undergoing PCI.


Coded Term


Novastan Procedures91 patients underwent 112 procedures. Some patients may have experienced more than 1 event.

(n = 112)


Myocardial infarction


4 (3.5%)


Angina pectoris


2 (1.8%)


Coronary thrombosis


2 (1.8%)


Myocardial ischemia


2 (1.8%)


Occlusion coronary


2 (1.8%)


Chest pain


1 (0.9%)


Fever


1 (0.9%)


Retroperitoneal hemorrhage


1 (0.9%)


Aortic stenosis


1 (0.9%)


Arterial thrombosis


1 (0.9%)


Gastrointestinal hemorrhage


1 (0.9%)


Gastrointestinal disorder (GERD)


1 (0.9%)


Cerebrovascular disorder


1 (0.9%)


Lung edema


1 (0.9%)


Vascular disorder


1 (0.9%)

6.3 Intracranial Bleeding in Other Populations

Increased risks for intracranial bleeding have been observed in investigational studies of Novastan for other uses. In a study of patients with acute myocardial infarction receiving both Novastan and thrombolytic therapy (streptokinase or tissue plasminogen activator), the overall frequency of intracranial bleeding was 1% (8 out of 810 patients). Intracranial bleeding was not observed in 317 subjects or patients who did not receive concomitant thrombolysis .

The safety and effectiveness of Novastan for cardiac indications other than PCI in patients with HIT have not been established. Intracranial bleeding was also observed in a prospective, placebo-controlled study of Novastan in patients who had onset of acute stroke within 12 hours of study entry. Symptomatic intracranial hemorrhage was reported in 5 of 117 patients (4.3%) who received Novastan at 1 to 3 mcg/kg/min and in none of the 54 patients who received placebo. Asymptomatic intracranial hemorrhage occurred in 5 (4.3%) and 2 (3.7%) of the patients, respectively.

6.4 Allergic Reactions

One hundred fifty-six allergic reactions or suspected allergic reactions were observed in 1,127 individuals who were treated with Novastan in clinical pharmacology studies or for various clinical indications. About 95% (148/156) of these reactions occurred in patients who concomitantly received thrombolytic therapy (e.g., streptokinase) or contrast media.

Allergic reactions or suspected allergic reactions in populations other than patients with HIT (with or without thrombosis) include (in descending order of frequency):

  • Airway reactions (coughing, dyspnea): 10% or more
  • Skin reactions (rash, bullous eruption): 1 to < 10%
  • General reactions (vasodilation): 1 to 10%

Limited data are available on the potential formation of drug-related antibodies. Plasma from 12 healthy volunteers treated with Novastan over 6 days showed no evidence of neutralizing antibodies. No loss of anticoagulant activity was noted with repeated administration of Novastan to more than 40 patients.

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7 DRUG INTERACTIONS

  • Heparin: Allow sufficient time for heparin’s effect on aPTT to decrease before initiating Novastan Injection therapy
  • Warfarin: Concomitant use results in increased prolongation of PT and INR (7.2)
  • Thrombolytic agents or glycoprotein IIb/IIIa antagonists: Safety and effectiveness of concomitant use with Novastan have not been established (7.4, 7.5)

7.1 Heparin

If Novastan is to be initiated after cessation of heparin therapy, allow sufficient time for heparin’s effect on the aPTT to decrease prior to initiation of Novastan therapy.

7.2 Oral Anticoagulant Agents

Pharmacokinetic drug-drug interactions between Novastan and warfarin have not been demonstrated. However, the concomitant use of Novastan and warfarin (5 to 7.5 mg initial oral dose, followed by 2.5 to 6 mg/day orally for 6 to 10 days) results in prolongation of the prothrombin time (PT) and International Normalized Ratio (INR) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.2)].

7.3 Aspirin/Acetaminophen

No drug-drug interactions have been demonstrated between Novastan and concomitantly administered aspirin or acetaminophen [see Clinical Pharmacology (12.3)].

7.4 Thrombolytic Agents

The safety and effectiveness of Novastan with thrombolytic agents have not been established .

7.5 Glycoprotein IIb/IIIa Antagonists

The safety and effectiveness of Novastan with glycoprotein IIb/IIIa antagonists have not been established.

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8 USE IN SPECIFIC POPULATIONS

  • Nursing Mothers: Discontinue nursing or drug, taking into account the importance of the drug to the mother
  • Pediatric use: Safety and effectiveness have not been established; if used initial infusion doses are lower than in adult patients (2.4, 8.4, 12.3)

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of Novastan use in pregnant women. Developmental studies performed in rats with Novastan at intravenous doses up to 27 mg/kg/day (0.3 times the maximum recommended human dose, based on body surface area) and in rabbits at intravenous doses up to 10.8 mg/kg/day (0.2 times the maximum recommended human dose, based on body surface area) have revealed no evidence of impaired fertility or harm to the fetus. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Novastan is excreted in human milk. Novastan is detected in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Novastan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of Novastan, including the appropriate anticoagulation goals and duration of therapy, have not been established among pediatric patients. Novastan was studied among 18 seriously ill pediatric patients who required an alternative to heparin anticoagulation. Most patients were diagnosed with HIT or suspected HIT. Age ranges of patients were < 6 months, n = 8; six months to < 8 years, n = 6; 8 to 16 years, n = 4. All patients had serious underlying conditions and were receiving multiple concomitant medications. Thirteen patients received Novastan solely as a continuous infusion. Dosing was initiated in the majority of these 13 patients at 1 mcg/kg/min. Dosing was titrated as needed to achieve and maintain an aPTT of 1.5 to 3 times the baseline value. Most patients required multiple dose adjustments to maintain anticoagulation parameters within the desired range. During the 30-day study period, thrombotic events occurred during Novastan administration to two patients and following Novastan discontinuation in three other patients. Major bleeding occurred among two patients; one patient experienced an intracranial hemorrhage after 4 days of Novastan therapy in the setting of sepsis and thrombocytopenia. Another patient completed 14 days of Novastan treatment in the study, but experienced an intracranial hemorrhage while receiving Novastan following completion of the study treatment period.

When Novastan is used among seriously ill pediatric patients with HIT/HITTS who require an alternative to heparin and who have normal hepatic function, initiate a continuous infusion of Novastan at a dose of 0.75 mcg/kg/min. Initiate the infusion at a dose of 0.2 mcg/kg/min among seriously ill pediatric patients with impaired hepatic function . Check the aPTT two hours after the initiation of the Novastan infusion and adjust the dose to achieve the target aPTT. These dose recommendations are based upon a goal of aPTT prolongation of 1.5 to 3 times the baseline value and avoidance of an aPTT > 100 seconds. Increments of 0.1 to 0.25 mcg/kg/min for pediatric patients with normal hepatic function and increments of 0.05 mcg/kg/min or lower for pediatric patients with impaired hepatic function may be considered but dose selection must take into account multiple factors including the current Novastan dose, the current aPTT, target aPTT, and the clinical status of the patient. These dose recommendations are based upon a goal of aPTT prolongation of 1.5 to 3 times the baseline value and avoidance of an aPTT > 100 seconds.

8.5 Geriatric Use

Of the total number of subjects (1340) in clinical studies of Novastan, 35% were 65 and over. In the clinical studies of adult patients with HIT (with or without thrombosis), the effectiveness of Novastan was not affected by age. No trends were observed across age groups for both aPTT and the ACT. The safety analysis did suggest that older patients tended to have an increased incidence of events compared to younger patients; however, older patients had increased underlying conditions, which may predispose them to events. The studies were not sized appropriately to detect differences in safety between age groups.

8.6 Hepatic Impairment

Dose reduction and careful titration are required when administering Novastan to patients with hepatic impairment. Reversal of anticoagulation effect may be prolonged in this population .

10 OVERDOSAGE

Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing Novastan or by decreasing the Novastan dose. In clinical studies, anticoagulation parameters generally returned from therapeutic levels to baseline within 2 to 4 hours after discontinuation of the drug. Reversal of anticoagulant effect may take longer in patients with hepatic impairment.

No specific antidote to Novastan is available; if life-threatening bleeding occurs and excessive plasma levels of Novastan are suspected, discontinue Novastan immediately and measure aPTT and other coagulation parameters. When Novastan was administered as a continuous infusion (2 mcg/kg/min) prior to and during a 4-hour hemodialysis session, approximately 20% of Novastan was cleared through dialysis.

Single intravenous doses of Novastan at 200, 124, 150, and 200 mg/kg were lethal to mice, rats, rabbits, and dogs, respectively. The symptoms of acute toxicity were loss of righting reflex, tremors, clonic convulsions, paralysis of hind limbs, and coma.

11 DESCRIPTION

Novastan is a synthetic direct thrombin inhibitor and the chemical name is 1-[5-[amino]1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid, monohydrate. Novastan has 4 asymmetric carbons. One of the asymmetric carbons has an R configuration (stereoisomer Type I) and an S configuration (stereoisomer Type II). Novastan consists of a mixture of R and S stereoisomers at a ratio of approximately 65:35.

The molecular formula of Novastan is C23H36N6O5S∙H2O. Its molecular weight is 526.66 g/mol. The structural formula is:

Figure 4. Time to First Event for the Composite Efficacy Endpoint: HITTS Patients STUDY 1

In Study 2, a total of 264 patients were enrolled as follows: HIT (n = 125) or HITTS (n = 139). There was a significant improvement in the composite efficacy outcome for argatroban-treated patients, versus the same historical control group from Study 1, among patients having HIT (25.6% vs. 38.8%), patients having HITTS (41.0% vs. 56.5%), and patients having either HIT or HITTS (33.7% vs. 43.0%). Time-to-event analyses showed significant improvements in the time-to-first event in patients with HIT or HITTS treated with Novastan versus those in the historical control group. The between-group differences in the proportion of patients who remained free of death, amputation, or new thrombosis were statistically significant in favor of Novastan.

Anticoagulant Effect

In Study 1, the mean (± SE) dose of Novastan administered was 2.0 ± 0.1 mcg/kg/min in the HIT arm and 1.9 ± 0.1 mcg/kg/min in the HITTS arm. Seventy-six percent of patients with HIT and 81% of patients with HITTS achieved a target aPTT at least 1.5-fold greater than the baseline aPTT at the first assessment occurring on average at 4.6 hours (HIT) and 3.9 hours (HITTS) following initiation of Novastan therapy. No enhancement of aPTT response was observed in subjects receiving repeated administration of Novastan.

Platelet Count Recovery

In Study 1, 53% of patients with HIT and 58% of patients with HITTS, had a recovery of platelet count by Day 3. Platelet Count Recovery was defined as an increase in platelet count to > 100,000/µL or to at least 1.5-fold greater than the baseline count (platelet count at study initiation) by Day 3 of the study.

Figure 3. Figure 4.

14.2 Percutaneous Coronary Intervention (PCI) Patients with or at Risk for HIT

In 3 similarly designed trials, Novastan was administered to 91 patients with current or previous clinical diagnosis of HIT or heparin-dependent antibodies, who underwent a total of 112 percutaneous coronary interventions (PCIs) including percutaneous transluminal coronary angioplasty (PTCA), coronary stent placement, or atherectomy. Among the 91 patients undergoing their first PCI with Novastan, notable ongoing or recent medical history included myocardial infarction (n = 35), unstable angina (n = 23), and chronic angina (n = 34). There were 33 females and 58 males. The average age was 67.6 years (median 70.7, range 44 to 86), and the average weight was 82.5 kg (median 81.0 kg, range 49 to 141).

Twenty-one of the 91 patients had a repeat PCI using Novastan an average of 150 days after their initial PCI. Seven of 91 patients received glycoprotein IIb/IIIa inhibitors. Safety and efficacy were assessed against historical control populations who had been anticoagulated with heparin.

All patients received oral aspirin (325 mg) 2 to 24 hours prior to the interventional procedure. After venous or arterial sheaths were in place, anticoagulation was initiated with a bolus of Novastan of 350 mcg/kg via a large-bore intravenous line or through the venous sheath over 3 to 5 minutes. Simultaneously, a maintenance infusion of 25 mcg/kg/min was initiated to achieve a therapeutic activated clotting time (ACT) of 300 to 450 seconds. If necessary to achieve this therapeutic range, the maintenance infusion dose was titrated (15 to 40 mcg/kg/min) and/or an additional bolus dose of 150 mcg/kg could be given. Each patient’s ACT was checked 5 to 10 minutes following the bolus dose. The ACT was checked as clinically indicated. Arterial and venous sheaths were removed no sooner than 2 hours after discontinuation of Novastan and when the ACT was less than 160 seconds.

If a patient required anticoagulation after the procedure, Novastan could be continued, but at a lower infusion dose between 2.5 and 5 mcg/kg/min. An aPTT was drawn 2 hours after this dose reduction and the dose of Novastan then was adjusted as clinically indicated (not to exceed 10 mcg/kg/min), to reach an aPTT between 1.5 and 3 times baseline value (not to exceed 100 seconds).

In 92 of the 112 interventions (82%), the patient received the initial bolus of 350 mcg/kg and an initial infusion dose of 25 mcg/kg/min. The majority of patients did not require additional bolus dosing during the PCI procedure. The mean value for the initial ACT measurement after the start of dosing for all interventions was 379 sec (median 338 sec; 5th percentile-95th percentile 238 to 675 sec). The mean ACT value per intervention over all measurements taken during the procedure was 416 sec (median 390 sec; 5th percentile-95th percentile 261 to 698 sec). About 65% of patients had ACTs within the recommended range of 300 to 450 seconds throughout the procedure. The investigators did not achieve anticoagulation within the recommended range in about 23% of patients. However, in this small sample, patients with ACTs below 300 seconds did not have more coronary thrombotic events, and patients with ACTs over 450 seconds did not have higher bleeding rates.

Acute procedural success was defined as lack of death, emergent coronary artery bypass graft (CABG), or Q-wave myocardial infarction. Acute procedural success was reported in 98.2% of patients who underwent PCIs with Novastan anticoagulation compared with 94.3% of historical control patients anticoagulated with heparin (p = NS). Among the 112 interventions, 2 patients had emergency CABGs, 3 had repeat PTCAs, 4 had non-Q-wave myocardial infarctions, 3 had myocardial ischemia, 1 had an abrupt closure, and 1 had an impending closure (some patients may have experienced more than 1 event). No patients died.

16 HOW SUPPLIED/STORAGE AND HANDLING

Novastan Injection is supplied as a single use polyolefin bag containing 250 mg Novastan in 250 mL of aqueous sodium chloride solution (1 mg/mL). The polyolefin bag has a single port which is sealed with a rubber stopper and flip-off seal, and is stored in an aluminum foil overpouch with clear window.

NDC 0703-0020-32 one carton containing 5 polyolefin bags of Novastan Injection (each bag contains 250 mg of Novastan).

Storage

Store the bag in its original carton at 20º to 25º C (68º to 77°F). Do not freeze. Retain in the original carton to protect from light.

17 PATIENT COUNSELING INFORMATION

Inform patients of the risks associated with Novastan Injection as well as the plan for regular monitoring during administration of the drug. Specifically, inform patients to report:

  • the use of any other products known to affect bleeding.
  • any medical history that may increase the risk for bleeding, including a history of severe hypertension; recent lumbar puncture or spinal anesthesia; major surgery, especially involving the brain, spinal cord, or eye; hematologic conditions associated with increased bleeding tendencies such as congenital or acquired bleeding disorders and gastrointestinal lesions such as ulcerations.
  • any bleeding signs or symptoms.
  • the occurrence of any signs or symptoms of allergic reactions (e.g., airway reactions, skin reactions and vasodilation reactions).

Manufactured In Hungary By:

Teva Pharmaceutical Works Ltd. Hungary

H-2100 Gödöllö

Táncsics M. út 82 Hungary

Manufactured For:

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. B 5/2016

  • NDC 0703-0020-32 Rx only

Novastan

Injection in 0.9%

Sodium Chloride

250 mg/250 mL

(1 mg/mL)

Each milliliter contains:

  • Novastan 1 mg
  • sodium chloride 9 mg
  • sorbitol in water for injection 3 mg

For Intravenous Infusion Only

Do not dilute.

Single Use Bags. Discard Unused Portion

Sterile

Contains 5 Single Use Bags

TEVA

Novastan pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Novastan available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Novastan destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Novastan Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Novastan pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."ARGATROBAN INJECTION, SOLUTION [TEVA PARENTERAL MEDICINES, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Novastan?

Depending on the reaction of the Novastan after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Novastan not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Novastan addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Novastan, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Novastan consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

One visitor reported frequency of use

How often in a day do you take the medicine?
Are you taking the Novastan drug as prescribed by the doctor?

Few medications can be taken Once in a day more than prescribed when the doctor's advice mentions the medicine can be taken according to frequency or severity of symptoms. Most times, be very careful and clear about the number of times you are taking the medication. The report of sdrugs.com website users about the frequency of taking the drug Novastan is mentioned below.
Visitors%
Once in a day1
100.0%

Visitor reported doses

No survey data has been collected yet

Visitor reported time for results

No survey data has been collected yet

Visitor reported administration

No survey data has been collected yet

One visitor reported age

Visitors%
16-291
100.0%

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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