BIVASTAT Injection (Bivalirudin)

Table of Content

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

 

Qualitative and Quantitative Composition

Each lyophilized vial contains:

Bivalirudin…….. 250 mg

Excipients……….q.s.

Supplied with 5 ml Sterile Water for Injection, IP

Dosage Form and Strength 

Sterile lyophilized powder to be reconstituted, for single use, 250 mg

Clinical Particulars

Therapeutic Indications

Percutaneous Transluminal Coronary Angioplasty (PTCA)

BIVASTAT is indicated for use as an anticoagulant in patients with unstable angina undergoing PTCA.

Percutaneous Coronary Intervention (PCI)

BIVASTAT with provisional use of glycoprotein inhibitor (GPI) is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI).

BIVASTAT is indicated for patients with, or at risk of heparin induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) undergoing PCI.

Use with Aspirin

BIVASTAT in these indications is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin.

Limitation of Use

The safety and effectiveness of bivalirudin have not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.

Posology and Method of Administration

Recommended Dose

BIVASTAT is for IV administration only.

Bivalirudin is intended for use with aspirin (300–325 mg daily) and has been studied only in patients receiving concomitant aspirin.

For Patients who do not have HIT/HITTS

The recommended dose of BIVASTAT is an IV bolus dose of 0.75 mg/kg, followed by an infusion of 1.75 mg/kg/h for the duration of the PCI/PTCA procedure. An ACT should be performed 5 minutes after the bolus dose has been administered, and an additional bolus of 0.3 mg/kg should be given if needed.

Provisional use of GPI administration should be considered in the following circumstances:

  • Decreased thrombolysis in myocardial infraction (TIMI) flow (0–2) or slow reflow
  • Dissection with decreased flow
  • New or suspected thrombus
  • Persistent residual stenosis
  • Distal embolization
  • Unplanned stent
  • Suboptimal stenting
  • Side branch closure
  • Abrupt closure; clinical instability
  • Prolonged ischemia

For Patients who have HIT/HITTS

The recommended dose of BIVASTAT in patients with HIT/HITTS undergoing PCI is an I.V. bolus of 0.75 mg/kg. This should be followed by a continuous infusion at a rate of 1.75 mg/kg/h for the duration of the procedure.

For Ongoing Treatment Post-Procedure

BIVASTAT infusion may be continued following PCI/PTCA for up to 4 hours post-procedure at the discretion of the treating physician. In patients with ST segment elevation myocardial infarction (STEMI) continuation of the BIVASTAT infusion at a rate of 1.75 mg/kg/h following PCI/PTCA for up to 4 hours post-procedure should be considered to mitigate risk of stent thrombosis. After four hours, an additional IV infusion of BIVASTAT may be initiated at a rate of 0.2 mg/kg/h (low-rate infusion), for up to 20 hours, if needed.

Dosing in Renal Impairment

No reduction in the bolus dose is needed for any degree of renal impairment. The infusion dose of BIVASTAT may need to be reduced, and anticoagulant status monitored in patients with renal impairment. Patients with moderate renal impairment (30–59 mL/min) should receive an infusion of 1.75 mg/kg/h. If the creatinine clearance is less than 30 mL/min, reduction of the infusion rate to 1 mg/kg/h should be considered. If a patient is on hemodialysis, the infusion rate should be reduced to 0.25 mg/kg/h.

Instructions for Administration

BIVASTAT is intended for IV bolus injection and continuous infusion after reconstitution and dilution. To each 250 mg vial, add 5 mL of Sterile Water for Injection, IP. Gently swirl until all the material is dissolved. Each reconstituted vial should be further diluted in 50 mL of 5% Dextrose in Water or 0.9% Sodium Chloride for Injection to yield a final concentration of 5 mg/mL (e.g., one vial in 50 mL; two vials in 100 mL; five vials in 250 mL). The dose to be administered is adjusted according to the patient’s weight (see Table 1).

If the low-rate infusion is used after the initial infusion, a lower concentration bag should be prepared. In order to prepare this bag, reconstitute the 250 mg vial with 5 mL of Sterile Water for Injection, I.P. Gently swirl until all material is dissolved. Each reconstituted vial should be further diluted in 500 mL of 5% Dextrose in Water or 0.9% Sodium Chloride for Injection to yield a final concentration of 0.5 mg/mL. The infusion rate to be administered should be selected from the right-hand column in Table 1.

Table 1: Dosing table

 

Using 5 mg/mL Concentration

Using 0.5 mg/mL Concentration

Weight (kg)

Bolus 0.75 mg/k (mL)

Infusion 1.75 mg/kg/h (mL/h)

Subsequent Low-rate Infusion 0.2 mg/kg/h (mL/h)

43–47

7

16

18

48–52

7.5

17.5

20

53–57

8

19

22

58–62

9

21

24

63–67

10

23

26

68–72

10.5

24.5

28

73–77

11

26

30

78–82

12

28

32

83–87

13

30

34

88–92

13.5

31.5

36

93–97

14

33

38

98–102

15

35

40

103–107

16

37

42

108–112

16.5

38.5

44

113–117

17

40

46

118–122

18

42

48

123–127

19

44

50

128–132

19.5

45.5

52

133–137

20

47

54

138–142

21

49

56

143–147

22

51

58

148-152

22.5

52.5

60

Contraindications

  • Active major bleeding;
  • Hypersensitivity (e.g., anaphylaxis) to bivalirudin or its components

Special Warnings and Precautions for Use

Bleeding Events

Although most bleeding associated with the use of bivalirudin in PCI/PTCA occurs at the site of arterial puncture, hemorrhage can occur at any site. An unexplained fall in blood pressure or hematocrit should lead to serious consideration of a hemorrhagic event and cessation of bivalirudin administration. Bivalirudin should be used with caution in patients with disease states associated with an increased risk of bleeding.

Acute Stent Thrombosis in Patients with STEMI undergoing PCI

Acute stent thrombosis (AST) (<4 hours) has been observed at a greater frequency in bivalirudin treated patients (1.2%, 36/2889) compared to heparin treated patients (0.2%, 6/2911) with STEMI undergoing primary PCI. Among patients who experienced an AST, one fatality (0.03%) occurred in a bivalirudin treated patient and one fatality (0.03%) in a heparin treated patient. These patients have been managed by Target Vessel Revascularization (TVR). Patients should remain for at least 24 hours in a facility capable of managing ischemic complications and should be carefully monitored following primary PCI for signs and symptoms consistent with myocardial ischemia.

Coronary Artery Brachytherapy

An increased risk of thrombus formation, including fatal outcomes, has been associated with the use of bivalirudin in gamma brachytherapy.

If a decision is made to use bivalirudin during brachytherapy procedures, maintain meticulous catheter technique, with frequent aspiration and flushing, paying special attention to minimizing conditions of stasis within the catheter or vessels.

Laboratory Test Interference

Bivalirudin affects International Normalized Ratio (INR), therefore INR measurements made in patients who have been treated with bivalirudin may not be useful for determining the appropriate dose of warfarin.

Drug Interactions

In clinical trials in patients undergoing PCI/PTCA, co-administration of bivalirudin with heparin, warfarin, thrombolytics, or GPIs was associated with increased risks of major bleeding events compared to patients not receiving these concomitant medications.

There is no experience with co-administration of bivalirudin and plasma expanders such as dextran.

Use in Special Populations

Pregnancy

Category B

There are no available data on use of bivalirudin in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Reproduction studies in rats and rabbits administered subcutaneously (SC) doses up to 1.6 times and 3.2 times the maximum recommended human dose (MRHD) based on body surface area (BSA), respectively, revealed no evidence of fetal harm.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Reproductive studies have been performed in rats at subcutaneous doses up to 150 mg/kg/day, (1.6 times the maximum recommended human dose based on body surface area) and rabbits at subcutaneous doses up to 150 mg/kg/day (3.2 times the maximum recommended human dose based on body surface area). These studies revealed no evidence of impaired fertility or harm to the fetus attributable to bivalirudin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

At 500 mg/kg/day subcutaneously, litter sizes and live fetuses in rats were reduced. Fetal skeletal variations were also noted. Some of these changes could be attributed to maternal toxicity observed at high doses.

Bivalirudin is intended for use with aspirin. Because of possible adverse effects on the neonate and the potential for increased maternal bleeding, particularly during the third trimester, bivalirudin and aspirin should be used together during pregnancy only if clearly needed.

Lactation

It is not known whether bivalirudin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when bivalirudin is administered to a nursing mother.

Pediatric Use

The safety and effectiveness of bivalirudin in pediatric patients have not been established.

Geriatric Use

In studies of patients undergoing PCI, 44% were ≥65 years of age and 12% of patients were ≥75 years old. Elderly patients experienced more bleeding events than younger patients. Patients treated with bivalirudin experienced fewer bleeding events in each age stratum, compared to heparin.

Renal Impairment

The disposition of bivalirudin was studied in PTCA patients with mild, moderate and severe renal impairment. The clearance of bivalirudin was reduced approximately 20% in patients with moderate and severe renal impairment and was reduced approximately 80% in dialysis-dependent patients. The infusion dose of bivalirudin may need to be reduced, and anticoagulant status monitored in patients with renal impairment (see Posology and Method of Administration).

Undesirable Effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction 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.

Bleeding

In 6010 patients undergoing PCI treated in the REPLACE-2 trial, bivalirudin patients exhibited statistically significantly lower rates of bleeding, transfusions, and thrombocytopenia as noted in Table 2.

Table 2: Major hematologic outcomes in REPLACE-2 study (safety population)

 

Bivalirudin with “provisional” GPI1

n=2,914

Heparin + GPI

 

 

(n=2,987)

p-value

Protocol-defined major hemorrhage2 (%)

2.3%

4.0%

<0.001

Protocol-defined minor hemorrhage3 (%)

13.6%

25.8%

<0.001

TIMI defined bleeding4

 

 

 

- Major

0.6%

0.9%

0.259

- Minor

1.3%

2.9

<0.001

Non-access site bleeding

 

 

 

- Retroperitoneal bleeding

0.2%

0.5%

0.069

- Intracranial bleeding

<0.1%

0.1%

1.0

Access site bleeding

 

 

 

- Sheath site bleeding

0.9%

2.4%

<0.001

Thrombocytopenia5

 

 

 

- <100,000

0.7%

1.7%

<0.001

- <50,000

0.3%

0.6%

0.039

Transfusions

 

 

 

- RBC

1.3%

1.9%

0.08

- Platelets

0.3%

0.6%

0.095

1 GPIs were administered to 7.2% of patients in the bivalirudin with provisional GPI group.

2 Defined as the occurrence of any of the following: intracranial bleeding, retroperitoneal bleeding, a transfusion of >2 units of blood/blood products, a fall in haemoglobin (Hgb) >4g/dL, whether or not bleeding site is identified, spontaneous or non-spontaneous blood loss with a decrease in hemoglobin >3g/dL.

3 Defined as observed bleeding that does not meet the criteria for major hemorrhage.

4 TIMI major bleeding is defined as intracranial, or a fall in adjusted Hgb >5 g/dL or Hct of >15%: TIMI minor bleeding is defined as a fall in adjusted Hgb of 3 to <5 g/dL or a fall in adjusted Hct of 9 to <15%, with a bleeding site such as hematuria, hematemesis, hematomas, retroperitoneal bleeding or a decrease in Hgb of >4 g/dL with no bleeding site.

5 If <100,000 and >25% reduction from baseline, or <50,000.

In 4,312 patients undergoing PTCA for treatment of unstable angina in two randomized, double-blind studies comparing bivalirudin to heparin, bivalirudin patients exhibited lower rates of major bleeding and lower requirements for blood transfusions. The incidence of major bleeding is presented in Table 3. The incidence of major bleeding was lower in the bivalirudin group than in the heparin group.

Table 3: Major bleeding and transfusions in BAT trial (all patients)1

 

Bivalirudin

N= 2,161

Heparin

N=2,151

No. (%) patients with major hemorrhage2

79 (3.7)

199 (9.3)

  • With ≥3 g/dL fall in Hgb

41 (1.9)

124 (5.8)

  • With ≥5 g/dL fall in Hgb

14 (0.6)

47 (2.2)

  • Retroperitoneal bleeding

5 (0.2)

15 (0.7)

  • Intracranial bleeding

1 (<0.1)

2 (0.1)

  • Required transfusions

43 (2.0)

123 (5.7)

1No monitoring of ACT (or PTT) was done after a target ACT was achieved.

2 Major hemorrhage was defined as the occurrence of any of the following, intracranial bleeding, retroperitoneal bleeding, clinically overt bleeding with a decrease in hemoglobin >3 g/dL or leading to a transfusion of >2 units of blood. This table includes data from the entire hospitalization period.

In the AT-BAT study, of the 51 patients with HIT/HITTS, 1 patient who did not undergo PCI had major bleeding during coronary artery bypass graft (CABG) on the day following angiography. Nine patients had minor bleeding (mostly due to access site bleeding), and 2 patients developed thrombocytopenia.

Other Adverse Reactions

Adverse reactions, other than bleeding, observed in clinical trials were similar between the bivalirudin treated patients and the control groups.

Adverse reactions (related adverse events) seen in clinical studies in patients undergoing PCI and PTCA are shown in Tables 4 and 5.

Table 4: Most Frequent (>0.2%) Treatment-Related Adverse Events (Reactions) (Through 30 Days) in the REPLACE-2 Safety Population

 

Bivalirudin with “provisional” GPI1 (N= 2,914)

Heparin+ GPI

 

(N= 2,987)

 

n

%

n

%

Patients with at least one treatment-related adverse event

78

2.7

115

3.9

Thrombocytopenia

9

0.3

30

1.0

Nausea

15

0.5

7

0.2

Hypotension

7

0.2

11

0.4

Angina pectoris

5

0.2

12

0.4

Headache

6

0.2

5

0.2

Injection site pain

3

0.1

8

0.3

Nausea and vomiting

2

0.1

6

0.2

Vomiting

3

0.1

5

0.2

 

Note: A patient could have more than one event in any category.

Abbreviation: AE = adverse event.

Table 5: Adverse events other than bleeding occurring in ≥5% of patients in either treatment group in BAT trial

Event

Treatment Group

 

Bivalirudin

(N= 2,161)

Heparin

(N= 2,151)

 

Number of Patients (%)

Cardiovascular

 

Hypotension

262 (12)

371 (17)

Hypertension

135 (6)

115 (5)

Bradycardia

118 (5)

164 (8)

Gastrointestinal

 

Nausea

318 (15)

347 (16)

Vomiting

138 (6)

169 (8)

Dyspepsia

100 (5)

111 (5)

Genitourinary

 

Urinary retention

89 (4)

98 (5)

Miscellaneous

 

Back pain

916 (42)

944 (44)

Pain

330 (15)

358 (17)

Headache

264 (12)

225 (10)

Injection site pain

174 (8)

274 (13)

Insomnia

142 (7)

139 (6)

Pelvic pain

130 (6)

169 (8)

Anxiety

127 (6)

140 (7)

Abdominal pain

103 (5)

104 (5)

Fever

103 (5)

108 (5)

Nervousness

102 (5)

87 (4)

       

Serious, non-bleeding adverse events were experienced in 2% of 2,161 bivalirudin- treated patients and 2% of 2151 heparin-treated patients. The following individual serious non-bleeding adverse events were rare (>0.1% to <1%) and similar in incidence between bivalirudin- and heparin-treated patients. These events are listed by body system:

  • Body as a Whole: fever, infection, sepsis
  • Cardiovascular: hypotension, syncope, vascular anomaly, ventricular fibrillation
  • Nervous: cerebral ischemia, confusion, facial paralysis
  • Respiratory: lung edema
  • Urogenital: kidney failure, oliguria

In the BAT trial, 79 of the 2161 (3.7%) of subjects undergoing PCI for treatment of unstable angina and randomized to bivalirudin experienced intracranial bleeding, retroperitoneal bleeding, clinically overt bleeding with a decrease in hemoglobin greater than 3 g/dL or leading to a transfusion of greater than 2 units of blood.

Immunogenicity/Re-Exposure

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to bivalirudin in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In in vitro studies, bivalirudin exhibited no platelet aggregation response against sera from patients with a history of HIT/HITTS.

Among 494 subjects who received bivalirudin in clinical trials and were tested for antibodies, 2 subjects had treatment-emergent positive bivalirudin antibody tests. Neither subject demonstrated clinical evidence of allergic or anaphylactic reactions and repeat testing was not performed. Nine additional patients who had initial positive tests were negative on repeat testing.

Postmarketing Experience

Because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified during postapproval use of bivalirudin: fatal bleeding; hypersensitivity and allergic reactions, including reports of anaphylaxis; lack of anticoagulant effect; thrombus formation during PCI with and without intracoronary brachytherapy, including reports of fatal outcomes; pulmonary hemorrhage; cardiac tamponade; and INR increased.

Reporting of suspected adverse reactions

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly to the National Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779.

By reporting side effects, you can help provide more information on the safety of this product

Overdose

Cases of overdose of up to 10 times the recommended bolus or continuous infusion dose of bivalirudin have been reported in clinical trials and in post-marketing reports. A number of the reported overdoses were due to failure to adjust the infusion dose of bivalirudin in persons with renal dysfunction including persons on hemodialysis. Bleeding and also deaths due to hemorrhage have been observed in some reports of overdose. In cases of suspected overdosage, discontinue bivalirudin immediately and monitor the patient closely for signs of bleeding. There is no antidote to bivalirudin. Bivalirudin is hemodialyzable.

Pharmacological Properties

Mechanism of Action

Bivalirudin directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is a serine proteinase that plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release. The binding of bivalirudin to thrombin is reversible as thrombin slowly cleaves the bivalirudin-Arg3-Pro4 bond, resulting in recovery of thrombin active site functions

Pharmacodynamic Properties

 In healthy volunteers and patients (with ≥70% vessel occlusion undergoing routine percutaneous transluminal coronary angiography ), bivalirudin exhibited dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of the activated clotting time (ACT), aPTT, PT, and TT. Intravenous administration of bivalirudin produces an immediate anticoagulant effect. Coagulation times return to baseline approximately 1 hour following cessation of bivalirudin administration. Bivalirudin also increases INR.

In 291 patients with ≥70% vessel occlusion undergoing routine PTCA, a positive correlation was observed between the dose of bivalirudin and the proportion of patients achieving ACT values of 300 sec or 350 sec. At a bivalirudin dose of 1 mg/kg I.V. bolus plus 2.5 mg/kg/h intravenous (IV) infusion for 4 hours, followed by 0.2 mg/kg/h, all patients reached maximal ACT values >300 sec.

Pharmacokinetics Properties

Bivalirudin exhibits linear pharmacokinetics following I.V. administration to patients undergoing PTCA. In these patients, a mean steady state bivalirudin concentration of 12.3 ± 1.7 mcg/mL is achieved following an I.V. bolus of 1 mg/kg and a 4-hour, 2.5 mg/kg/h I.V. infusion.

Distribution

Bivalirudin does not bind to plasma proteins (other than thrombin) or to red blood cells.

Elimination

Bivalirudin has a half-life of 25 minutes in PTCA patients with normal renal function. The total body clearance of bivalirudin in PTCA patients with normal renal function is 3.4 mL/min/kg.  

Metabolism

Bivalirudin is metabolized by proteolytic cleavage.

Excretion

Bivalirudin undergoes glomerular filtration. Tubular secretion and tubular reabsorption are also implicated in the excretion of bivalirudin, although the extent is unknown.

Specific Populations

Patients with Renal Impairment

Total body clearance was similar for PTCA patients with normal renal function and with mild renal impairment. Clearance was reduced by 21% in patients with moderate and severe renal impairment with a half-life of 34 and 57 minutes, respectively. In dialysis patients, clearance was reduced by 70%, with a half-life of 3.5 hours. Approximately 25% bivalirudin is cleared by hemodialysis.

Nonclinical Properties

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of bivalirudin. Bivalirudin displayed no genotoxic potential in the in vitro bacterial cell reverse mutation assay (Ames test), the in vitro Chinese hamster ovary cell forward gene mutation test (CHO/HGPRT), the in vitro human lymphocyte chromosomal aberration assay, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) assay, and the in vitro rat micronucleus assay. Fertility and general reproductive performance in rats were unaffected by subcutaneous doses of bivalirudin up to 150 mg/kg/day, about  1.6 times the dose on a body surface area basis (mg/m2) of a 50 kg person given the maximum recommended dose of 15 mg/kg/day.

Description

BIVASTAT contains bivalirudin trifluoroacetate, which is a specific and reversible direct thrombin inhibitor. Bivalirudin trifluoroacetate is a synthetic, 20 amino acid peptide salt, with the chemical name of D-phenylalanyl-L-prolyl-L-arginyl-L-prolylglycylglycylglycylglycyl-Lasparagylglycyl-L-α-aspartyl-L-phenylalanyl-L-α-glutamyl-L-α-glutamyl-L-isoleucyl-L-prolyl-L-αglutamyl-L-α-glutamyl-L-tyrosyl-L-leucine trifluoroacetate. Each molecule of bivalirudin trifluoroacetate contains 1.7 to 2.6 equivalents of trifluoroacetic acid. The molecular formula of bivalirudin free base is C98H138N24O33 and its molecular weight is 2180.32 Daltons (anhydrous free base peptide). The structural formula of bivalirudin free base is:

Pharmaceutical Particulars

Incompatibilities

BIVASTAT should be administered via an IV line. No incompatibilities for bivalirudin have been observed with glass bottles or polyvinyl chloride bags and administration sets. The following drugs should not be administered in the same IV line with BIVASTAT, since they resulted in haze formation, microparticulate formation, or gross precipitation when mixed with bivalirudin: alteplase, amiodarone HCl, amphotericin B, chlorpromazine HCl, diazepam, prochlorperazine edisylate, reteplase, streptokinase, and vancomycin HCl. Dobutamine was compatible at concentrations up to 4 mg/mL but incompatible at a concentration of 12.5 mg/mL.

Shelf-Life

See on pack

Packaging Information

BIVASTAT 250 mg: Vial of 10 ml supplied with 5 ml of Sterile Water for Injection, IP

Storage and Handling Instructions

Store below 25oC. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Preparations of BIVASTAT containing particulate matter should not be used. Reconstituted material will be a clear to slightly opalescent, colorless to slightly yellow solution.

Storage after Reconstitution

Do not freeze reconstituted or diluted BIVASTAT. Reconstituted material may be stored at 2–8°C for up to 24 hours. Diluted BIVASTAT with a concentration of between 0.5 mg/mL and 5 mg/mL is stable at room temperature for up to 24 hours. Discard any unused portion of reconstituted solution remaining in the vial.

Patient Counselling Information

What is BIVASTAT and what is it used for?

BIVASTAT contains a substance called bivalirudin which is an antithrombotic medicine. Antithrombotics are medicines which prevent the formation of blood clots (thrombosis). 

BIVASTAT (Bivalirudin) is used to treat patients a undergoing a procedure to treat blockages in their blood vessels (angioplasty and/or percutaneous coronary intervention - PCI).

What is the most important information I should know about Bivastat (Bivalirudin)?

Do not use Bivalirudin

  • if you have, or have recently had, active major bleeding
  • if you are allergic to bivalirudin or any of the other ingredients of this medicine

Check with the doctor if you are unsure.

Warnings and precautions

Talk to your doctor before using Bivalirudin.

  • if bleeding occurs (if this happens, treatment with Bivalirudin will be stopped). Throughout your treatment, the doctor will check you for any signs of bleeding.
  • if you have been treated before with medicines similar to Bivalirudin (e.g. lepirudin).
  • before the start of the injection or infusion, the doctor will tell you about the signs of allergic reaction. if you are having radiation treatment in the vessels that supply blood to the heart (treatment called beta or gamma brachytherapy).

After being treated with Bivalirudin for a cardiac event, you should stay in the hospital for at least 24 hours and you should be monitored for any symptoms or signs similar to the ones that remind you of your cardiac event and resulted in your hospitalisation.

Children and adolescents

  • if you are a child (less than 18 years of age), this medicine is not appropriate for you.

Other medicines and Bivalirudin

Tell your doctor or pharmacist

  • if you are taking/using, or have recently taken/used or might take/use any other medicines.
  • if you are taking blood thinners or medicines to prevent blood clots (anticoagulants or antithrombotics e.g. warfarin, dabigatran, apixaban, rivaroxaban, acetylsalicylic acid, clopidogrel, prasugrel, ticagrelor).

These medicines may increase the risk of side effects such as bleeding when given at the same time as Bivalirudin.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Bivalirudin should not be used during pregnancy, unless clearly necessary. Your doctor will decide whether or not this treatment is appropriate for you. If you are breast-feeding, the doctor will decide whether Bivalirudin should be used.

Driving and using machines

The effects of this medicine are known to be short-term. Bivalirudin is only given when a patient is in hospital. It is, therefore, unlikely to affect your ability to drive or to use machines.

How should I take Bivastat (Bivalirudin)?

Your treatment with Bivalirudin will be supervised by a doctor. The doctor will decide how much Bivalirudin you receive, and will prepare the medicine.

Dosage

Bivalirudin is for injection, followed by infusion (drip), into a vein (never into a muscle). This is administered and supervised by a doctor experienced in caring for patients with heart disease.

Bivalirudin is intended for use with aspirin (300–325 mg daily) and has been studied only in patients receiving concomitant aspirin.

For patients starting with percutaneous coronary intervention (PCI) the recommended dose is:

  • 0.75 mg/kg body weight as an intravenous injection, followed immediately by an infusion (drip) into vein of 1.75 mg/kg body weight, per hour for at least the duration of the PCI.

If you have kidney problems, the dose of Bivalirudin may need to be reduced.

In the elderly, if their kidney function is decreased, the dose may need to be reduced.

The doctor will decide for how long you should be treated.

What are the possible side effects of Bivastat (Bivalirudin)?

Watch carefully for any signs of bleeding or bruising and report these to your healthcare provider when they occur.

If you get any of the following, potentially serious or less serious, side effects:

  • while you are in hospital: tell the doctor or nurse immediately
  • after you’ve left hospital: contact your doctor directly or go immediately to the Emergency Department of your nearest hospital

The serious side effect of treatment with bivalirudin, is major bleeding which could occur anywhere inside the body (e.g. stomach, digestive system (including vomiting blood or passing blood with the stools), abdomen, lungs, groin, bladder, heart, eye, ear, nose or brain). This may, rarely, result in a stroke or be fatal. Swelling or pain in the groin or the arm, back pain, bruising, headache, coughing blood, pink or red urine, sweating, feeling faint or sick or dizzy due to low blood pressure may be signs of internal bleeding. Bleeding is more likely to occur when bivalirudin is used in combination with other anticoagulant or antithrombotic medicines (see section ‘Undesirable Effects’ ).

Serious non-bleeding adverse effects with bivalirudin include fever, infection, sepsis, hypotension, syncope, abnormal heart beats, confusion, facial paralysis, lung edema, kidney failure, oliguria.

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or by calling on 18002677779 (Cipla number). By reporting side-effects, you can help provide more information on the safety of this product. 

How should I store Bivastat?

As Bivalirudin is a hospital only medicine, storage of Bivalirudin is the responsibility of healthcare professionals.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after ‘EXP’. The expiry date refers to the last day of that month.

Reconstituted solution: Store at 2-8 ºC in a refrigerator. Do not freeze.

Diluted solution: Do not store above 25°C. Do not refrigerate. Do not freeze.

The solution should be a clear to slightly opalescent, colourless to slightly yellow solution.

The doctor will check the solution and will discard it, if it contains particles or is discoloured

Contents of the pack:

BIVASTAT Injection 250 mg Vial of 10 ml with 5 ml sterile water for injection IP.

Details of Manufacturer

BDR Pharmaceuticals Int’l Pvt. Ltd.

Shivam Complex No.1, S - 11, B/4, Dunetha, Nani Daman - 396210,

At: Survey No 46/1-4, Kadaiya Village, Nani Daman - 396 210

Details of Permission or Licence Number with Date

DD/L/610 date 05/08/2019

Marketed By

Cipla Ltd

Registered Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg Lower Parel, Mumbai – 400 013, India

Date of Revision

August 2020