Aggrastat

Aggrastat information, interactions and side effects, AGGRASTAT contains tirofiban hydrochloride, a non-peptide antagonist of the platelet GP IIb/IIIa receptor, inhibits platelet aggregation.

Tirofiban hydrochloride monohydrate is chemically described as N(butylsulfonyl)-O-[4-(4-piperidinyl)butyl]-L-tyrosine monohydrochloride monohydrate.

Its molecular formula is C22H36N2O5S•HCl•H2O and its structural formula is:

Aggrastat

Tirofiban hydrochloride monohydrate is a white to off-white, non-hygroscopic, free-flowing powder, with a molecular weight of 495.08. It is very slightly soluble in water.

AGGRASTAT Injection Premixed is supplied as a sterile solution in water for injection, for intravenous use only, in plastic containers of 100 mL or 250 mL. Each 100 mL of the premixed, iso-osmotic intravenous injection contains 5.618 mg tirofiban hydrochloride monohydrate equivalent to 5 mg tirofiban (50 mcg/mL) and the following inactive ingredients: 0.9 g sodium chloride, 54 mg sodium citrate dihydrate, and 3.2 mg citric acid anhydrous. Each 250 mL of the premixed, iso-osmotic intravenous injection contains 14.045 mg tirofiban hydrochloride monohydrate equivalent to 12.5 mg tirofiban (50 mcg/mL) and the following inactive ingredients: 2.25 g sodium chloride, 135 mg sodium citrate dihydrate, and 8 mg citric acid anhydrous.

The pH of the solution ranges from 5.5 to 6.5 and may have been adjusted with hydrochloric acid and/or sodium hydroxide. The flexible container is manufactured from a specially designed multilayer plastic (PL 2408). Solutions in contact with the plastic container leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials.

INDICATIONS

AGGRASTAT is indicated to reduce the rate of thrombotic cardiovascular events (combined endpoint of death, myocardial infarction, or refractory ischemia/repeat cardiac procedure) in patients with non-ST elevation acute coronary syndrome (NSTE-ACS).

DOSAGE AND ADMINISTRATION

Administer intravenously 25 mcg/kg over 3 minutes and then 0.15 mcg/kg/min (or 0.075 mcg/kg/min for patients with serum creatinine ≤ 60 mL/min), for up to 18 hours. This is not the regimen that was used in studies that established effectiveness of AGGRASTAT.

The instructions by weight and creatinine clearance are tabulated in Table 1.

Table 1 : Dosing by Weight and CrCl

 

Weight (kg) First 3 min All Patients (mL) Maintenance Infusion Rate (mL/hr.)
CrCl > 60 mL/min CrCl ≤ 60 mL/min
30-37 17 6 3
38-45 21 7.5 3.75
46-54 25 9 4.5
55-62 29 10.5 5.25
63-70 33 12 6
71-79 37.5 13.5 6.75
80-87 42 15 7.5
88-95 46 16.5 8.25
96-104 50 18 9
105-112 54 19.5 9.75
113-120 58 21 10.5
121-128 62 22.5 11.25
129-137 66.5 24 12
138-145 71 25.5 12.75
146-153 75 27 13.5

 

Important Administration Instructions

  1. To open the container, first tear off its foil overpouch. The plastic may be somewhat opaque because of moisture absorption during sterilization; the opacity will diminish gradually. Check for leaks by squeezing the inner bag firmly; if any leaks are found or sterility is suspect then the solution should be discarded. Do not use unless the solution is clear and the seal is intact. Suspend the container from its eyelet support, remove the plastic protector from the outlet port, and attach a conventional administration set.
  2. You may administer AGGRASTAT in the same intravenous line as atropine sulfate, dobutamine, dopamine, epinephrine hydrochloride (HCl), famotidine injection, furosemide, lidocaine, midazolam HCl, morphine sulfate, nitroglycerin, potassium chloride, and propranolol HCl. Do not administer AGGRASTAT through the same IV line as diazepam.
  3. Do not add other drugs or remove solution directly from the bag with a syringe.
  4. Do not use plastic containers in series connections; such use can result in air embolism by drawing air from the first container if it is empty of solution.
  5. Discard any unused portion left in the bag.

HOW SUPPLIED

Dosage Forms And Strengths

FOR INTRAVENOUS USE ONLY

AGGRASTAT Injection Premixed 5 mg tirofiban per 100 mL (50 mcg per mL) and 12.5 mg tirofiban per 250 mL (50 mcg per mL) are clear, non-preserved, sterile solutions premixed in a vehicle made iso-osmotic with sodium chloride.

Storage And Handling

AGGRASTAT Injection Premixed 5 mg tirofiban per 100 mL (50 mcg per mL) and 12.5 mg tirofiban per 250 mL (50 mcg per mL) are clear, non-preserved, sterile solutions premixed in a vehicle made iso-osmotic with sodium chloride, and are supplied as follows:

NDC 25208-002-01, 100 mL single-dose INTRAVIA containers (PL 2408 Plastic).
NDC 25208-002-02, 250 mL single-dose INTRAVIA containers (PL 2408 Plastic).

FOR INTRAVENOUS USE ONLY

Store AGGRASTAT at 25°C (77°F) with excursions permitted between 15-30°C (59-86°F). Do not freeze. Protect from light during storage.

SIDE EFFECTS

Clinical Trial 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 clinical practice.

In the PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management), PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management — Patients Limited by Unstable Signs and Symptoms) and RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis) trials, 1946 patients received AGGRASTAT in combination with heparin and 2002 patients received AGGRASTAT alone for about 3 days. Forty-three percent of the population was > 65 years of age and approximately 30% of patients were female. In clinical studies with the recommended regimen (25 mcg/kg bolus followed by a 0.15 mcg/kg/min maintenance infusion), AGGRASTAT was administered in combination with aspirin, clopidogrel and heparin or bivalirudin to over 8000 patients for typically ≤ 24 hours. Approximately 30% of the population was > 65 years of age and approximately 25% were female.

Bleeding

PRISM-PLUS Regimen

The incidences of major and minor bleeding using the TIMI criteria in the PRISM-PLUS study are shown below.

Table 2 : TIMI Major and Minor Bleeding in PRISM-PLUS

 

Bleeding (TIMI Criteria)‡ § AGGRASTAT* + heparin
(N=773)
Heparin alone
(N=797)
Major Bleeding 1.4% 0.8%
Minor Bleeding 10.5% 8.0%
Transfusions 4.0% 2.8%
* 0.4 mcg/kg/min initial infusion; 0.10 mcg/kg/min maintenance infusion.
‡ Major = Hemoglobin drop of > 5.0 g/L with or without an identified site, intracranial hemorrhage, or cardiac tamponade.
§ Minor = Hemoglobin drop of > 3.0 g/L with bleeding from a known site, spontaneous gross hematuria, hematemesis or hemoptysis. The incidence rates of TIMI major bleeding in patients undergoing percutaneous procedures in PRISM-PLUS are shown below.

 

Table 3 : TIMI Major Bleeding Associated with Percutaneous Procedures in PRISM-PLUS

 

AGGRASTAT+ heparin Heparin alone
N % N %
Prior to Procedures 773 0.3 797 0.1
Following Angiography 697 1.3 708 0.7
Following PTCA 239 2.5 236 2.2

The incidence rates of TIMI major bleeding in patients undergoing coronary artery bypass graft surgery (CABG) in PRISM-PLUS within one day of discontinuation of AGGRASTAT were 17% on AGGRASTAT plus heparin (N=29) and 35% on heparin alone (N=31).

Recommended (“High-Dose Bolus”) Regimen

Rates of major bleeds (including any intracranial, intraocular or retroperitoneal hemorrhage, clinically overt signs of hemorrhage associated with a drop in hemoglobin of > 3 g/dL or any drop in hemoglobin by 4g/dL, bleeding requiring transfusion of > 2U blood products, bleeding directly resulting in death within 7 days or hemodynamic compromise requiring intervention) were consistent with the rates observed in subjects administered the PRISM-PLUS regimen of AGGRASTAT. There was a trend toward greater bleeding in ST segment elevation myocardial infarction (STEMI) patients treated with fibrinolytics prior to administration of AGGRASTAT using the recommended regimen during rescue PCI.

Non-Bleeding

The incidences of non-bleeding adverse events that occurred at an incidence of > 1% and numerically higher than control, regardless of drug relationship, are shown below:

Table 4 : Non-bleeding Adverse Reactions in PRISM-PLUS

 

AGGRASTAT + heparin
(N=1953)
%
Heparin alone
(N=1887)
%
Body as a Whole
  Edema/swelling 2 1
  Pain, pelvic 6 5
  Reaction, vasovagal 2 1
Cardiovascular System
  Bradycardia 4 3
  Dissection, coronary artery 5 4
Musculoskeletal System
  Pain, leg 3 2
Nervous System/Psychiatric
  Dizziness 3 2
Skin and Skin Appendage
  Sweating 2 1

 

Thrombocytopenia

Patients treated with AGGRASTAT plus heparin, were more likely to experience decreases in platelet counts than were those on heparin alone. These decreases were reversible upon discontinuation of AGGRASTAT. The percentage of patients with a decrease of platelets to < 90,000/mm³ was 1.5%, compared with 0.6% in the patients who received heparin alone. The percentage of patients with a decrease of platelets to < 50,000/mm³ was 0.3%, compared with 0.1% of the patients who received heparin alone.

Post-Marketing Experience

The following additional adverse reactions have been identified during post-approval use of AGGRASTAT. Because these 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 the drug exposure.

Hypersensitivity

Severe allergic reactions including anaphylactic reactions have occurred during the first day of AGGRASTAT infusion, during initial treatment, and during readministration of AGGRASTAT. Some cases have been associated with severe thrombocytopenia (platelet counts < 10,000/mm³). No information is available on the formation of antibodies to tirofiban.

DRUG INTERACTIONS

Use of thrombolytics, anticoagulants, and other antiplatelet agents

Coadministration of antiplatelet agents, thrombolytics, heparin, and aspirin increases the risk of bleeding.

PRECAUTIONS

General Risk of Bleeding

Bleeding is the most common complication encountered during therapy with AGGRASTAT. Most bleeding associated with AGGRASTAT occurs at the arterial access site for cardiac catheterization. Minimize the use of traumatic or potentially traumatic procedures such arterial and venous punctures, intramuscular injections, nasotracheal intubation, etc. Fatal bleeding events have been reported.

Concomitant use of fibrinolytics, oral anticoagulants and antiplatelet drugs increases the risk of bleeding.

Thrombocytopenia

Profound thrombocytopenia has been reported with AGGRASTAT. Monitor platelet counts beginning about 6 hours after treatment initiation and daily thereafter. If the platelet count decreases to < 90,000/mm³, monitor platelet counts to exclude pseudothrombocytopenia. If thrombocytopenia is confirmed, discontinue AGGRASTAT and heparin. Previous exposure to a glycoprotein (GP) IIb/IIIa receptor antagonist may increase the risk of developing thrombocytopenia.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of AGGRASTAT has not been evaluated.

Tirofiban HCl was negative in the in vitro microbial mutagenesis and V-79 mammalian cell mutagenesis assays. In addition, there was no evidence of direct genotoxicity in the in vitro alkaline elution and in vitro chromosomal aberration assays. There was no induction of chromosomal aberrations in bone marrow cells of male mice after the administration of intravenous doses up to 5 mg tirofiban/kg (about 3 times the maximum recommended daily human dose when compared on a body surface area basis).

Fertility and reproductive performance were not affected in studies with male and female rats given intravenous doses of tirofiban up to 5 mg/kg/day (about 5 times the maximum recommended daily human dose when compared on a body surface area basis).

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Tirofiban has been shown to cross the placenta in pregnant rats and rabbits. Studies with tirofiban HCl at intravenous doses up to 5 mg/kg/day (about 5 and 13 times the maximum recommended daily human dose for rat and rabbit, respectively, when compared on a body surface area basis) have revealed no harm to the fetus.

Nursing Mothers

It is not known whether tirofiban is excreted in human milk. However, significant levels of tirofiban were shown to be present in rat milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects on the nursing infant, discontinue nursing or discontinue AGGRASTAT.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of patients in controlled clinical studies of AGGRASTAT, 43% were 65 years and over, while 12% were 75 and over. With respect to efficacy, the effect of AGGRASTAT in the elderly ( ≥ 65 years) appeared similar to that seen in younger patients ( < 65 years). Elderly patients receiving AGGRASTAT with heparin or heparin alone had a higher incidence of bleeding complications than did younger patients, but the incremental risk of bleeding in patients treated with AGGRASTAT in combination with heparin compared to the risk in patients treated with heparin alone was similar regardless of age. No dose adjustment is recommended for the elderly population.

Renal Insufficiency

Patients with moderate to severe renal insufficiency have decreased plasma clearance of AGGRASTAT. Reduce the dosage of AGGRASTAT in patients with severe renal insufficiency.

Safety and efficacy of AGGRASTAT has not been established in patients on hemodialysis.

OVERDOSE

In clinical trials, inadvertent overdosage with AGGRASTAT occurred in doses up to 2 times the recommended dose for initial infusion doses. Inadvertent overdosage occurred in doses up to 9.8 times the 0.15 mcg/kg/min maintenance infusion rate.

The most frequently reported manifestation of overdosage was bleeding, primarily minor mucocutaneous bleeding events and minor bleeding at the sites of cardiac catheterization.

Overdosage of AGGRASTAT should be treated by assessment of the patient’s clinical condition and cessation or adjustment of the drug infusion as appropriate.

AGGRASTAT can be removed by hemodialysis.

CONTRAINDICATIONS

AGGRASTAT is contraindicated in patients with:

  • Severe hypersensitivity reaction to AGGRASTAT (i.e., anaphylactic reactions).
  • A history of thrombocytopenia following prior exposure to AGGRASTAT.
  • Active internal bleeding or a history of bleeding diathesis, major surgical procedure or severe physical trauma within the previous month.
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