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Intiflo

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Intiflo uses


1 INDICATIONS AND USAGE

Intiflo is a platelet aggregation inhibitor indicated for:

1.1 Acute Coronary Syndrome (ACS)

Intiflo ® is indicated to decrease the rate of a combined endpoint of death or new myocardial infarction (MI) in patients with ACS (unstable angina [UA]/non-ST-elevation myocardial infarction [NSTEMI]), including patients who are to be managed medically and those undergoing percutaneous coronary intervention (PCI).

1.2 Percutaneous Coronary Intervention

Intiflo is indicated to decrease the rate of a combined endpoint of death, new MI, or need for urgent intervention in patients undergoing PCI, including those undergoing intracoronary stenting .

2 DOSAGE AND ADMINISTRATION

Before infusion of Intiflo, the following laboratory tests should be performed to identify pre-existing hemostatic abnormalities: hematocrit or hemoglobin, platelet count, serum creatinine, and PT/aPTT. In patients undergoing PCI, the activated clotting time should also be measured.

The activated partial thromboplastin time (aPTT) should be maintained between 50 and 70 seconds unless PCI is to be performed. In patients treated with heparin, bleeding can be minimized by close monitoring of the aPTT and ACT.

ACS or PCI: 180 mcg/kg IV bolus as soon as possible after diagnosis followed by infusion at 2 mcg/kg/min. (2.1, 2.2)

PCI: Add a second 180 mcg/kg bolus at 10 minutes. (2.2)

In patients with creatinine clearance less than 50 mL/min, reduce the infusion to 1 mcg/kg/min. (2.1, 2.2, 2.3)

2.1 Dosage in Acute Coronary Syndrome (ACS)

Indication Normal Renal Function Creatinine Clearance less than 50 mL/min
Patients with ACS 180 mcg/kg intravenous (IV) bolus as soon as possible after diagnosis, followed by continuous infusion of 2 mcg/kg/min 180 mcg/kg IV bolus as soon as possible after diagnosis, followed by continuous infusion of 1 mcg/kg/min
  • Infusion should continue until hospital discharge or initiation of coronary artery bypass graft surgery (CABG), up to 72 hours
  • If a patient is to undergo PCI, the infusion should be continued until hospital discharge or for up to 18 to 24 hours after the procedure, whichever comes first, allowing for up to 96 hours of therapy
  • Aspirin, 160 to 325 mg, should be given daily

Intiflo should be given concomitantly with heparin dosed to achieve the following parameters:

2.2 Dosage in Percutaneous Coronary Intervention

Indication Normal Renal Function Creatinine Clearance less than 50 mL/min
Patients with PCI 180 mcg/kg IV bolus immediately before PCI followed by continuous infusion of 2 mcg/kg/min and a second bolus of 180 mcg/kg (given 10 minutes after the first bolus) 180 mcg/kg IV bolus immediately before PCI followed by continuous infusion of 1 mcg/kg/min and a second bolus of 180 mcg/kg (given 10 minutes after the first bolus)
  • Infusion should be continued until hospital discharge, or for up to 18 to 24 hours, whichever comes first. A minimum of 12 hours of infusion is recommended.
  • In patients who undergo CABG surgery, Intiflo infusion should be discontinued prior to surgery.
  • Aspirin, 160 to 325 mg, should be given 1 to 24 hours prior to PCI and daily thereafter

Patients requiring thrombolytic therapy should discontinue Intiflo.

2.3 Important Administration Instructions


Administer Intiflo by volume according to patient weight.

Patient Weight 180-mcg/kg

Bolus Volume

 2-mcg/kg/min

Infusion Volume

(CrCl greater than or equal to 50 mL/min)

 1-mcg/kg/min

Infusion Volume

(CrCl less than 50 mL/min)
(kg) (lb) (from 2-mg/mL vial) (from 2-mg/mL 100-mL vial) (from 0.75-mg/mL 100-mL vial) (from 2-mg/mL 100-mL vial) (from 0.75-mg/mL 100-mL vial)
37-41 81-91 3.4 mL 2 mL/h 6 mL/h 1 mL/h 3 mL/h
42-46 92-102 4 mL 2.5 mL/h 7 mL/h 1.3 mL/h 3.5 mL/h
47-53 103-117 4.5 mL 3 mL/h 8 mL/h 1.5 mL/h 4 mL/h
54-59 118-130 5 mL 3.5 mL/h 9 mL/h 1.8 mL/h 4.5 mL/h
60-65 131-143 5.6 mL 3.8 mL/h 10 mL/h 1.9 mL/h 5 mL/h
66-71 144-157 6.2 mL 4 mL/h 11 mL/h 2 mL/h 5.5 mL/h
72-78 158-172 6.8 mL 4.5 mL/h 12 mL/h 2.3 mL/h 6 mL/h
79-84 173-185 7.3 mL 5 mL/h 13 mL/h 2.5 mL/h 6.5 mL/h
85-90 186-198 7.9 mL 5.3 mL/h 14 mL/h 2.7 mL/h 7 mL/h
91-96 199-212 8.5 mL 5.6 mL/h 15 mL/h 2.8 mL/h 7.5 mL/h
97-103 213-227 9 mL 6 mL/h 16 mL/h 3.0 mL/h 8 mL/h
104-109 228-240 9.5 mL 6.4 mL/h 17 mL/h 3.2 mL/h 8.5 mL/h
110-115 241-253 10.2 mL 6.8 mL/h 18 mL/h 3.4 mL/h 9 mL/h
116-121 254-267 10.7 mL 7 mL/h 19 mL/h 3.5 mL/h 9.5 mL/h
>121 >267 11.3 mL 7.5 mL/h 20 mL/h 3.7 mL/h 10 mL/h
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3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

Treatment with Intiflo is contraindicated in patients with:

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5 WARNINGS AND PRECAUTIONS

5.1 Bleeding

Bleeding is the most common complication encountered during Intiflo therapy. Administration of Intiflo is associated with an increase in major and minor bleeding, as classified by the criteria of the Thrombolysis in Myocardial Infarction Study group (TIMI) . Most major bleeding associated with Intiflo has been at the arterial access site for cardiac catheterization or from the gastrointestinal or genitourinary tract. Minimize the use of arterial and venous punctures, intramuscular injections, and the use of urinary catheters, nasotracheal intubation, and nasogastric tubes. When obtaining intravenous access, avoid non-compressible sites (e.g., subclavian or jugular veins).

Use of Thrombolytics, Anticoagulants, and Other Antiplatelet Agents

Risk factors for bleeding include older age, a history of bleeding disorders, and concomitant use of drugs that increase the risk of bleeding (thrombolytics, oral anticoagulants, nonsteroidal anti-inflammatory drugs, and P2Y12 inhibitors). Concomitant treatment with other inhibitors of platelet receptor glycoprotein (GP) IIb/IIIa should be avoided. In patients treated with heparin, bleeding can be minimized by close monitoring of the aPTT and ACT .

Care of the Femoral Artery Access Site in Patients Undergoing Percutaneous Coronary Intervention (PCI)

In patients undergoing PCI, treatment with Intiflo is associated with an increase in major and minor bleeding at the site of arterial sheath placement. After PCI, Intiflo infusion should be continued until hospital discharge or up to 18 to 24 hours, whichever comes first. Heparin use is discouraged after the PCI procedure. Early sheath removal is encouraged while Intiflo is being infused. Prior to removing the sheath, it is recommended that heparin be discontinued for 3 to 4 hours and an aPTT of <45 seconds or ACT <150 seconds be achieved. In any case, both heparin and Intiflo should be discontinued and sheath hemostasis should be achieved at least 2 to 4 hours before hospital discharge. If bleeding at access site cannot be controlled with pressure, infusion of Intiflo and heparin should be discontinued immediately.

5.2 Thrombocytopenia

There have been reports of acute, profound thrombocytopenia (immune-mediated and non-immune mediated) with Intiflo. In the event of acute profound thrombocytopenia or a confirmed platelet decrease to <100,000/mm3, discontinue Intiflo and heparin (unfractionated or low-molecular weight). Monitor serial platelet counts, assess the presence of drug-dependent antibodies, and treat as appropriate .

There has been no clinical experience with Intiflo initiated in patients with a baseline platelet count <100,000/mm3. If a patient with low platelet counts is receiving Intiflo, their platelet count should be monitored closely.

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6 ADVERSE REACTIONS

The following serious adverse reaction is also discussed elsewhere in the labeling:


Bleeding and hypotension are the most commonly reported adverse reactions. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies 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.

A total of 16,782 patients were treated in the Phase III clinical trials (PURSUIT, ESPRIT, and IMPACT II) . These 16,782 patients had a mean age of 62 years (range: 20-94 years). Eighty-nine percent of the patients were Caucasian, with the remainder being predominantly Black (5%) and Hispanic (5%). Sixty-eight percent were men. Because of the different regimens used in PURSUIT, IMPACT II, and ESPRIT, data from the 3 studies were not pooled.

Bleeding and hypotension were the most commonly reported adverse reactions (incidence ≥5% and greater than placebo) in the Intiflo controlled clinical trial database.

Bleeding

The incidence of bleeding and transfusions in the PURSUIT and ESPRIT studies are shown in Table 2. Bleeding was classified as major or minor by the criteria of the TIMI study group. Major bleeding consisted of intracranial hemorrhage and other bleeding that led to decreases in hemoglobin greater than 5 g/dL. Minor bleeding included spontaneous gross hematuria, spontaneous hematemesis, other observed blood loss with a hemoglobin decrease of more than 3 g/dL, and other hemoglobin decreases that were greater than 4 g/dL but less than 5 g/dL. In patients who received transfusions, the corresponding loss in hemoglobin was estimated through an adaptation of the method of Landefeld et al.

PURSUIT (ACS)
Placebo Intiflo

180/2
n (%) n (%)
Note: Denominator is based on patients for whom data are available.
Patients 4696 4679
Major bleedingFor major and minor bleeding, patients are counted only once according to the most severe classification. 425 (9.3%) 498 (10.8%)
Minor bleeding 347 (7.6%) 604 (13.1%)
Requiring transfusionsIncludes transfusions of whole blood, packed red blood cells, fresh frozen plasma, cryoprecipitate, platelets, and autotransfusion during the initial hospitalization. 490 (10.4%) 601 (12.8%)
ESPRIT (PCI)
Placebo Intiflo

180/2/180

n (%) n (%)
Patients 1024 1040
Major bleeding 4 (0.4%) 13 (1.3%)
Minor bleeding 18 (2%) 29 (3%)
Requiring transfusions 11 (1.1%) 16 (1.5%)

The majority of major bleeding reactions in the ESPRIT study occurred at the vascular access site (1 and 8 patients, or 0.1% and 0.8% in the placebo and Intiflo groups, respectively). Bleeding at "other" locations occurred in 0.2% and 0.4% of patients, respectively.

In the PURSUIT study, the greatest increase in major bleeding in INTEGRILIN-treated patients compared to placebo-treated patients was also associated with bleeding at the femoral artery access site (2.8% versus 1.3%). Oropharyngeal (primarily gingival), genitourinary, gastrointestinal, and retroperitoneal bleeding were also seen more commonly in INTEGRILIN-treated patients compared to placebo-treated patients.

Among patients experiencing a major bleed in the IMPACT II study, an increase in bleeding on Intiflo versus placebo was observed only for the femoral artery access site (3.2% versus 2.8%).

Table 3 displays the incidence of TIMI major bleeding according to the cardiac procedures carried out in the PURSUIT study. The most common bleeding complications were related to cardiac revascularization (CABG-related or femoral artery access site bleeding). A corresponding table for ESPRIT is not presented, as every patient underwent PCI in the ESPRIT study and only 11 patients underwent CABG.

Placebo Intiflo
180/2
n (%) n (%)
Note: Denominators are based on the total number of patients whose TIMI classification was resolved.
Patients 4577 4604
Overall incidence of major bleeding 425 (9.3%) 498 (10.8%)
Breakdown by procedure:
CABG 375 (8.2%) 377 (8.2%)
Angioplasty without CABG 27 (0.6%) 64 (1.4%)
Angiography without angioplasty or CABG 11 (0.2%) 29 (0.6%)
Medical therapy only 12 (0.3%) 28 (0.6%)

In the PURSUIT and ESPRIT studies, the risk of major bleeding with Intiflo increased as patient weight decreased. This relationship was most apparent for patients weighing less than 70 kg.

Bleeding resulting in discontinuation of the study drug was more frequent among patients receiving Intiflo than placebo (4.6% versus 0.9% in ESPRIT, 8% versus 1% in PURSUIT, 3.5% versus 1.9% in IMPACT II).

Intracranial Hemorrhage and Stroke

Intracranial hemorrhage was rare in the PURSUIT, IMPACT II, and ESPRIT clinical studies. In the PURSUIT study, 3 patients in the placebo group, 1 patient in the group treated with Intiflo 180/1.3, and 5 patients in the group treated with Intiflo 180/2 experienced a hemorrhagic stroke. The overall incidence of stroke was 0.5% in patients receiving Intiflo 180/1.3, 0.7% in patients receiving Intiflo 180/2, and 0.8% in placebo patients.

In the IMPACT II study, intracranial hemorrhage was experienced by 1 patient treated with Intiflo 135/0.5, 2 patients treated with Intiflo 135/0.75, and 2 patients in the placebo group. The overall incidence of stroke was 0.5% in patients receiving 135/0.5 Intiflo, 0.7% in patients receiving Intiflo 135/0.75, and 0.7% in the placebo group.

In the ESPRIT study, there were 3 hemorrhagic strokes, 1 in the placebo group and 2 in the Intiflo group. In addition there was 1 case of cerebral infarction in the Intiflo group.

Immunogenicity/Thrombocytopenia

The potential for development of antibodies to Intiflo has been studied in 433 subjects. Intiflo was nonantigenic in 412 patients receiving a single administration of Intiflo (135-mcg/kg bolus followed by a continuous infusion of either 0.5 mcg/kg/min or 0.75 mcg/kg/min), and in 21 subjects to whom Intiflo (135-mcg/kg bolus followed by a continuous infusion of 0.75 mcg/kg/min) was administered twice, 28 days apart. In both cases, plasma for antibody detection was collected approximately 30 days after each dose. The development of antibodies to Intiflo at higher doses has not been evaluated.

In patients with suspected INTEGRILIN-related immune-mediated thrombocytopenia, IgG antibodies that react with the GP IIb/IIIa complex were identified in the presence of Intiflo and in INTEGRILIN-naïve patients. These findings suggest acute thrombocytopenia after the administration of Intiflo can develop as a result of naturally occurring drug-dependent antibodies or those induced by prior exposure to Intiflo. Similar antibodies were identified with other GP IIb/IIIa ligand-mimetic agents. Immune-mediated thrombocytopenia with Intiflo may be associated with hypotension and/or other signs of hypersensitivity.

In the PURSUIT and IMPACT II studies, the incidence of thrombocytopenia (<100,000/mm3 or ≥50% reduction from baseline) and the incidence of platelet transfusions were similar between patients treated with Intiflo and placebo. In the ESPRIT study, the incidence was 0.6% in the placebo group and 1.2% in the Intiflo group.

Other Adverse Reactions

In the PURSUIT and ESPRIT studies, the incidence of serious nonbleeding adverse reactions was similar in patients receiving placebo or Intiflo (19% and 19%, respectively, in PURSUIT; 6% and 7%, respectively, in ESPRIT). In PURSUIT, the only serious nonbleeding adverse reaction that occurred at a rate of at least 1% and was more common with Intiflo than placebo (7% versus 6%) was hypotension. Most of the serious nonbleeding adverse reactions consisted of cardiovascular reactions typical of a UA population. In the IMPACT II study, serious nonbleeding adverse reactions that occurred in greater than 1% of patients were uncommon and similar in incidence between placebo- and INTEGRILIN-treated patients.

Discontinuation of study drug due to adverse reactions other than bleeding was uncommon in the PURSUIT, IMPACT II, and ESPRIT studies, with no single reaction occurring in >0.5% of the study population (except for "other" in the ESPRIT study).

6.2 Postmarketing Experience

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

The following adverse reactions have been reported in postmarketing experience, primarily with Intiflo in combination with heparin and aspirin: cerebral, GI, and pulmonary hemorrhage. Fatal bleeding reactions have been reported. Acute profound thrombocytopenia, as well as immune-mediated thrombocytopenia, has been reported .

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7 DRUG INTERACTIONS

7.1 Use of Thrombolytics, Anticoagulants, and Other Antiplatelet Agents

Coadministration of antiplatelet agents, thrombolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. Concomitant treatment with other inhibitors of platelet receptor GP IIb/IIIa should be avoided.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Teratology studies have been performed by continuous intravenous infusion of Intiflo in pregnant rats at total daily doses of up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis) and in pregnant rabbits at total daily doses of up to 36 mg/kg/day (also about 4 times the recommended maximum daily human dose on a body surface area basis). These studies revealed no evidence of harm to the fetus due to Intiflo. There are, however, no adequate and well-controlled studies in pregnant women with Intiflo. Because animal reproduction studies are not always predictive of human response, Intiflo should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness of Intiflo in pediatric patients have not been studied.

8.5 Geriatric Use

The PURSUIT and IMPACT II clinical studies enrolled patients up to the age of 94 years. There was no apparent difference in efficacy between older and younger patients treated with Intiflo. The incidence of bleeding complications was higher in the elderly in both placebo and Intiflo groups, and the incremental risk of INTEGRILIN-associated bleeding was greater in the older patients. No dose adjustment was made for elderly patients, but patients over 75 years of age had to weigh at least 50 kg to be enrolled in the PURSUIT study; no such limitation was stipulated in the ESPRIT study .

8.6 Renal Impairment

Approximately 50% of Intiflo is cleared by the kidney in patients with normal renal function. Total drug clearance is decreased by approximately 50% and steady-state plasma Intiflo concentrations are doubled in patients with an estimated CrCl <50 mL/min (using the Cockcroft-Gault equation). Therefore, the infusion dose should be reduced to 1 mcg/kg/min in such patients . The safety and efficacy of Intiflo in patients dependent on dialysis has not been established.

10 OVERDOSAGE

There has been only limited experience with overdosage of Intiflo. There were 8 patients in the IMPACT II study, 9 patients in the PURSUIT study, and no patients in the ESPRIT study who received bolus doses and/or infusion doses more than double those called for in the protocols. None of these patients experienced an intracranial bleed or other major bleeding.

Intiflo was not lethal to rats, rabbits, or monkeys when administered by continuous intravenous infusion for 90 minutes at a total dose of 45 mg/kg (about 2 to 5 times the recommended maximum daily human dose on a body surface area basis). Symptoms of acute toxicity were loss of righting reflex, dyspnea, ptosis, and decreased muscle tone in rabbits and petechial hemorrhages in the femoral and abdominal areas of monkeys.

From in vitro studies, Intiflo is not extensively bound to plasma proteins and thus may be cleared from plasma by dialysis.

11 DESCRIPTION

Intiflo is a cyclic heptapeptide containing 6 amino acids and 1 mercaptopropionyl (des-amino cysteinyl) residue. An interchain disulfide bridge is formed between the cysteine amide and the mercaptopropionyl moieties. Chemically it is N6-(aminoiminomethyl)-N2-(3-mercapto-1-oxopropyl)-L-lysylglycyl-L-α-aspartyl-L-tryptophyl-L-prolyl-L-cysteinamide, cyclic (1→6)-disulfide. Intiflo binds to the platelet receptor glycoprotein (GP) IIb/IIIa of human platelets and inhibits platelet aggregation.

The Intiflo peptide is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase liquid chromatography and lyophilized. The structural formula is:

Intiflo Injection is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use with an empirical formula of C35H49N11O9S2 and a molecular weight of 831.96. Each 10-mL vial contains 2 mg/mL of Intiflo and each 100-mL vial contains either 0.75 mg/mL of Intiflo or 2 mg/mL of Intiflo. Each vial of either size also contains 5.25 mg/mL citric acid and sodium hydroxide to adjust the pH to 5.35.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Intiflo reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to GP IIb/IIIa. When administered intravenously, Intiflo inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. Platelet aggregation inhibition is reversible following cessation of the Intiflo infusion; this is thought to result from dissociation of Intiflo from the platelet.

12.2 Pharmacodynamics

Infusion of Intiflo into baboons caused a dose-dependent inhibition of ex vivo platelet aggregation, with complete inhibition of aggregation achieved at infusion rates greater than 5 mcg/kg/min. In a baboon model that is refractory to aspirin and heparin, doses of Intiflo that inhibit aggregation prevented acute thrombosis with only a modest prolongation of the bleeding time. Platelet aggregation in dogs was also inhibited by infusions of Intiflo, with complete inhibition at 2 mcg/kg/min. This infusion dose completely inhibited canine coronary thrombosis induced by coronary artery injury (Folts model).

Human pharmacodynamic data were obtained in healthy subjects and in patients presenting with UA or NSTEMI and/or undergoing percutaneous coronary intervention. Studies in healthy subjects enrolled only males; patient studies enrolled approximately one-third women. In these studies, Intiflo inhibited ex vivo platelet aggregation induced by adenosine diphosphate (ADP) and other agonists in a dose- and concentration-dependent manner. The effect of Intiflo was observed immediately after administration of a 180-mcg/kg intravenous bolus. Table 4 shows the effects of dosing regimens of Intiflo used in the IMPACT II and PURSUIT studies on ex vivo platelet aggregation induced by 20 µM ADP in PPACK-anticoagulated platelet-rich plasma and on bleeding time. The effects of the dosing regimen used in ESPRIT on platelet aggregation have not been studied.

PURSUIT

180/2180-mcg/kg bolus followed by a continuous infusion of 2 mcg/kg/min.

Inhibition of platelet aggregation 15 min after bolus 84%
Inhibition of platelet aggregation at steady state >90%
Bleeding-time prolongation at steady state <5x
Inhibition of platelet aggregation 4h after infusion discontinuation <50%
Bleeding-time prolongation 6h after infusion discontinuation 1.4x

The Intiflo dosing regimen used in the ESPRIT study included two 180-mcg/kg bolus doses given 10 minutes apart combined with a continuous 2-mcg/kg/min infusion.

When administered alone, Intiflo has no measurable effect on PT or aPTT.

There were no important differences between men and women or between age groups in the pharmacodynamic properties of Intiflo. Differences among ethnic groups have not been assessed.

12.3 Pharmacokinetics

The pharmacokinetics of Intiflo are linear and dose-proportional for bolus doses ranging from 90 to 250 mcg/kg and infusion rates from 0.5 to 3 mcg/kg/min. Plasma elimination half-life is approximately 2.5 hours. Administration of a single 180-mcg/kg bolus combined with an infusion produces an early peak level, followed by a small decline prior to attaining steady state (within 4-6 hours). This decline can be prevented by administering a second 180-mcg/kg bolus 10 minutes after the first. The extent of Intiflo binding to human plasma protein is about 25%. Clearance in patients with coronary artery disease is about 55 mL/kg/h. In healthy subjects, renal clearance accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as Intiflo, deaminated Intiflo, and other, more polar metabolites. No major metabolites have been detected in human plasma.

Special Populations

Geriatric

Patients in clinical studies were older (range: 20-94 years) than those in the clinical pharmacology studies. Elderly patients with coronary artery disease demonstrated higher plasma levels and lower total body clearance of Intiflo when given the same dose as younger patients. Limited data are available on lighter weight (<50 kg) patients over 75 years of age.

Renal Impairment

In patients with moderate to severe renal insufficiency (CrCl <50 mL/min using the Cockcroft-Gault equation), the clearance of Intiflo is reduced by approximately 50% and steady-state plasma levels approximately doubled .

Hepatic Impairment

No studies have been conducted in patients with hepatic impairment.

Gender

Males and females have not demonstrated any clinically significant differences in the pharmacokinetics of Intiflo.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of Intiflo. Intiflo was not genotoxic in the Ames test, the mouse lymphoma cell (L 5178Y, TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Administered by continuous intravenous infusion at total daily doses up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis), Intiflo had no effect on fertility and reproductive performance of male and female rats.

14 CLINICAL STUDIES

Intiflo was studied in 3 placebo-controlled, randomized studies. PURSUIT evaluated patients with acute coronary syndromes: UA or NSTEMI. Two other studies, ESPRIT and IMPACT II, evaluated patients about to undergo a PCI. Patients underwent primarily balloon angioplasty in IMPACT II and intracoronary stent placement, with or without angioplasty, in ESPRIT.

14.1 Non-ST-Segment Elevation Acute Coronary Syndrome

Non-ST-segment elevation acute coronary syndrome is defined as prolonged symptoms of cardiac ischemia within the previous 24 hours associated with either ST-segment changes (elevations between 0.6 mm and 1 mm or depression >0.5 mm), T-wave inversion (>1 mm), or positive CK-MB. This definition includes "unstable angina" and "NSTEMI" but excludes MI that is associated with Q waves or greater degrees of ST-segment elevation.

PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Intiflo Therapy)

PURSUIT was a 726-center, 27-country, double-blind, randomized, placebo-controlled study in 10,948 patients presenting with UA or NSTEMI. Patients could be enrolled only if they had experienced cardiac ischemia at rest (≥10 minutes) within the previous 24 hours and had either ST-segment changes (elevations between 0.6 mm and 1 mm or depression >0.5 mm), T-wave inversion (>1 mm), or increased CK-MB. Important exclusion criteria included a history of bleeding diathesis, evidence of abnormal bleeding within the previous 30 days, uncontrolled hypertension, major surgery within the previous 6 weeks, stroke within the previous 30 days, any history of hemorrhagic stroke, serum creatinine >2 mg/dL, dependency on renal dialysis, or platelet count <100,000/mm3.

Patients were randomized to placebo, to Intiflo 180-mcg/kg bolus followed by a 2-mcg/kg/min infusion (180/2), or to Intiflo 180-mcg/kg bolus followed by a 1.3-mcg/kg/min infusion (180/1.3). The infusion was continued for 72 hours, until hospital discharge, or until the time of CABG, whichever occurred first, except that if PCI was performed, the Intiflo infusion was continued for 24 hours after the procedure, allowing for a duration of infusion up to 96 hours.

The lower-infusion-rate arm was stopped after the first interim analysis when the 2 active-treatment arms appeared to have the same incidence of bleeding.

Patient age ranged from 20 to 94 (mean 63) years, and 65% were male. The patients were 89% Caucasian, 6% Hispanic, and 5% Black, recruited in the United States and Canada (40%), Western Europe (39%), Eastern Europe (16%), and Latin America (5%).

This was a "real world" study; each patient was managed according to the usual standards of the investigational site; frequencies of angiography, PCI, and CABG therefore differed widely from site to site and from country to country. Of the patients in PURSUIT, 13% were managed with PCI during drug infusion, of whom 50% received intracoronary stents; 87% were managed medically (without PCI during drug infusion).

The majority of patients received aspirin (75-325 mg once daily). Heparin was administered intravenously or subcutaneously, at the physician's discretion, most commonly as an intravenous bolus of 5000 units followed by a continuous infusion of 1000 units/h. For patients weighing less than 70 kg, the recommended heparin bolus dose was 60 units/kg followed by a continuous infusion of 12 units/kg/h. A target aPTT of 50 to 70 seconds was recommended. A total of 1250 patients underwent PCI within 72 hours after randomization, in which case they received intravenous heparin to maintain an ACT of 300 to 350 seconds.

The primary endpoint of the study was the occurrence of death from any cause or new MI (evaluated by a blinded Clinical Endpoints Committee) within 30 days of randomization.

Compared to placebo, Intiflo administered as a 180-mcg/kg bolus followed by a 2-mcg/kg/min infusion significantly (p=0.042) reduced the incidence of endpoint events. The reduction in the incidence of endpoint events in patients receiving Intiflo was evident early during treatment, and this reduction was maintained through at least 30 days. Table 5 also shows the incidence of the components of the primary endpoint, death (whether or not preceded by an MI) and new MI in surviving patients at 30 days.

Placebo Intiflo p-value

Death or MI

(n=4739)

n (%)

 (180 mcg/kg bolus then 2 mcg/kg/min infusion)

(n=4722)

n (%)
3 days 359 (7.6%) 279 (5.9%) 0.001
7 days 552 (11.6%) 477 (10.1%) 0.016
30 days
Death or MI (primary endpoint) 745 (15.7%) 672 (14.2%) 0.042
Death 177 (3.7%) 165 (3.5%)
Nonfatal MI 568 (12%) 507 (10.7%)
Figure 1: Kaplan-Meier Plot of Time to Death or Myocardial Infarction Within 30 Days of Randomization in the PURSUIT Study


Treatment with Intiflo prior to determination of patient management strategy reduced clinical events regardless of whether patients ultimately underwent diagnostic catheterization, revascularization (i.e., PCI or CABG surgery) or continued to receive medical management alone. Table 6 shows the incidence of death or MI within 72 hours.

Placebo Intiflo

(180 mcg/kg bolus then 2 mcg/kg/min infusion)
Overall patient population n=4739 n=4722
– At 72 hours 7.6% 5.9%
Patients undergoing early PCI n=631 n=619
– Pre-procedure (nonfatal MI only) 5.5% 1.8%
– At 72 hours 14.4% 9%
Patients not undergoing early PCI n=4108 n=4103
– At 72 hours 6.5% 5.4%

All of the effect of Intiflo was established within 72 hours (during the period of drug infusion), regardless of management strategy. Moreover, for patients undergoing early PCI, a reduction in events was evident prior to the procedure.

An analysis of the results by sex suggests that women who would not routinely be expected to undergo PCI receive less benefit from Intiflo (95% confidence limits for relative risk of 0.94 - 1.28) than do men (0.72 - 0.9). This difference may be a true treatment difference, the effect of other differences in these subgroups, or a statistical anomaly. No differential outcomes were seen between male and female patients undergoing PCI .

Follow-up data were available through 165 days for 10,611 patients enrolled in the PURSUIT trial (96.9% of the initial enrollment). This follow-up included 4566 patients who received Intiflo at the 180/2 dose. As reported by the investigators, the occurrence of death from any cause or new MI for patients followed for at least 165 days was reduced from 13.6% with placebo to 12.1% with Intiflo 180/2.

Figure 1

14.2 Percutaneous Coronary Intervention (PCI)

IMPACT II (INTEGRILIN to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II)

IMPACT II was a multicenter, double-blind, randomized, placebo-controlled study conducted in the United States in 4010 patients undergoing PCI. Major exclusion criteria included a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy.

Patient age ranged from 24 to 89 (mean 60) years, and 75% were male. The patients were 92% Caucasian, 5% Black, and 3% Hispanic. Forty-one percent of the patients underwent PCI for ongoing ACS. Patients were randomly assigned to 1 of 3 treatment regimens, each incorporating a bolus dose initiated immediately prior to PCI followed by a continuous infusion lasting 20 to 24 hours:


Each patient received aspirin and an intravenous heparin bolus of 100 units/kg, with additional bolus infusions of up to 2000 additional units of heparin every 15 minutes to maintain an ACT of 300 to 350 seconds.

The primary endpoint was the composite of death, MI, or urgent revascularization, analyzed at 30 days after randomization in all patients who received at least 1 dose of study drug.

As shown in Table 7, each Intiflo regimen reduced the rate of death, MI, or urgent intervention, although at 30 days, this finding was statistically significant only in the lower-dose Intiflo group. As in the PURSUIT study, the effects of Intiflo were seen early and persisted throughout the 30-day period.

Placebo

n (%)

 Intiflo (135 mcg/kg bolus then 0.5 mcg/kg/min infusion)

n (%)

 Intiflo (135 mcg/kg bolus then 0.75 mcg/kg/min infusion)

n (%)
Patients 1285 1300 1286
Abrupt Closure 65 (5.1%) 36 (2.8%) 43 (3.3%)
p-value versus placebo 0.003 0.03
Death, MI, or Urgent Intervention
24 hours 123 (9.6%) 86 (6.6%) 89 (6.9%)
p-value versus placebo 0.006 0.014
48 hours 131 (10.2%) 99 (7.6%) 102 (7.9%)
p-value versus placebo 0.021 0.045
30 days (primary endpoint) 149 (11.6%) 118 (9.1%) 128 (10%)
p-value versus placebo 0.035 0.179
Death or MI
30 days 110 (8.6%) 89 (6.8%) 95 (7.4%)
p-value versus placebo 0.102 0.272
6 months 151 (11.9%)Kaplan-Meier estimate of event rate. 136 (10.6%) 130 (10.3%)
p-value versus placebo 0.297 0.182

ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Intiflo Therapy)

The ESPRIT study was a multicenter, double-blind, randomized, placebo-controlled study conducted in the United States and Canada that enrolled 2064 patients undergoing elective or urgent PCI with intended intracoronary stent placement. Exclusion criteria included MI within the previous 24 hours, ongoing chest pain, administration of any oral antiplatelet or oral anticoagulant other than aspirin within 30 days of PCI (although loading doses of thienopyridine on the day of PCI were encouraged), planned PCI of a saphenous vein graft or subsequent "staged" PCI, prior stent placement in the target lesion, PCI within the previous 90 days, a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy.

Patient age ranged from 24 to 93 (mean 62) years, and 73% of patients were male. The study enrolled 90% Caucasian, 5% African American, 2% Hispanic, and 1% Asian patients. Patients received a wide variety of stents. Patients were randomized either to placebo or Intiflo administered as an intravenous bolus of 180 mcg/kg followed immediately by a continuous infusion of 2 mcg/kg/min, and a second bolus of 180 mcg/kg administered 10 minutes later (180/2/180). Intiflo infusion was continued for 18 to 24 hours after PCI or until hospital discharge, whichever came first. Each patient received at least 1 dose of aspirin (162-325 mg) and 60 units/kg of heparin as a bolus (not to exceed 6000 units) if not already receiving a heparin infusion. Additional boluses of heparin (10-40 units/kg) could be administered in order to reach a target ACT between 200 and 300 seconds.

The primary endpoint of the ESPRIT study was the composite of death, MI, urgent target vessel revascularization (UTVR), and "bailout" to open-label Intiflo due to a thrombotic complication of PCI (TBO) (e.g., visible thrombus, "no reflow," or abrupt closure) at 48 hours. MI, UTVR, and TBO were evaluated by a blinded Clinical Events Committee.

As shown in Table 8, the incidence of the primary endpoint and selected secondary endpoints was significantly reduced in patients who received Intiflo. A treatment benefit in patients who received Intiflo was seen by 48 hours and at the end of the 30-day observation period.

Placebo IntifloIntiflo was administered as 180 mcg/kg boluses at times 0 and 10 minutes and an infusion at 2 mcg/kg/min. Relative Risk

(95% CI)

p-value
(n=1024) (n=1040)
Death, MI, UTVR, or Thrombotic "Bailout"
48 hours (primary endpoint) 108 (10.5%) 69 (6.6%) 0.629 (0.471, 0.84) 0.0015
30 days 120 (11.7%) 78 (7.5%) 0.64 (0.488, 0.84) 0.0011
Death, MI, or UTVR
48 hours 95 (9.3%) 62 (6%) 0.643 (0.472, 0.875) 0.0045
30 days (key secondary endpoint) 107 (10.4%) 71 (6.8%) 0.653 (0.49, 0.871) 0.0034
Death or MI
48 hours 94 (9.2%) 57 (5.5%) 0.597 (0.435, 0.82) 0.0013
30 days 104 (10.2%) 66 (6.3%) 0.625 (0.465, 0.84) 0.0016

The need for thrombotic "bailout" was significantly reduced with Intiflo at 48 hours (2.1% for placebo, 1% for Intiflo; p=0.029). Consistent with previous studies of GP IIb/IIIa inhibitors, most of the benefit achieved acutely with Intiflo was in the reduction of MI. Intiflo reduced the occurrence of MI at 48 hours from 9% for placebo to 5.4% (p=0.0015) and maintained that effect with significance at 30 days.

There was no treatment difference with respect to sex in ESPRIT. Intiflo reduced the incidence of the primary endpoint in both men (95% confidence limits for relative risk: 0.54, 1.07) and women (0.24, 0.72) at 48 hours.

Follow-up (12-month) mortality data were available for 2024 patients (1017 on Intiflo) enrolled in the ESPRIT trial (98.1% of the initial enrollment). Twelve-month clinical event data were available for 1964 patients (988 on Intiflo), representing 95.2% of the initial enrollment. As shown in Table 9, the treatment effect of Intiflo seen at 48 hours and 30 days appeared preserved at 6 months and 1 year. Most of the benefit was in reduction of MI.

Placebo Intiflo Hazard Ratio
(n=1024) (n=1040) (95% CI)
Percentages are Kaplan-Meier event rates.
Death, MI, or Target Vessel Revascularization
6 months 187 (18.5%) 146 (14.3%) 0.744 (0.599, 0.924)
1 year 222 (22.1%) 178 (17.5%) 0.762 (0.626, 0.929)
Death, MI
6 months 117 (11.5%) 77 (7.4%) 0.631 (0.473, 0.841)
1 year 126 (12.4%) 83 (8%) 0.63 (0.478, 0.832)

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Intiflo injection is supplied as a sterile solution in 10-mL vials containing 20 mg of Intiflo (NDC 0085-1177-01) and 100-mL vials containing either 75 mg of Intiflo (NDC 0085-1136-01) or 200 mg of Intiflo (NDC 0085-1177-02).

16.2 Storage

Vials should be stored refrigerated at 2-8°C (36-46°F). Vials may be transferred to room temperature storageStore at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). for a period not to exceed 2 months. Upon transfer, vial cartons must be marked by the dispensing pharmacist with a "DISCARD BY" date (2 months from the transfer date or the labeled expiration date, whichever comes first).

Protect from light until administration.

17 PATIENT COUNSELING INFORMATION

Instruct patients to inform the doctor or healthcare provider about any medical conditions, medications, and allergies.

Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of

MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Manufactured by:

Patheon Italia S.p. A, Ferentino, 03013, Italy

For patent information: www.merck.com/product/patent/home.html

Intiflo is a registered trademark of Millennium Pharmaceuticals, Inc.

uspi-mk6936-iv-1404r012

PRINCIPAL DISPLAY PANEL - 0.75 mg/mL Vial Carton

NDC 0085-1136-01

75 mg/100 mL vial for

weight-adjusted infusion

(eptifibatide) Injection

Intiflo ®

0.75 mg/mL

SINGLE USE VIAL

FOR INTRAVENOUS

USE ONLY

PRINCIPAL DISPLAY PANEL - 0.75 mg/mL Vial Carton

PRINCIPAL DISPLAY PANEL - 2 mg/mL Vial Carton

NDC 0085-1177-02

200 mg/100 mL vial for

weight-adjusted infusion

(eptifibatide) Injection

Intiflo ®

2 mg/mL

SINGLE USE VIAL

FOR INTRAVENOUS

USE ONLY

PRINCIPAL DISPLAY PANEL - 2 mg/mL Vial Carton

Intiflo pharmaceutical active ingredients containing related brand and generic drugs:


Intiflo available forms, composition, doses:


Intiflo destination | category:


Intiflo Anatomical Therapeutic Chemical codes:


Intiflo pharmaceutical companies:


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References

  1. Dailymed."INTEGRILIN (EPTIFIBATIDE) INJECTION, SOLUTION [MERCK SHARP & DOHME CORP.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "Eptifibatide". https://pubchem.ncbi.nlm.nih.gov/su... (accessed August 28, 2018).
  3. "Eptifibatide - DrugBank". http://www.drugbank.ca/drugs/DB0006... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Intiflo?

Depending on the reaction of the Intiflo after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Intiflo 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 Intiflo 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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sdrugs.com conducted a study on Intiflo, 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 Intiflo 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.

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