Angiomax

bivalirudin

Dosage Form: injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION

 INDICATIONS AND USAGE

  Percutaneous Transluminal Coronary Angioplasty (PTCA)

Angiomax® (bivalirudin) is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA).

  Percutaneous Coronary Intervention (PCI)

Angiomax with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) as listed in the REPLACE-2 trial [see Clinical Studies (14.1)] is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI).

Angiomax 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

Angiomax in these indications is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin [see Dosage and Administration (2.1) and Clinical Studies (14.1)].

  Limitation of Use

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

 DOSAGE AND ADMINISTRATION

  Recommended Dose

Angiomax is for intravenous administration only.

Angiomax 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 Angiomax is an intravenous (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. Five min after the bolus dose has been administered, an activated clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg should be given if needed.

GPI administration should be considered in the event that any of the conditions listed in the REPLACE-2 clinical trial description [see Clinical Studies (14.1)] is present.

For patients who have HIT/HITTS

The recommended dose of Angiomax in patients with HIT/HITTS undergoing PCI is an IV 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

Continuation of the Angiomax infusion following PCI/PTCA for up to 4 hours post-procedure is optional, at the discretion of the treating physician. After four hours, an additional IV infusion of Angiomax 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 Angiomax 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 [see Use In Specific Population (8.6)].

  Instructions for Administration

Angiomax is intended for intravenous bolus injection and continuous infusion after reconstitution and dilution. To each 250 mg vial, add 5 mL of Sterile Water for Injection, USP. Gently swirl until all 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., 1 vial in 50 mL; 2 vials in 100 mL; 5 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, USP. 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

Angiomax should be administered via an intravenous line. No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets. The following drugs should not be administered in the same intravenous line with Angiomax, since they resulted in haze formation, microparticulate formation, or gross precipitation when mixed with Angiomax: 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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Preparations of Angiomax 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 Angiomax. Reconstituted material may be stored at 2-8°C for up to 24 hours. Diluted Angiomax 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.

 DOSAGE FORMS AND STRENGTHS

Angiomax is supplied as a sterile, lyophilized powder in single-use, glass vials. After reconstitution, each vial delivers 250 mg of Angiomax.

 CONTRAINDICATIONS

Angiomax is contraindicated in patients with:

• Active major bleeding;


• Hypersensitivity (e.g., anaphylaxis) to Angiomax or its components [see Adverse Reactions (6.3)].

 WARNINGS AND PRECAUTIONS

  Bleeding Events

Although most bleeding associated with the use of Angiomax 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 Angiomax administration [see Adverse Reactions (6.1)]. Angiomax should be used with caution in patients with disease states associated with an increased risk of bleeding.

  Coronary Artery Brachytherapy

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

If a decision is made to use Angiomax 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 [see Adverse Reactions (6.3)].

 ADVERSE REACTIONS

  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, Angiomax patients exhibited statistically significantly lower rates of bleeding, transfusions, and thrombocytopenia as noted in Table 2.

Table 2. Major Hematologic Outcomes REPLACE-2 Study (Safety Population)

	Angiomax with "provisional" GPI1 (n=2914)	HEPARIN + GPI (n=2987)	p-value
1 GPIs were administered to 7.2% of patients in the Angiomax with provisional GPI group 2 Defined as the occurence of any of the following: intracranial bleeding, retroperitoneal bleeding, a transfusion of ≥2 units of blood/blood products, a fall in hemoglobin >4 g/dL, whether of not bleeding site is identified, spontaneous or non-spontaneous blood loss with a decrease in hemoglobin >3 g/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
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

In 4312 patients undergoing PTCA for treatment of unstable angina in 2 randomized, double-blind studies comparing Angiomax to heparin, Angiomax 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 Angiomax group than in the heparin group.

Table 3. Major Bleeding and Transfusions in BAT Trial (all patients)1

	Angiomax N=2161	Heparin N=2151
1 No monitoring of ACT (or PTT) was done after a target ACT was achieved. 2 Major hemorrhage was defined as the occurence 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.
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)

In the AT-BAT study, of the 51 patients with HIT/HITTS, 1 patient who did not undergo PCI had major bleeding during 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 Angiomax 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

	Angiomax with "provisional" GPI1 (N = 2914)		Heparin+GPI (N = 2987)
Note: A patient could have more than one event in any category. Abbreviation: AE = adverse event.
	n	(%)	n	(%)
Patients with at least one treatment-related AE	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)

Table 5. Adverse Events Other Than Bleeding Occurring In ≥5% Of Patients In Either Treatment Group In BAT Trial

	Treatment Group
EVENT	Angiomax N=2161	Heparin N=2151
	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 2161 Angiomax-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 Angiomax- 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, there was no causality assessment for adverse events.

  Immunogenicity/Re-Exposure

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

Among 494 subjects who received Angiomax 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 Angiomax: 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.

 DRUG INTERACTIONS

In clinical trials in patients undergoing PCI/PTCA, co-administration of Angiomax 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 Angiomax and plasma expanders such as dextran.

 USE IN SPECIFIC POPULATIONS

  Pregnancy

Pregnancy Category B

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 Angiomax. 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.

Angiomax is intended for use with aspirin [see Indications and Usage (1.3)]. Because of possible adverse effects on the neonate and the potential for increased maternal bleeding, particularly during the third trimester, Angiomax and aspirin should be used together during pregnancy only if clearly needed.

  Nursing Mothers

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

  Pediatric Use

The safety and effectiveness of Angiomax 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 Angiomax experienced fewer bleeding events in each age stratum, compared to heparin.

  Renal Impairment

The disposition of Angiomax was studied in PTCA patients with mild, moderate and severe renal impairment. The clearance of Angiomax was reduced approximately 20% in patients with moderate and severe renal impairment and was reduced approximately 80% in dialysis-dependent patients. [see Clinical Pharmacology (12.3)].

The infusion dose of Angiomax may need to be reduced, and anticoagulant status monitored in patients with renal impairment [see Dosage and Administration (2.2)].

 OVERDOSAGE

Single bolus doses of Angiomax up to 7.5 mg/kg have been reported without associated bleeding or other adverse reactions. In cases of overdosage, treatment with Angiomax should be immediately discontinued and the patient monitored closely for signs of bleeding. Angiomax is hemodialyzable [see Clinical Pharmacology (12.3)]. There is no known antidote to Angiomax.

 DESCRIPTION

Angiomax is a specific and reversible direct thrombin inhibitor. The active substance is a synthetic, 20 amino acid peptide. The chemical name is D - phenylalanyl - L - prolyl - L - arginyl - L - prolyl - glycyl - glycyl - glycyl - glycyl - L - asparagyl - glycyl - L - aspartyl - L - phenylalanyl - L - glutamyl - L - glutamyl - L - isoleucyl - L - prolyl - L - glutamyl - L - glutamyl - L - tyrosyl - L - leucine trifluoroacetate (salt) hydrate (Figure 1). The molecular weight of Angiomax is 2180 daltons (anhydrous free base peptide).

Angiomax is supplied in single-use vials as a white lyophilized cake, which is sterile. Each vial contains 250 mg bivalirudin, 125 mg mannitol, and sodium hydroxide to adjust the pH to 5-6 (equivalent of approximately 12.5 mg sodium). When reconstituted with Sterile Water for Injection, the product yields a clear to opalescent, colorless to slightly yellow solution, pH 5-6.

Figure 1. Structural Formula for Bivalirudin

 CLINICAL PHARMACOLOGY

  Mechanism of Action

Angiomax 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 Angiomax to thrombin is reversible as thrombin slowly cleaves the Angiomax-Arg3-Pro4 bond, resulting in recovery of thrombin active site functions.

In in vitro studies, Angiomax inhibited both soluble (free) and clot-bound thrombin, was not neutralized by products of the platelet release reaction, and prolonged the activated partial thromboplastin time (aPTT), thrombin time (TT), and prothrombin time (PT) of normal human plasma in a concentration-dependent manner. The clinical relevance of these findings is unknown.

  Pharmacodynamics

In healthy volunteers and patients (with ≥70% vessel occlusion undergoing routine PTCA), Angiomax exhibited dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT, and TT. Intravenous administration of Angiomax produces an immediate anticoagulant effect. Coagulation times return to baseline approximately 1 hour following cessation of Angiomax administration.

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

  Pharmacokinetics

Angiomax exhibits linear pharmacokinetics following IV administration to patients undergoing PTCA. In these patients, a mean steady state Angiomax concentration of 12.3 ± 1.7 mcg/mL is achieved following an IV bolus of 1 mg/kg and a 4-hour 2.5 mg/kg/h IV infusion. Angiomax does not bind to plasma proteins (other than thrombin) or to red blood cells. Angiomax is cleared from plasma by a combination of renal mechanisms and proteolytic cleavage, with a half-life in patients with normal renal function of 25 min.

The disposition of Angiomax was studied in PTCA patients with mild, moderate, and severe renal impairment. Drug elimination was related to glomerular filtration rate (GFR). Total body clearance was similar for patients with normal renal function and with mild renal impairment (60-89 mL/min). Clearance was reduced in patients with moderate and severe renal impairment and in dialysis-dependent patients (See Table 6 for pharmacokinetic parameters).

Angiomax is hemodialyzable, with approximately 25% cleared by hemodialysis.

Table 6. PK Parameters in Patients with Renal Impairment*

Renal Function (GFR, mL/min)	Clearance (mL/min/kg)	Half-life (min)
* The ACT should be monitored in renally-impaired patients
Normal renal function (≥90 mL/min)	3.4	25
Mild renal impairment (60-89 mL/min)	3.4	22
Moderate renal impairment (30-59 mL/min)	2.7	34
Severe renal impairment (10-29 mL/min)	2.8	57
Dialysis-dependent patients (off dialysis)	1.0	3.5 hours

 NONCLINICAL TOXICOLOGY

  Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of Angiomax. Angiomax 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 vivo rat micronucleus assay. Fertility and general reproductive performance in rats were unaffected by subcutaneous doses of Angiomax 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.

 CLINICAL STUDIES

  PCI/PTCA

Angiomax has been evaluated in five randomized, controlled interventional cardiology trials reporting 11,422 patients. Stents were deployed in 6062 of the patients in these trials - mainly in trials performed since 1995. Percutaneous transluminal coronary angioplasty, atherectomy or other procedures were performed in the remaining patients.

REPLACE-2 Trial

This was a randomized, double-blind, multicenter study reporting 6002 (intent-to-treat) patients undergoing PCI. Patients were randomized to treatment with Angiomax with the "provisional" use of platelet glycoprotein IIb/IIIa inhibitor (GPI) or heparin plus planned use of GPI. GPIs were added on a "provisional" basis to patients who were randomized to Angiomax in the following circumstances:

• decreased TIMI flow (0 to 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; and


• prolonged ischemia.

During the study, one or more of these circumstances occurred in 12.7% of patients in the Angiomax with provisional GPI arm. GPIs were administered to 7.2% of patients in the Angiomax with provisional GPI arm (62.2% of eligible patients).

Patients ranged in age from 25-95 years (median, 63); weight ranged from 35-199 kg (median 85.5); 74.4% were male and 25.6% were female. Indications for PCI included unstable angina (35% of patients), myocardial infarction within 7 days prior to intervention (8% of patients), stable angina (25%) and positive ischemic stress test (24%). Stents were deployed in 85% of patients. Ninety-nine percent of patients received aspirin and 86% received thienopyridines prior to study treatment.

Angiomax was administered as a 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion for the duration of the procedure. The activated clotting time (ACT - measured by a Hemochron® device) was measured 5 min after the first bolus of study medication. If the ACT was <225 seconds, an additional bolus of 0.3 mg/kg was given. At investigator discretion, the infusion could be continued following the procedure for up to 4 hours. The median infusion duration was 44 min. Heparin was administered as a 65 U/kg bolus. The activated clotting time (ACT - measured by a Hemochron® device) was measured 5 min after the first bolus of study medication. If the ACT was <225 seconds, an additional bolus of 20 units/kg was given. GPIs (either abciximab or eptifibatide) were given according to manufacturers' instructions. Both randomized groups could be given "provisional" treatments during the PCI at investigator discretion, but under double-blind conditions. "Provisional" treatment with GPI was requested in 5.2% of patients randomized to heparin plus GPI (they were given placebo) and 7.2% patients randomized to Angiomax with provisional GPI (they were given abciximab or eptifibatide according to pre-randomization investigator choice and patient stratification).

The percent of patients reaching protocol-specified levels of anticoagulation was greater in the Angiomax with provisional GPI group than in the heparin plus GPI group. For patients randomized to Angiomax with provisional GPI, the median 5 min ACT was 358 sec (interquartile range 320-400 sec) and the ACT was <225 sec in 3%. For patients randomized to heparin plus GPI, the median 5 min ACT was 317 sec (interquartile range 263-373 sec) and the ACT was <225 sec in 12%. At the end of the procedure, median ACT values were 334 sec (Angiomax group) and 276 sec (heparin plus GPI group).

For the composite endpoint of death, MI, or urgent revascularization adjudicated under double-blind conditions, the frequency was higher (7.6%)(95% confidence interval 6.7%-8.6%) in the Angiomax with "provisional" GPI arm when compared to the heparin plus GPI arm (7.1%)(95% confidence interval 6.1%-8.0%). However, major hemorrhage was reported significantly less frequently in the Angiomax with provisional GPI arm (2.4%) compared to the heparin plus GPI arm (4.1%). Study outcomes are shown in Table 7.

Table 7. Incidences of Clinical Endpoints at 30 Days for REPLACE-2, a Randomized Double-blind Clinical Trial

Intent-to-treat Population	Angiomax with "Provisional" GPI n=2994	HEPARIN+GPI n=3008
* Defined as intracranial bleeding, retroperitoneal bleeding, a transfusion of ≥2 units of blood/blood products, a fall in Hgb >4 g/dL, whether or not bleeding site is identified, spontaneous or non-spontaneous blood loss with a decrease in Hgb >3 g/dL. † p-value <0.001 between groups.
Efficacy Endpoints
Death, MI, or urgent revascularization	7.6%	7.1%
Death	0.2%	0.4%
MI	7.0%	6.2%
Urgent revascularization	1.2%	1.4%
Safety Endpoint
Major hemorrhage*†	2.4%	4.1%

At 12 months' follow-up, mortality was 1.9% among patients randomized to Angiomax with "provisional" GPIs and 2.5% among patients randomized to heparin plus GPI.

Bivalirudin Angioplasty Trial (BAT)

Angiomax was evaluated in patients with unstable angina undergoing PTCA in two randomized, double-blind, multicenter studies with identical protocols. Patients must have had unstable angina defined as: (1) a new onset of severe or accelerated angina or rest pain within the month prior to study entry or (2) angina or ischemic rest pain which developed between four hours and two weeks after an acute myocardial infarction (MI). Overall, 4312 patients with unstable angina, including 741 (17%) patients with post-MI angina, were treated in a 1:1 randomized fashion with Angiomax or heparin. Patients ranged in age from 29-90 (median 63) years, their weight was a median of 80 kg (39-120 kg), 68% were male, and 91% were Caucasian. Twenty-three percent of patients were treated with heparin within one hour prior to randomization. All patients were administered aspirin 300-325 mg prior to PTCA and daily thereafter. Patients randomized to Angiomax were started on an intravenous infusion of Angiomax (2.5 mg/kg/h). Within 5 min after starting the infusion, and prior to PTCA, a 1 mg/kg loading dose was administered as an intravenous bolus. The infusion was continued for 4 hours, then the infusion was changed under double-blinded conditions to Angiomax (0.2 mg/kg/h) for up to an additional 20 hours (patients received this infusion for an average of 14 hours). The ACT was checked at 5 min and at 45 min following commencement. If on either occasion the ACT was <350 sec, an additional double-blinded bolus of placebo was administered. The Angiomax dose was not titrated to ACT. Median ACT values were: ACT in sec (5th percentile-95th percentile): 345 sec (240-595 sec) at 5 min and 346 sec (range 269-583 sec) at 45 min after initiation of dosing. Patients randomized to heparin were given a loading dose (175 IU/kg) as an intravenous bolus 5 min before the planned procedure, with immediate commencement of an infusion of heparin (15 IU/kg/h). The infusion was continued for 4 hours. After 4 hours of infusion, the heparin infusion was changed under double-blinded conditions to heparin (15 IU/kg/h) for up to 20 additional hours. The ACT was checked at 5 min and at 45 m

ascorbic acid and iron polysaccharide

Generic Name: ascorbic acid and iron polysaccharide (as KORE bik AS id and EYE urn SAK a ride)

Brand names: Fe-Tinic 150, Ferrex 150 Plus, Niferex-150, Niferex-150 (obsolete1), Rexavite 150

What is ascorbic acid and iron polysaccharide?

Ascorbic acid is found in citrus fruit, tomatoes, potatoes, and leafy vegetables. Ascorbic acid is important for the skin and connective tissues, for normal chemical and hormonal production, and for the immune system.

Iron polysaccharide is a form of the mineral iron. Iron is important for many functions in the body, especially for the transport of oxygen in the blood.

Ascorbic acid is used to treat and prevent vitamin C deficiency.

Iron polysaccharide is used as a dietary supplement, and to prevent and to treat iron deficiencies and iron deficiency anemia.

Ascorbic acid and iron polysaccharide may also be used for purposes not listed in this medication guide.

What is the most important information I should know about ascorbic acid and iron polysaccharide?

Do not take more ascorbic acid and iron polysaccharide than is prescribed for you or than is directed on the package. Keep this product out of reach of children. Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. In case of accidental overdose, call a doctor or poison control center immediately.

Ascorbic acid and iron polysaccharide may decrease the absorption of other medicines. Talk to your doctor and pharmacist before taking ascorbic acid and iron polysaccharide if you take any other prescription or over-the-counter medicines.

What should I discuss with my healthcare provider before taking ascorbic acid and iron polysaccharide?

If you do not have an iron deficiency, talk to your doctor about the use of ascorbic acid and iron polysaccharide. Generally, ascorbic acid and iron polysaccharide should not be taken chronically by individuals with a normal iron balance.

To make sure you can safely take ascorbic acid and iron polysaccharide, tell your doctor if you have any of these other conditions:

• 
  

  diabetes;

  
  


• 
  

  hemosiderosis;

  
  


• 
  

  hemolytic anemia;

  
  


• 
  

  hemochromatosis;

  
  


• 
  

  kidney disease or an increased risk of kidney stones;

  
  


• 
  

  if you are on a sodium restricted diet; or

  
  


• 
  

  if you are allergic to sulfites or tartrazine.

  
  

FDA pregnancy category C. It is not known whether ascorbic acid and iron polysaccharide will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether ascorbic acid and iron polysaccharide passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take ascorbic acid and iron polysaccharide?

Keep this product out of reach of children. Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. In case of accidental overdose, call a doctor or poison control center immediately.

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Take this medicine with a full glass of water.

Ascorbic acid and iron polysaccharide may decrease the absorption of other medicines. Talk to your doctor and pharmacist before taking ascorbic acid and iron polysaccharide if you take any other prescription or over-the-counter medicines.

This medication can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using ascorbic acid and iron polysaccharide.

Store at room temperature, away from moisture and heat.

See also: Ascorbic acid and iron polysaccharide dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose can cause decreased energy, nausea, vomiting, abdominal pain, tarry stools, weak or rapid pulse, fever, or seizure (convulsions).

What should I avoid while taking ascorbic acid and iron polysaccharide?

Do not take ascorbic acid and iron polysaccharide within 2 hours before or after you take any of the following medicines

• 
  

  levodopa (Larodopa, Dopar, Sinemet);

  
  


• 
  

  levothyroxine (Synthroid, Levoxyl, others);

  
  


• 
  

  methyldopa (Aldomet);

  
  


• 
  

  penicillamine (Cuprimine);

  
  


• 
  

  antacids (Amphojel, Maalox, Mylanta, Rolaids, Rulox, Tums, and others);

  
  


• 
  

  a tetracycline antibiotic such as demeclocycline (Declomycin), doxycycline (Adoxa, Doryx, Oracea, Vibramycin), minocycline (Dynacin, Minocin, Solodyn, Vectrin), or tetracycline (Brodspec, Panmycin, Sumycin, Tetracap); or

  
  


• 
  

  an antibiotic such as ciprofloxacin (Cipro), ofloxacin (Floxin), norfloxacin (Noroxin), levofloxacin (Levaquin), lomefloxacin (Maxaquin), and others.

  
  

Ascorbic acid and iron polysaccharide may decrease the absorption of the drugs listed above.

Ascorbic acid and iron polysaccharide side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have a serious side effect such as:

• 
  

  fever;

  
  


• 
  

  severe lower back pain;

  
  


• 
  

  painful or difficult urination;

  
  


• 
  

  blood in your urine; or

  
  


• 
  

  black or dark stools.

  
  

Less serious side effects may include:

• 
  

  stomach upset;

  
  


• 
  

  nausea or vomiting;

  
  


• 
  

  diarrhea;

  
  


• 
  

  constipation; or

  
  


• 
  

  temporary staining of the teeth.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Ascorbic acid and iron polysaccharide Dosing Information

Usual Adult Dose for Dietary Supplement:

Dose: 1 or 2 capsules daily of the ascorbic acid 50 mg and iron polysaccharide 150 mg capsules

What other drugs will affect ascorbic acid and iron polysaccharide?

Tell your doctor about all other medicines you use, especially:

• 
  

  a blood thinner such as warfarin (Coumadin).

  
  


• 
  

  an estrogen such as Premarin, Ogen, Estratest, Vivelle, Climara, Estring, Estrace, and others; or

  
  


• 
  

  an oral birth control pill such as Alesse, Levlen, Ovral, Triphasil, Tri-Levlen, Lo-Ovral, and others.

  
  

This list is not complete and other drugs may interact with ascorbic acid and iron polysaccharide. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More ascorbic acid and iron polysaccharide resources

• Ascorbic acid and iron polysaccharide Dosage
• Ascorbic acid and iron polysaccharide Use in Pregnancy & Breastfeeding
• Ascorbic acid and iron polysaccharide Drug Interactions
• Ascorbic acid and iron polysaccharide Support Group
• 0 Reviews for Ascorbic acid and iron polysaccharide - Add your own review/rating

Compare ascorbic acid and iron polysaccharide with other medications

• Dietary Supplementation

Where can I get more information?

• Your pharmacist can provide more information about ascorbic acid and iron polysaccharide.

Ansaid

flurbiprofen

Dosage Form: tablet, film coated
Ansaid®

(flurbiprofen tablets, USP) 50 mg and 100 mg

Cardiovascular Risk

• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).


• Ansaid® is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk

• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

Ansaid Description

Ansaid Tablets contain flurbiprofen, which is a member of the phenylalkanoic acid derivative group of nonsteroidal anti-inflammatory drugs. Ansaid Tablets are white, oval, film-coated tablets for oral administration. Flurbiprofen is a racemic mixture of (+)S- and (-)R- enantiomers. Flurbiprofen is a white or slightly yellow crystalline powder. It is slightly soluble in water at pH 7.0 and readily soluble in most polar solvents. The chemical name is [1,1'-biphenyl]-4-acetic acid, 2-fluoro-alpha-methyl-, (±)-. The molecular weight is 244.26. Its molecular formula is C15H13FO2 and it has the following structural formula:

The inactive ingredients in Ansaid (both strengths) include carnauba wax, colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, and titanium dioxide. In addition, the 100 mg tablet contains FD&C Blue No. 2.

Ansaid - Clinical Pharmacology

Pharmacodynamics

Ansaid Tablets contain flurbiprofen, a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Ansaid, like that of other nonsteroidal anti-inflammatory drugs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Pharmacokinetics

Absorption

The mean oral bioavailability of flurbiprofen from Ansaid Tablets 100 mg is 96% relative to an oral solution. Flurbiprofen is rapidly and non-stereoselectively absorbed from Ansaid, with peak plasma concentrations occurring at about 2 hours (see Table 1). Administration of Ansaid with either food or antacids may alter the rate but not the extent of flurbiprofen absorption. Ranitidine has been shown to have no effect on either the rate or extent of flurbiprofen absorption from Ansaid.

Distribution

The apparent volume of distribution (Vz/F) of both R- and S-flurbiprofen is approximately 0.12 L/Kg. Both flurbiprofen enantiomers are more than 99% bound to plasma proteins, primarily albumin. Plasma protein binding is relatively constant for the typical average steady-state concentrations (≤10 µg/mL) achieved with recommended doses. Flurbiprofen is poorly excreted into human milk. The nursing infant dose is predicted to be approximately 0.1 mg/day in the established milk of a woman taking Ansaid 200 mg/day (see PRECAUTIONS, Nursing Mothers).

Metabolism

Several flurbiprofen metabolites have been identified in human plasma and urine. These metabolites include 4'-hydroxy-flurbiprofen, 3', 4'-dihydroxy-flurbiprofen, 3'-hydroxy-4'-methoxy-flurbiprofen, their conjugates, and conjugated flurbiprofen. Unlike other arylpropionic acid derivatives (eg, ibuprofen), metabolism of R-flurbiprofen to S-flurbiprofen is minimal. Flurbiprofen metabolism is predominantly mediated via cytochrome P450 CYP 2C9 in the liver. Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered flurbiprofen with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. The major metabolite, 4'-hydroxy-flurbiprofen, showed little anti-inflammatory activity in animal models of inflammation. Flurbiprofen does not induce enzymes that alter its metabolism.

The total plasma clearance of unbound flurbiprofen is not stereoselective, and clearance of flurbiprofen is independent of dose when used within the therapeutic range.

Excretion

Following dosing with Ansaid, less than 3% of flurbiprofen is excreted unchanged in the urine, with about 70% of the dose eliminated in the urine as parent drug and metabolites. Because renal elimination is a significant pathway of elimination of flurbiprofen metabolites, dosing adjustment in patients with moderate or severe renal dysfunction may be necessary to avoid accumulation of flurbiprofen metabolites. The mean terminal disposition half-lives (t½) of R- and S-flurbiprofen are similar, about 4.7 and 5.7 hours, respectively. There is little accumulation of flurbiprofen following multiple doses of Ansaid.

Table 1. Mean (SD) R,S-Flurbiprofen Pharmacokinetic Parameters Normalized to a 100 mg Dose of Ansaid

Pharmacokinetic Parameter	Normal Healthy Adults* (18 to 40 years) N=15	Geriatric Arthritis Patients† (65 to 83 years) N=13	End Stage Renal Disease Patients* (23 to 42 years) N=8	Alcoholic Cirrhosis Patients‡ (31 to 61 years) N=8
* 100 mg single-dose † Steady-state evaluation of 100 mg every 12 hours ‡ 200 mg single-dose § Calculated from mean parameter values of both flurbiprofen enantiomers ¶ Not available # AUC from 0 to infinity for single doses and from 0 to the end of the dosing interval for multiple-doses Þ Value for S-flurbiprofen
Peak Concentration (Tg/mL)	14 (4)	16 (5)	9§	9§
Time of Peak Concentration (h)	1.9 (1.5)	2.2 (3)	2.3§	1.2§
Urinary Recovery of Unchanged Flurbiprofen (% of Dose)	2.9 (1.3)	0.6 (0.6)	0.02 (0.02)	NA¶
Area Under the Curve (AUC)# (Tg h/mL)	83 (20)	77 (24)	44§	50§
Apparent Volume of Distribution (Vz/F, L)	14 (3)	12 (5)	10§	14§
Terminal Disposition Half-life (t½, h)	7.5 (0.8)	5.8 (1.9)	3.3Þ	5.4Þ

Special Populations

Pediatric

The pharmacokinetics of flurbiprofen have not been investigated in pediatric patients.

Race

No pharmacokinetic differences due to race have been identified.

Geriatric

Flurbiprofen pharmacokinetics were similar in geriatric arthritis patients, younger arthritis patients, and young healthy volunteers receiving Ansaid Tablets 100 mg as either single or multiple doses.

Hepatic insufficiency

Hepatic metabolism may account for >90% of flurbiprofen elimination, so patients with hepatic disease may require reduced doses of Ansaid Tablets compared to patients with normal hepatic function. The pharmacokinetics of R- and S-flurbiprofen were similar, however, in alcoholic cirrhosis patients (N=8) and young healthy volunteers (N=8) following administration of a single 200 mg dose of Ansaid tablets.

Flurbiprofen plasma protein binding may be decreased in patients with liver disease and serum albumin concentrations below 3.1 g/dL (see PRECAUTIONS, Hepatic Effects).

Renal insufficiency

Renal clearance is an important route of elimination for flurbiprofen metabolites, but a minor route of elimination for unchanged flurbiprofen (≤3% of total clearance). The unbound clearances of R- and S-flurbiprofen did not differ significantly between normal healthy volunteers (N=6, 50 mg single dose) and patients with renal impairment (N=8, inulin clearances ranging from 11 to 43 mL/min, 50 mg multiple doses). Flurbiprofen plasma protein binding may be decreased in patients with renal impairment and serum albumin concentrations below 3.9 g/dL. Elimination of flurbiprofen metabolites may be reduced in patients with renal impairment (see WARNINGS, Renal Effects).

Flurbiprofen is not significantly removed from the blood into dialysate in patients undergoing continuous ambulatory peritoneal dialysis.

Drug-Drug Interactions

(see also PRECAUTIONS, Drug Interactions)

Antacids

Administration of Ansaid to volunteers under fasting conditions or with antacid suspension yielded similar serum flurbiprofen-time profiles in young adult subjects (n=12). In geriatric subjects (n=7), there was a reduction in the rate but not the extent of flurbiprofen absorption.

Aspirin

Concurrent administration of Ansaid and aspirin resulted in 50% lower serum flurbiprofen concentrations. This effect of aspirin (which is also seen with other nonsteroidal anti-inflammatory drugs) has been demonstrated in patients with rheumatoid arthritis (n=15) and in healthy volunteers (n=16) (see PRECAUTIONS, Drug Interactions).

Beta-adrenergic blocking agents

The effect of flurbiprofen on blood pressure response to propranolol and atenolol was evaluated in men with mild uncomplicated hypertension (n=10). Flurbiprofen pretreatment attenuated the hypotensive effect of a single dose of propranolol but not atenolol. Flurbiprofen did not appear to affect the beta-blocker-mediated reduction in heart rate. Flurbiprofen did not affect the pharmacokinetic profile of either drug (see PRECAUTIONS, Drug Interactions).

Cimetidine, Ranitidine

In normal volunteers (n=9), pretreatment with cimetidine or ranitidine did not affect flurbiprofen pharmacokinetics, except for a small (13%) but statistically significant increase in the area under the serum concentration curve of flurbiprofen in subjects who received cimetidine.

Digoxin

In studies of healthy males (n=14), concomitant administration of flurbiprofen and digoxin did not change the steady state serum levels of either drug.

Diuretics

Studies in healthy volunteers have shown that, like other nonsteroidal anti-inflammatory drugs, flurbiprofen can interfere with the effects of furosemide. Although results have varied from study to study, effects have been shown on furosemide-stimulated diuresis, natriuresis, and kaliuresis. Other nonsteroidal anti-inflammatory drugs that inhibit prostaglandin synthesis have been shown to interfere with thiazide and potassium-sparing diuretics (see PRECAUTIONS, Drug Interactions).

Lithium

In a study of 11 women with bipolar disorder receiving lithium carbonate at a dosage of 600 to 1200 mg/day, administration of 100 mg Ansaid every 12 hours increased plasma lithium concentrations by 19%. Four of 11 patients experienced a clinically important increase (>25% or >0.2 mmol/L). Nonsteroidal anti-inflammatory drugs have also been reported to decrease the renal clearance of lithium by about 20% (see PRECAUTIONS, Drug Interactions).

Methotrexate

In a study of six adult arthritis patients, coadministration of methotrexate (10 to 25 mg/dose) and Ansaid (300 mg/day) resulted in no observable interaction between these two drugs.

Oral Hypoglycemic Agents

In a clinical study, flurbiprofen was administered to adult diabetics who were already receiving glyburide (n=4), metformin (n=2), chlorpropamide with phenformin (n=3), or glyburide with phenformin (n=6). Although there was a slight reduction in blood sugar concentrations during concomitant administration of flurbiprofen and hypoglycemic agents, there were no signs or symptoms of hypoglycemia.

Indications and Usage for Ansaid

Carefully consider the potential benefits and risks of Ansaid and other treatment options before deciding to use Ansaid. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Ansaid is indicated:

• For relief of the signs and symptoms of rheumatoid arthritis.


• For relief of the signs and symptoms of osteoarthritis.

Contraindications

Ansaid Tablets are contraindicated in patients with known hypersensitivity to flurbiprofen.

Ansaid should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other nonsteroidal anti-inflammatory drugs. Severe, rarely fatal, anaphylactic-like reactions to nonsteroidal anti-inflammatory drugs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions, and PRECAUTIONS, Preexisting Asthma).

Ansaid is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Warnings

CARDIOVASCULAR EFFECTS

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs including Ansaid, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Ansaid, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. Ansaid should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including Ansaid, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3–6 months, and in about 2–4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

In clinical studies, the elimination half-life of flurbiprofen was unchanged in patients with renal impairment. Flurbiprofen metabolites are eliminated primarily by the kidneys. Elimination of 4'-hydroxy-flurbiprofen was reduced in patients with moderate to severe renal impairment. Therefore, treatment with Ansaid is not recommended in these patients with advanced renal disease. If Ansaid therapy must be initiated, close monitoring of the patients renal function is advisable (see CLINICAL PHARMACOLOGY).

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Ansaid. Ansaid should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including Ansaid, can cause serious skin adverse events such as exfoliative dermatitis, Steven-Johnson Syndrom (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Pregnancy

In late pregnancy, as with other NSAIDs, Ansaid should be avoided because it may cause premature closure of the ductus arteriosus.

Precautions

General

Ansaid cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of Ansaid in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hepatic effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking nonsteroidal anti-inflammatory drugs, including Ansaid. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with nonsteroidal anti-inflammatory drugs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test values, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Ansaid. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), Ansaid should be discontinued.

Hematological effects

Anemia is sometimes seen in patients receiving nonsteroidal anti-inflammatory drugs, including Ansaid. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with nonsteroidal anti-inflammatory drugs, including Ansaid, should have their hemoglobin or hematocrit checked periodically even if they do not exhibit any signs or symptoms of anemia.

Nonsteroidal anti-inflammatory drugs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Ansaid does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT). Patients receiving Ansaid who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Ansaid should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Vision changes

Blurred and/or diminished vision has been reported with the use of Ansaid and other nonsteroidal anti-inflammatory drugs. Patients experiencing eye complaints should have ophthalmologic examinations.

Information For Patients

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

• Ansaid, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, CARDIOVASCULAR EFFECTS).


• Ansaid, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding and Perforation).


• Ansaid, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs hypersensitivity such as itching, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.


• Patients should promptly report, signs or symptoms of unexplained weight gain, or edema to their physicians.


• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.


• Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS, Anaphylactoid Reactions).


• In late pregnancy, as with other NSAIDs, Ansaid should be avoided because it may cause premature closure of the ductus arteriosus.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs of symptoms of GI bleeding. Patients on long-term treatment with nonsteroidal anti-inflammatory drugs should have their CBC and chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash etc.), or abnormal liver tests persist or worsen, Ansaid should be discontinued.

Drug Interactions

ACE-inhibitors

Reports suggest that nonsteroidal anti-inflammatory drugs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking nonsteroidal anti-inflammatory drugs concomitantly with ACE-inhibitors.

Anticoagulants

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. The physician should be cautious when administering Ansaid to patients taking warfarin or other anticoagulants.

Aspirin

Concurrent administration of aspirin lowers serum flurbiprofen concentrations (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions). The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of flurbiprofen and aspirin is not generally recommended because of the potential for increased adverse effects.

Beta-adrenergic blocking agents

Flurbiprofen attenuated the hypotensive effect of propranolol but not atenolol (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions). The mechanism underlying this interference is unknown. Patients taking both flurbiprofen and a beta-blocker should be monitored to ensure that a satisfactory hypotensive effect is achieved.

Diuretics

Clinical studies, as well as post marketing observations, have shown that Ansaid can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as diuretic efficacy.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%.

These effects have been attributed to inhibition of renal prostaglandin synthesis by the nonsteroidal anti-inflammatory drug. Thus, when nonsteroidal anti-inflammatory drugs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate

Nonsteroidal anti-inflammatory drugs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when nonsteroidal anti-inflammatory drugs are administered concomitantly with methotrexate.

Pregnancy

Teratogenic effects: Pregnancy Category C

Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Ansaid should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic effects

Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided.

Labor and Delivery

In rat studies with nonsteroidal anti-inflammatory drugs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Ansaid on labor and delivery in pregnant women are unknown.

Nursing Mothers

Concentrations of flurbiprofen in breast milk and plasma of nursing mothers suggest that a nursing infant could receive approximately 0.10 mg flurbiprofen per day in the established milk of a woman taking Ansaid 200 mg/day. Because of possible adverse effects of prostaglandin-inhibiting drugs on neonates, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

As with any NSAID, caution should be exercised in treating the elderly (65 years and older).

Clinical experience with Ansaid suggests that elderly patients may have a higher incidence of gastrointestinal complaints than younger patients, including ulceration, bleeding, flatulence, bloating, and abdominal pain. To minimize the potential risk for gastrointestinal events, the lowest effective dose should be used for the shortest possible duration (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation). Likewise, elderly patients are at greater risk of developing renal decompensation (see WARNINGS, Renal Effects).

The pharmacokinetics of flurbiprofen do not seem to differ in elderly patients from those in younger individuals (see CLINICAL PHARMACOLOGY, Special Populations). The rate of absorption of Ansaid was reduced in elderly patients who also received antacids, although the extent of absorption was not affected (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions).

Adverse Reactions

TABLE 2. Reported adverse events in patients receiving Ansaid or other nonsteroidal anti-inflammatory drugs

Reported in patients treated with Ansaid
Incidence of 1% or greater*	Incidence < 1% - Causal Relationship Probable†	Incidence < 1% - Causal Relationship Unknown†	Reported in patients treated with other products but not Ansaid
* from clinical trials † from clinical trials, post-marketing surveillance, or literature
BODY AS A WHOLE
edema	anaphylactic reaction chills fever		< 1%: death infection sepsis
CARDIOVASCULAR SYSTEM
	congestive heart failure hypertension vascular diseases vasodilation	angina pectoris arrhythmias myocardial infarction	< 1%: hypotension palpitations syncope tachycardia vasculitis
DIGESTIVE SYSTEM
abdominal pain   constipation   diarrhea   dyspepsia/heartburn   elevated liver enzymes   flatulence   GI bleeding   nausea   vomiting	bloody diarrhea esophageal disease gastric/peptic ulcer disease gastritis jaundice (cholestatic and noncholestatic) hematemesis hepatitis stomatitis/glossitis	appetite changes cholecystitis colitis dry mouth exacerbation of inflammatory bowel disease periodontal abscess small intestine inflammation with loss of blood and protein	> 1%: GI perforation GI ulcers (gastric/duodenal) < 1%: eructation liver failure pancreatitis
HEMIC AND
LYMPHATIC SYSTEM	aplastic anemia (including agranulocytosis or pancytopenia) decrease in hemoglobin and hematocrit ecchymosis/purpura eosinophilia hemolytic anemia iron deficiency anemia leukopenia thrombocytopenia	lymphadenopathy	> 1%: anemia increased bleeding time < 1%: melena rectal bleeding
METABOLIC AND NUTRITIONAL SYSTEM
body weight changes	hyperuricemia	hyperkalemia	< 1%: hyperglycemia
NERVOUS SYSTEM
headache   nervousness and other manifestations of central nervous system (CNS) stimulation (eg, anxiety, insomnia, increased reflexes, tremor)   symptoms associated with CNS inhibition (eg, amnesia, asthenia, depression, malaise, somnolence)	ataxia cerebrovascular ischemia confusion paresthesia twitching	convulsion cerebrovascular accident emotional lability hypertonia meningitis myasthenia subarachnoid hemorrhage	< 1%: coma dream abnormalities drowsiness hallucinations
RESPIRATORY SYSTEM
rhinitis	asthma epistaxis	bronchitis dyspnea hyperventilation laryngitis pulmonary embolism pulmonary infarct	< 1%: pneumonia respiratory depression
SKIN AND APPENDAGES
rash	angioedema eczema exfoliative dermatitis photosensitivity pruritus toxic epidermal necrolysis urticaria	alopecia dry skin herpes simplex/zoster nail disorder sweating	< 1%: erythema multiforme Stevens Johnson syndrome
SPECIAL SENSES
changes in vision   dizziness/vertigo   tinnitus	conjunctivitis parosmia	changes in taste corneal opacity ear disease glaucoma retinal hemorrhage retrobulbar neuritis transient hearing loss	> 1%: pruritus < 1%: hearing impairment
UROGENITAL SYSTEM
signs and symptoms suggesting urinary tract infection	hematuria interstitial nephritis renal failure	menstrual disturbances prostate disease vaginal and uterine hemorrhage vulvovaginitis	> 1%: abnormal renal function < 1%: dysuria oliguria polyuria proteinuria

Overdosage

Symptoms following acute overdoses with nonsteroidal anti-inflammatory drugs are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of nonsteroidal anti-inflammatory drugs, and may occur following an overdose.

Patients should be managed by symptomatic and supportive care following overdose with a nonsteroidal anti-inflammatory drug. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms, or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

Ansaid Dosage and Administration

Carefully consider the potential benefits and risks of Ansaid and other treatment options before deciding to use Ansaid. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

After observing the response to initial therapy with Ansaid, the dose and frequency should be adjusted to suit an individual patient's needs.

For relief of the signs and symptoms of rheumatoid arthritis or osteoarthritis, the recommended starting dose of Ansaid is 200 to 300 mg per day, divided for administration two, three, or four times a day. The largest recommended single dose in a multiple-dose daily regimen is 100 mg.

How is Ansaid Supplied

Ansaid Tablets are available as follows:

50 mg: white, oval, film-coated, imprinted Ansaid 50 mg

    Bottles of 2000        NDC 0009-0170-24

100 mg: blue, oval, film-coated, imprinted Ansaid 100 mg

    Bottles of 100          NDC 0009-0305-03

    Bottles of 2000        NDC 0009-0305-30

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

Rx Only

LAB-0104-7.0

February 2010

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

(See the end of this Medication Guide for a list of prescription NSAID medicines.)

What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:

• with longer use of NSAID medicines


• in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)."

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:

• can happen without warning symptoms


• may cause death

The chance of a person getting an ulcer or bleeding increases with:

• taking medicines called "corticosteroids" and "anticoagulants"


• longer use


• smoking


• drinking alcohol


• older age


• having poor health

NSAID medicines should only be used:

• exactly as prescribed


• at the lowest dose possible for your treatment


• for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:

• different types of arthritis


• menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:

• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine


• for pain right before or after heart bypass surgery

Tell your healthcare provider:

• about all of your medical conditions.


• about all of the medicines you take. NSA