Free PLR Content Directory Tanzania

Tuesday, October 18, 2016

Trental

Generic Name: pentoxifylline

Dosage Form: tablet, film coated
Trental®

(pentoxifylline)

Tablets, 400 mg

Trental Description

Trental® (pentoxifylline) tablets for oral administration contain 400 mg of the active drug and the following inactive ingredients: FD&C Red No. 3, hypromellose USP, magnesium stearate NF, polyethylene glycol NF, povidone USP, talc USP, titanium dioxide USP, and hydroxyethyl cellulose USP in an extended-release formulation. Trental is a tri-substituted xanthine derivative designated chemically as 1-(5-oxohexyl)-3,7-dimethylxanthine that, unlike theophylline, is a hemorrheologic agent, i.e. an agent that affects blood viscosity. Pentoxifylline is soluble in water and ethanol, and sparingly soluble in toluene. The CAS Registry Number is 6493-05-6.

The chemical structure is:

Trental - Clinical Pharmacology

Mode of Action

Pentoxifylline and its metabolites improve the flow properties of blood by decreasing its viscosity. In patients with chronic peripheral arterial disease, this increases blood flow to the affected microcirculation and enhances tissue oxygenation. The precise mode of action of pentoxifylline and the sequence of events leading to clinical improvement are still to be defined. Pentoxifylline administration has been shown to produce dose-related hemorrheologic effects, lowering blood viscosity, and improving erythrocyte flexibility. Leukocyte properties of hemorrheologic importance have been modified in animal and in vitro human studies. Pentoxifylline has been shown to increase leukocyte deformability and to inhibit neutrophil adhesion and activation. Tissue oxygen levels have been shown to be significantly increased by therapeutic doses of pentoxifylline in patients with peripheral arterial disease.

Pharmacokinetics and Metabolism

After oral administration in aqueous solution pentoxifylline is almost completely absorbed. It undergoes a first-pass effect and the various metabolites appear in plasma very soon after dosing. Peak plasma levels of the parent compound and its metabolites are reached within 1 hour. The major metabolites are Metabolite l (1-[5-hydroxyhexyl]-3,7-dimethylxanthine) and Metabolite V (1-[3-carboxypropyl]-3,7-dimethylxanthine), and plasma levels of these metabolites are 5 and 8 times greater, respectively, than pentoxifylline.

Following oral administration of aqueous solutions containing 100 to 400 mg of pentoxifylline, the pharmacokinetics of the parent compound and Metabolite l are dose-related and not proportional (non-linear), with half-life and area under the blood-level time curve (AUC) increasing with dose. The elimination kinetics of Metabolite V are not dose-dependent. The apparent plasma half-life of pentoxifylline varies from 0.4 to 0.8 hours and the apparent plasma half-lives of its metabolites vary from 1 to 1.6 hours. There is no evidence of accumulation or enzyme induction (Cytochrome P450) following multiple oral doses.

Excretion is almost totally urinary; the main biotransformation product is Metabolite V. Essentially no parent drug is found in the urine. Despite large variations in plasma levels of parent compound and its metabolites, the urinary recovery of Metabolite V is consistent and shows dose proportionality. Less than 4% of the administered dose is recovered in feces. Food intake shortly before dosing delays absorption of an immediate-release dosage form but does not affect total absorption. The pharmacokinetics and metabolism of Trental have not been studied in patients with renal and/or hepatic dysfunction. The pentoxifylline AUC was increased and elimination rate decreased in an older population (60–68 years, n=6) compared to younger individuals (22–30 years, n=6) (see PRECAUTIONS, Geriatric Use).

After administration of the 400 mg extended-release Trental tablet, plasma levels of the parent compound and its metabolites reach their maximum within 2 to 4 hours and remain constant over an extended period of time. Coadministration of Trental tablets with meals resulted in an increase in mean Cmax and AUC by about 28% and 13% for pentoxifylline, respectively. Cmax for Metabolite 1 also increased by about 20%. The extended release of pentoxifylline from the tablet eliminates peaks and troughs in plasma levels for improved gastrointestinal tolerance.

Indications and Usage for Trental

Trental is indicated for the treatment of patients with intermittent claudication on the basis of chronic occlusive arterial disease of the limbs. Trental can improve function and symptoms but is not intended to replace more definitive therapy, such as surgical bypass, or removal of arterial obstructions when treating peripheral vascular disease.

Contraindications

Trental should not be used in patients with recent cerebral and/or retinal hemorrhage or in patients who have previously exhibited intolerance to this product or methylxanthines such as caffeine, theophylline, and theobromine.

Precautions

General

Patients with chronic occlusive arterial disease of the limbs frequently show other manifestations of arteriosclerotic disease. Trental has been used safely for treatment of peripheral arterial disease in patients with concurrent coronary artery and cerebrovascular diseases, but there have been occasional reports of angina, hypotension, and arrhythmia. Controlled trials do not show that Trental causes such adverse effects more often than placebo, but, as it is a methylxanthine derivative, it is possible some individuals will experience such responses. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration, cerebral and/or retinal bleeding) should have periodic examinations for bleeding including, hematocrit and/or hemoglobin.

Drug Interactions

Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with Trental with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of Trental and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. Trental has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with Trental; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Long-term studies of the carcinogenic potential of pentoxifylline were conducted in mice and rats by dietary administration of the drug at doses up to 450 mg/kg (approximately 19 times the maximum recommended human daily dose (MRHD) in both species when based on body weight; 1.5 times the MRHD in the mouse and 3.3 times the MRHD in the rat when based on body surface area). In mice, the drug was administered for 18 months, whereas in rats, the drug was administered for 18 months followed by an additional 6 months without drug exposure. In the rat study, there was a statistically significant increase in benign mammary fibroadenomas in females of the 450 mg/kg group. The relevance of this finding to human use is uncertain. Pentoxifylline was devoid of mutagenic activity in various strains of Salmonella (Ames test) and in cultured mammalian cells (unscheduled DNA synthesis test) when tested in the presence and absence of metabolic activation. It was also negative in the in vivo mouse micronucleus test.

Pregnancy

Category C. Teratogenicity studies have been performed in rats and rabbits using oral doses up to 576 and 264 mg/kg, respectively. On a weight basis, these doses are 24 and 11 times the maximum recommended human daily dose (MRHD); on a body-surface-area basis, they are 4.2 and 3.5 times the MRHD. No evidence of fetal malformation was observed. Increased resorption was seen in rats of the 576 mg/kg group. There are no adequate and well controlled studies in pregnant women. Trental (pentoxifylline) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Pentoxifylline and its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for pentoxifylline in rats, a decision should be made whether to discontinue nursing or 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

Clinical studies of Trental did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The active metabolite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse Reactions

Clinical trials were conducted using either extended-release Trental tablets for up to 60 weeks or immediate-release Trental capsules for up to 24 weeks. Dosage ranges in the tablet studies were 400 mg bid to tid and in the capsule studies, 200–400 mg tid. The table summarizes the incidence (in percent) of adverse reactions considered drug related, as well as the numbers of patients who received extended-release Trental tablets, immediate-release Trental capsules, or the corresponding placebos. The incidence of adverse reactions was higher in the capsule studies (where dose related increases were seen in digestive and nervous system side effects) than in the tablet studies. Studies with the capsule include domestic experience, whereas studies with the extended-release tablets were conducted outside the U.S.

The table indicates that in the tablet studies few patients discontinued because of adverse effects.

INCIDENCE (%) OF SIDE EFFECTS
	Extended-Release Tablets		Immediate-Release Capsules
	Commercially Available		Used only for Controlled Clinical Trials
	Trental	Placebo	Trental	Placebo
(Numbers of Patients at Risk)	(321)	(128)	(177)	(138)
Discontinued for Side Effect	3.1	0	9.6	7.2
CARDIOVASCULAR SYSTEM
Angina/Chest Pain	0.3	-	1.1	2.2
Arrhythmia/Palpitation	-	-	1.7	0.7
Flushing	-	-	2.3	0.7
DIGESTIVE SYSTEM
Abdominal Discomfort	-	-	4.0	1.4
Belching/Flatus/Bloating	0.6	-	9.0	3.6
Diarrhea	-	-	3.4	2.9
Dyspepsia	2.8	4.7	9.6	2.9
Nausea	2.2	0.8	28.8	8.7
Vomiting	1.2	-	4.5	0.7
NERVOUS SYSTEM
Agitation/Nervousness	-	-	1.7	0.7
Dizziness	1.9	3.1	11.9	4.3
Drowsiness	-	-	1.1	5.8
Headache	1.2	1.6	6.2	5.8
Insomnia	-	-	2.3	2.2
Tremor	0.3	0.8	-	-
Blurred Vision	-	-	2.3	1.4

Trental has been marketed in Europe and elsewhere since 1972. In addition to the above symptoms, the following have been reported spontaneously since marketing or occurred in other clinical trials with an incidence of less than 1%; the causal relationship was uncertain:

: Cardiovascular - dyspnea, edema, hypotension.
: Digestive - anorexia, cholecystitis, constipation, dry mouth/thirst.
: Nervous - anxiety, confusion, depression, seizures, aseptic meningitis.
: Respiratory - epistaxis, flu-like symptoms, laryngitis, nasal congestion.
: Skin and Appendages - brittle fingernails, pruritus, rash, urticaria, angioedema.
: Special Senses - blurred vision, conjunctivitis, earache, scotoma.
: Miscellaneous - bad taste, excessive salivation, leukopenia, malaise, sore throat/swollen neck glands, weight change.

A few rare events have been reported spontaneously worldwide since marketing in 1972. Although they occurred under circumstances in which a causal relationship with pentoxifylline could not be established, they are listed to serve as information for physicians. Cardiovascular — angina, arrhythmia, tachycardia, anaphylactoid reactions. Digestive — hepatitis, jaundice, increased liver enzymes; and Hemic and Lymphatic — decreased serum fibrinogen, pancytopenia, aplastic anemia, leukemia, purpura, thrombocytopenia.

Overdosage

Overdosage with Trental has been reported in pediatric patients and adults. Symptoms appear to be dose related. A report from a poison control center on 44 patients taking overdoses of enteric-coated pentoxifylline tablets noted that symptoms usually occurred 4–5 hours after ingestion and lasted about 12 hours. The highest amount ingested was 80 mg/kg; flushing, hypotension, convulsions, somnolence, loss of consciousness, fever, and agitation occurred. All patients recovered. In addition to symptomatic treatment and gastric lavage, special attention must be given to supporting respiration, maintaining systemic blood pressure, and controlling convulsions. Activated charcoal has been used to absorb pentoxifylline in patients who have overdosed.

Trental Dosage and Administration

The usual dosage of Trental in extended-release tablet form is one tablet (400 mg) three times a day with meals.

While the effect of Trental may be seen within 2 to 4 weeks, it is recommended that treatment be continued for at least 8 weeks. Efficacy has been demonstrated in double-blind clinical studies of 6 months duration.

Digestive and central nervous system side effects are dose related. If patients develop these effects it is recommended that the dosage be lowered to one tablet twice a day (800 mg/day). If side effects persist at this lower dosage, the administration of Trental should be discontinued.

How is Trental Supplied

Trental (pentoxifylline) is available for oral administration as 400-mg pink film-coated oblong tablets imprinted Trental; supplied in bottles of 100 (NDC 0039-0078-10).

Store between 59 and 86° F (15 and 30° C).

Dispense in well-closed, light-resistant containers.

Rev. October 2007

US Patents 3,737,433 & 4,189,469

US Patent 3,737,433 patent term has been extended.

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

PRINCIPAL DISPLAY PANEL - Label

NDC 0039-0078-10

Trental®

pentoxifylline

Tablets

400mg

100 Tablets

sanofi aventis

Trental
pentoxifylline tablet, film coated

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	NDC Product Code (Source)	0039-0078
Route of Administration	ORAL	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
pentoxifylline (pentoxifylline)	pentoxifylline	400 mg

Inactive Ingredients
Ingredient Name	Strength
FD&C Red No. 3
hypromellose
magnesium stearate
polyethylene glycol
povidone
talc
titanium dioxide
hydroxyethyl cellulose (2000 CPS AT 1%)

Product Characteristics
Color	PINK	Score	no score
Shape	OVAL (capsule-shaped)	Size	17mm
Flavor		Imprint Code	Trental
Contains

Packaging
#	NDC	Package Description	Multilevel Packaging
1	0039-0078-10	100 TABLET In 1 BOTTLE	None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA018631	08/30/1984

Labeler - Sanofi-Aventis U.S. LLC (824676584)

Establishment
Name	Address	ID/FEI	Operations
Patheon Pharmaceuticals Inc.		005286822	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
sanofi-aventis Canada Inc.		251046934	MANUFACTURE

Revised: 03/2010Sanofi-Aventis U.S. LLC

More Trental resources

Trental Side Effects (in more detail)
Trental Dosage
Trental Use in Pregnancy & Breastfeeding
Drug Images
Trental Drug Interactions
Trental Support Group
2 Reviews for Trental - Add your own review/rating

Trental Concise Consumer Information (Cerner Multum)

Trental MedFacts Consumer Leaflet (Wolters Kluwer)

Trental Advanced Consumer (Micromedex) - Includes Dosage Information

Pentoxifylline Professional Patient Advice (Wolters Kluwer)

Pentoxifylline Monograph (AHFS DI)

Compare Trental with other medications

Intermittent Claudication

treprostinil injection

Generic Name: treprostinil injection (tre PROS ti nil)

Brand Names: Remodulin

What is treprostinil injection?

Treprostinil dilates (or widens) the arteries and decreases the amount of blood clotting platelets in your body. These effects lower blood pressure in the pulmonary artery that leads from the heart to the lungs.

Treprostinil is used to treat pulmonary arterial hypertension (PAH). It improves your ability to exercise and prevents your condition from getting worse.

Treprostinil may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about treprostinil injection?

Before using this medication, tell your doctor if you have low blood pressure, liver disease, or a bleeding or blood clotting disorder.

Your doctor may want you to be in a hospital when you start using treprostinil. This is so you can be watched for any signs of serious side effects from the medicine.

You will probably have to use this medicine for several months or years to control your condition and keep it from getting worse.

Use treprostinil regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely. Make sure you have a backup infusion pump and infusion sets available so as not to interrupt your treatment if one infusion pump stops working.

Call your doctor if your symptoms do not improve or if they get worse.

What should I discuss with my healthcare provider before using treprostinil injection?

If you have certain conditions, you may need a dose adjustment or special tests to safely use this medication:

low blood pressure;

liver disease; or

bleeding or blood clotting disorder.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether treprostinil 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 is treprostinil injection given?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results.

Treprostinil is given as an continuous (around-the-clock) injection using an infusion pump. The medicine enters the body through a catheter placed under your skin or into a vein. Your doctor, nurse, or pharmacist will give you specific instructions on how to use an infusion pump and inject your medicine. Do not give yourself an injection if you do not understand these instructions. Call your doctor, nurse, or pharmacist for help with injection instructions.

Your doctor may want you to be in a hospital when you start using treprostinil. This is so you can be watched for any signs of serious side effects from the medicine.

You will probably have to use this medicine for several months or years to control your condition and keep it from getting worse.

Do not use the medication if it has changed colors or has any particles in it. Call your doctor for a new prescription.

Store unopened vials (bottles) of treprostinil at room temperature away from moisture and heat. After the medicine has been placed into a syringe or pump, it should be given within 72 hours. If the medicine has been diluted (mixed with a liquid), you must use the medicine within 48 hours after mixing. Call your doctor if your symptoms do not improve or if they get worse.

What happens if I miss a dose?

Call your doctor for instructions if you miss a dose of treprostinil.

What happens if I overdose?

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

Overdose symptoms may include warmth and redness or tingling under your skin, headache, feeling light-headed, fainting, nausea, vomiting, diarrhea, or seizure (convulsions).

What should I avoid while using treprostinil injection?

Do not stop using treprostinil without first talking to your doctor. You may need to use less and less before you stop the medication completely.

Treprostinil injection 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. Call your doctor at once if you have any of these serious side effects:

new or worsening PAH symptoms such as feeling short of breath (even with mild exertion), tiredness, chest pain, and pale skin;

swelling in your hands or feet; or

feeling like you might pass out.

Less serious side effects may include:

pain, swelling, redness, bleeding, or a hard lump where your catheter is placed;

dizziness;

mild skin rash;

headache or jaw pain;

flushing (warmth, redness or tingling); or

diarrhea or nausea.

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.

Treprostinil injection Dosing Information

Usual Adult Dose for Pulmonary Hypertension:

Infusion:
Initial dose: 1.25 nanogram/kg per minute by continuous infusion. The subcutaneous route is preferred but the drug may be administered by a central intravenous line if the subcutaneous route is not tolerated. The rate may be decreased to 0.625 nanogram/kg/minute if the initial dose is not tolerated by the patient.
Maintenance dose: The infusion rate may be increased in increments of no more than 1.25 nanogram/kg/minute per week for the first 4 weeks, and thereafter by no more than 2.5 nanograms/kg/minute per week. Dosage adjustments should be titrated to a dose where PAH symptoms are improved and adverse effects are minimized (headache, nausea, emesis, restlessness, anxiety, and infusion site pain or reaction). Although doses of up to 100 nanograms/kg/minute have been reported, there is little experience with doses greater than 40 nanograms/kg/minute.

Inhalation:
Use only with the Tyvaso Inhalation System. Administer undiluted, as supplied. A single breath of Tyvaso delivers approximately 6 mcg of treprostinil
Initial dosage: 3 breaths [18 mcg] per treatment session. If 3 breaths are not tolerated, reduce to 1 or 2 breaths. Administer in 4 separate treatment sessions each day approximately four hours apart, during waking hours.
Maintenance dose: Dosage should be increased by an additional 3 breaths at approximately 1-2 week intervals, if tolerated. Titrate to target maintenance dosage of 9 breaths or 54 mcg per treatment session as tolerated.

Usual Pediatric Dose for Pulmonary Hypertension:

Inhalation:
Less than 16 years: Safety and efficacy have not been established.
16 to 18 years:
Initial dose: 1.25 nanogram/kg per minute by continuous infusion. The subcutaneous route is preferred but the drug may be administered by a central intravenous line if the subcutaneous route is not tolerated. The rate may be decreased to 0.625 nanogram/kg/minute if the initial dose is not tolerated by the patient.
Maintenance dose: The infusion rate may be increased in increments of no more than 1.25 nanogram/kg/minute per week for the first 4 weeks, and thereafter by no more than 2.5 nanograms/kg/minute per week. Dosage adjustments should be titrated to a dose where PAH symptoms are improved and adverse effects are minimized (headache, nausea, emesis, restlessness, anxiety, and infusion site pain or reaction). There is little experience with doses greater than 40 nanograms/kg/minute.

What other drugs will affect treprostinil injection?

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

gemfibrozil (Lopid);

a blood thinner such as warfarin (Coumadin);

blood pressure medication such as a diuretic (water pill); or

medication used to prevent blood clots, such as alteplase (Activase), cilostazol (Pletal), clopidogrel (Plavix), dipyridamole (Persantine), ticlopidine (Ticlid), and urokinase (Abbokinase).

This list is not complete and other drugs may interact with treprostinil. 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 treprostinil injection resources

Treprostinil injection Side Effects (in more detail)
Treprostinil injection Dosage
Treprostinil injection Use in Pregnancy & Breastfeeding
Treprostinil injection Drug Interactions
Treprostinil injection Support Group
4 Reviews for Treprostinil - Add your own review/rating

Compare treprostinil injection with other medications

Pulmonary Arterial Hypertension

Where can I get more information?

Your doctor or pharmacist can provide more information about treprostinil injection.

See also: treprostinil side effects (in more detail)

treprostinil inhalation

Generic Name: treprostinil inhalation (tre PROS ti nil)

Brand Names: Tyvaso, Tyvaso Refill Kit, Tyvaso Starter Kit

What is treprostinil inhalation?

Treprostinil works by dilating (widening) blood vessels in your lungs and by keeps the platelets in your blood from coagulating (clotting) to prevent unwanted blood clots. These effects lower blood pressure in the pulmonary artery that leads from your heart to your lungs.

Treprostinil is used to treat pulmonary arterial hypertension (PAH). It improves your ability to exercise and prevents your condition from getting worse.

Treprostinil may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about treprostinil inhalation?

Before using this medication, tell your doctor if you have a breathing disorder such as asthma or COPD (chronic obstructive pulmonary disease), an infection in your lungs (including pneumonia), low blood pressure, liver or kidney disease, or a bleeding or blood clotting disorder.

Treprostinil inhalation should be used only with a Tyvaso inhalation system. The inhalation system comes with patient instructions for safe and effective use. Do not use the medication at home if you do not fully understand how to use the inhalation system and properly clean it daily. Ask your doctor or pharmacist if you have any questions.

The effects of treprostinil inhalation will lessen over time between doses. Talk with your doctor if you need to time your dosing around any planned activities.

It is important to use treprostinil regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely. Make sure you have a backup inhalation system available so as not to interrupt your treatment if one system stops working.

Call your doctor if your symptoms do not improve or if they get worse.

What should I discuss with my healthcare provider before using treprostinil inhalation?

If you have certain conditions, you may need a dose adjustment or special tests to safely use this medication:

a breathing disorder such as asthma or COPD (chronic obstructive pulmonary disease);

an infection in your lungs, including pneumonia;

low blood pressure;

liver disease;

kidney disease; or

a bleeding or blood clotting disorder.

FDA pregnancy category B. It is not known whether this medication is harmful to an unborn baby. Use an effective form of birth control while you are using treprostinil inhalation. Tell your doctor if you become pregnant during treatment. It is not known whether treprostinil 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 is treprostinil inhalation given?

Use this medication exactly as it was prescribed for you. Do not use the medication in larger amounts, or use it for longer than recommended by your doctor. Follow the directions on your prescription label.

The inhalation form of treprostinil is usually given 4 times per day at evenly spaced intervals during waking hours. Each time you use the medication, you will inhale up to 9 breaths of the medication. Follow your doctor's instructions.

Your doctor may occasionally change your dose to make sure you get the best results from this medication. Most people start treatment with 1 to 3 breaths per treatment session, slowly increasing the number to 9 breaths per session.

Do not use more than 9 breaths per treatment session. Wash your hands before preparing your treprostinil doses in the inhalation system.

One ampule of treprostinil inhalation contains enough medicine for all 4 of a day's doses.

Before your first dose of each day, twist off the top of one ampule and squeeze out the entire contents into the medicine cup of the inhalation system. At the end of the day after the last dose has been given, empty and rinse out the medicine cup, even if there is still unused treprostinil left in it.

To keep the medicine in the cup from spilling, store the inhalation system upright and tightly capped with the plugs when not in use.

The effects of treprostinil inhalation will lessen over time between doses. Talk with your doctor if you need to time your dosing around any planned activities.

Call your doctor if your symptoms do not improve or if they get worse.

Store treprostinil ampules in their foil pouch at room temperature away from moisture, heat, and light. Once you have opened a foil pouch, the ampules in it should be used within 7 days.

Any treprostinil placed into the medicine cup of the inhalation system must be used within 24 hours. Throw away any unused medicine at the end of the day after your last dose.

What happens if I miss a dose?

Call your doctor for instructions.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include flushing (warmth, redness or tingling), headache, nausea, vomiting, diarrhea, feeling light-headed, or fainting.

What should I avoid while using treprostinil inhalation?

Avoid getting treprostinil in your eyes or on your skin. If this does happen, rinse with water. Do not swallow treprostinil inhalation. The medication should be inhaled using only the Tyvaso inhalation system. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Treprostinil inhalation side effects

new or worsening PAH symptoms such as feeling short of breath (even with mild exertion), tiredness, chest pain, and pale skin;

feeling like you might pass out;

fever, chills, cough with yellow or green mucus, stabbing chest pain, wheezing;

unusual bleeding such as nosebleeds, bleeding gums, or any bleeding that will not stop;

pale skin, weakness, easy bruising;

unexpected vaginal bleeding;

blood in your urine or stools, black or tarry stools;

coughing up blood or vomit that looks like coffee grounds; or

swelling of your ankles or feet.

Less serious side effects may include:

cough, sore throat;

pain or irritation in your throat after use;

dizziness;

nausea, diarrhea;

headache or jaw pain; or

flushing (warmth, redness or tingling).

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.

Treprostinil inhalation Dosing Information

Usual Adult Dose for Pulmonary Hypertension:

Usual Pediatric Dose for Pulmonary Hypertension:

What other drugs will affect treprostinil inhalation?

Before using treprostinil, tell your doctor if you are using any of the following drugs:

gemfibrozil (Lopid);

delavirdine (Rescriptor);

nicardipine (Cardene);

pioglitazone (Actos, ActoPlus Met, Duetact);

tolbutamide (Orinase);

an antibiotic such as rifampin (Rifater, Rifadin, Rifamate) or rifapentine (Priftin);

antifungal medication such as fluconazole (Diflucan), or ketoconazole (Nizoral);

blood pressure medication;

a blood thinner such as warfarin (Coumadin).

a diuretic (water pill);

medication to treat congestive heart failure, such as hydralazine (Apresoline, BiDil), nesiritide (Natrecor), nitroglycerin, or nitroprusside (Nitropress);

an NSAID (non-steroidal anti-inflammatory drug) such as flurbiprofen (Ansaid), ibuprofen (Advil, Motrin), indomethacin (Indocin), mefenamic acid (Ponstel), or piroxicam (Feldene);

seizure medication such as carbamazepine (Carbatrol, Tegretol), phenytoin (Dilantin) fosphenytoin (Cerebyx), phenobarbital (Solfoton), primidone (Mysoline), or secobarbital (Seconal);or

sulfa drugs such as sulfisoxazole (Bactrim, Cotrim, Gantanol, Gantrisin, Septra), and others.

This list is not complete and there may be other drugs that can interact with treprostinil. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More treprostinil inhalation resources

Treprostinil inhalation Side Effects (in more detail)
Treprostinil inhalation Dosage
Treprostinil inhalation Use in Pregnancy & Breastfeeding
Treprostinil inhalation Drug Interactions
Treprostinil inhalation Support Group
4 Reviews for Treprostinil - Add your own review/rating

Compare treprostinil inhalation with other medications

Pulmonary Arterial Hypertension

Where can I get more information?

Your doctor or pharmacist can provide more information about treprostinil inhalation.

See also: treprostinil side effects (in more detail)

Travel-Ease Chewable Tablets

Pronunciation: MEK-li-zeen
Generic Name: Meclizine
Brand Name: Travel-Ease

Travel-Ease Chewable Tablets are used for:

Preventing and treating nausea, vomiting, and dizziness associated with motion sickness. It may also be used for other conditions as determined by your doctor.

Travel-Ease Chewable Tablets are an anticholinergic. It works by blocking a chemical messenger that is activating the vomiting center and thus prevents or reduces nausea and vomiting due to motion.

Do NOT use Travel-Ease Chewable Tablets if:

you are allergic to any ingredient in Travel-Ease Chewable Tablets

you are taking sodium oxybate (GHB) or you drink alcohol

Contact your doctor or health care provider right away if any of these apply to you.

Before using Travel-Ease Chewable Tablets:

Some medical conditions may interact with Travel-Ease Chewable Tablets. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

if you are pregnant, planning to become pregnant, or are breast-feeding

if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement

if you have allergies to medicines, foods, or other substances

if you have asthma; chronic obstructive pulmonary disease (COPD); chronic bronchitis, or emphysema; blockage of the stomach, intestine, or urinary tract;enlargement of the prostate; or glaucoma

Some MEDICINES MAY INTERACT with Travel-Ease Chewable Tablets. Tell your health care provider if you are taking any other medicines, especially any of the following:

Ethanol or sodium oxybate (GHB) because an increase in sleep duration and a decrease in the ability to breathe are likely to occur

This may not be a complete list of all interactions that may occur. Ask your health care provider if Travel-Ease Chewable Tablets may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Travel-Ease Chewable Tablets:

Use Travel-Ease Chewable Tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Take Travel-Ease Chewable Tablets by mouth with or without food.

Travel-Ease Chewable Tablets may be chewed or swallowed whole.

For prevention of motion sickness, take Travel-Ease Chewable Tablets at least 1 hour before activity or travel.

If you miss a dose of Travel-Ease Chewable Tablets and you are using it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Travel-Ease Chewable Tablets.

Important safety information:

Travel-Ease Chewable Tablets may cause drowsiness or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Travel-Ease Chewable Tablets with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.

Do not drink alcohol or use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Travel-Ease Chewable Tablets; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.

This product may contain tartrazine dye (FD&C Yellow No. 5). This may cause an allergic reaction in some patients. If you have ever had an allergic reaction to tartrazine, ask your pharmacist if your product has tartrazine in it.

Travel-Ease Chewable Tablets should not be used in CHILDREN younger than 12 years old; safety and effectiveness in these children have not been confirmed.

PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Travel-Ease Chewable Tablets while you are pregnant. It is unknown if Travel-Ease Chewable Tablets are found in breast milk. If you are or will be breast-feeding while you use Travel-Ease Chewable Tablets, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Travel-Ease Chewable Tablets:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Drowsiness; dry mouth.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Travel-Ease side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include drowsiness; hallucinations; seizures; unusual excitability; very slow or shallow breathing.

Proper storage of Travel-Ease Chewable Tablets:

Store at room temperature, below 86 degrees F (30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Travel-Ease Chewable Tablets out of the reach of children and away from pets.

General information:

If you have any questions about Travel-Ease Chewable Tablets, please talk with your doctor, pharmacist, or other health care provider.

Travel-Ease Chewable Tablets are to be used only by the patient for whom it is prescribed. Do not share it with other people.

If your symptoms do not improve or if they become worse, check with your doctor.

Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Travel-Ease Chewable Tablets. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

More Travel-Ease resources

Travel-Ease Side Effects (in more detail)
Travel-Ease Use in Pregnancy & Breastfeeding
Travel-Ease Drug Interactions
Travel-Ease Support Group
0 Reviews for Travel-Ease - Add your own review/rating

Compare Travel-Ease with other medications

Motion Sickness
Nausea/Vomiting
Vertigo

Trecator

Generic Name: ethionamide (e thye on AM ide)

Brand Names: Trecator

What is Trecator (ethionamide)?

Ethionamide is an antibiotic. It prevents the growth of bacteria in your body.

Ethionamide is used to treat tuberculosis (TB).

Ethionamide may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Trecator (ethionamide)?

Take all of the ethionamide that has been prescribed for you even if you begin to feel better. Your symptoms may begin to improve before the infection is completely treated.

Ethionamide may cause stomach upset, a loss of appetite, a metallic taste in your mouth, or excessive salivation (mouth watering). Notify your doctor if these side effects are persistent or severe.

Who should not take Trecator (ethionamide)?

Before taking this medication, tell your doctor if you

have ever had an allergic reaction to ethionamide;

have liver disease; or

have diabetes mellitus.

You may not be able to take ethionamide, or you may require a lower dose or special monitoring during treatment if you have any of the conditions listed above.

It is not known whether ethionamide will harm an unborn baby. Do not take this medication without first talking to your doctor if you are pregnant. It is also not known whether ethionamide will harm a nursing baby. Do not take this medication without first talking to your doctor if you are breast-feeding a baby.

How should I take Trecator (ethionamide)?

Take ethionamide exactly as directed by your doctor. If you do not understand these instructions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass (8 ounces) of water.

Ethionamide can be taken with or without food. Taking ethionamide with food may decrease stomach upset.

Take all of the ethionamide that has been prescribed for you even if you begin to feel better. Your symptoms may begin to improve before the infection is completely treated.

Ethionamide is usually combined with one or more other tuberculosis medicines.

Store this medication at room temperature away from moisture and heat.

See also: Trecator dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for your next regularly scheduled dose, skip the missed dose and take the next one as directed. Do not take a double dose of this medication.

What happens if I overdose?

Seek emergency medical attention.

Symptoms of an ethionamide overdose are unknown.

What should I avoid while taking Trecator (ethionamide)?

There are no restrictions on foods, beverages, or activities during treatment with ethionamide unless your doctor directs otherwise.

Trecator (ethionamide) side effects

If you experience any of the following serious side effects, stop taking ethionamide and seek emergency medical attention:

an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives);

yellow skin or eyes;

dark urine;

numbness or tingling in your hands or feet;

seizures;

blurred or double vision; or

confusion or abnormal behavior.

Other, less serious side effects may be more likely to occur. Continue to take ethionamide and talk to your doctor if you experience

nausea, vomiting, or loss of appetite;

a metallic taste in your mouth;

excessive salivation;

diarrhea;

unusual fatigue or weakness;

headache;

mild dizziness;

tremors (shaking); or

a rash.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Trecator (ethionamide)?

The risk of seizures may be increased when ethionamide is used in combination with cycloserine (Seromycin) or isoniazid (Nydrazid). Special monitoring may be necessary if you are taking a combination of these medicines.

Drugs other than those listed here may also interact with ethionamide. Talk to your doctor and pharmacist before taking or using any other prescription or over-the-counter medicines.

More Trecator resources

Trecator Side Effects (in more detail)
Trecator Dosage
Trecator Use in Pregnancy & Breastfeeding
Trecator Drug Interactions
Trecator Support Group
0 Reviews for Trecator - Add your own review/rating

Trecator Prescribing Information (FDA)

Trecator MedFacts Consumer Leaflet (Wolters Kluwer)

Trecator Monograph (AHFS DI)

Trecator Advanced Consumer (Micromedex) - Includes Dosage Information

Ethionamide Professional Patient Advice (Wolters Kluwer)

Compare Trecator with other medications

Tuberculosis, Active

Where can I get more information?

Your pharmacist has additional information about ethionamide written for health professionals that you may read.

See also: Trecator side effects (in more detail)

Trasylol

Pronunciation: a-proe-TYE-nin
Generic Name: Aprotinin
Brand Name: Trasylol

Trasylol may cause severe and sometimes fatal allergic reactions (eg, rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; fast heartbeat; pale skin; severe low blood pressure; loss of consciousness possibly leading to a lack of heartbeat or breathing). The risk is increased in patients who have previously received Trasylol. The risk of fatal allergic reactions may be greater in patients who receive Trasylol more than once in a 12-month period of time. Tell your doctor if you think you have ever had Trasylol in the past.

Trasylol is used for:

Reducing blood loss and the need for blood transfusions in patients undergoing certain types of heart surgery.

Trasylol is a protease inhibitor. It works by reducing the inflammatory response associated with cardiopulmonary bypass surgery.

Do NOT use Trasylol if:

you are allergic to any ingredient in Trasylol

you have received Trasylol within the past 12 months

Contact your doctor or health care provider right away if any of these apply to you.

Before using Trasylol:

Some medical conditions may interact with Trasylol. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

if you are pregnant, planning to become pregnant, or are breast-feeding

if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement

if you have allergies to medicines, foods, or other substances

if you have kidney problems

if you have previously had heart surgery

Some MEDICINES MAY INTERACT with Trasylol. Tell your health care provider if you are taking any other medicines, especially any of the following:

Aminoglycosides (eg, gentamicin) or medicines that alter kidney function because the risk of kidney damage may be increased

Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril) or fibrinolytics (eg, streptokinase) because the effectiveness of these medicines may be decreased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Trasylol may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Trasylol:

Use Trasylol as directed by your doctor. Check the label on the medicine for exact dosing instructions.

An extra patient leaflet is available with Trasylol. Talk to your pharmacist if you have questions about this information.

Trasylol is administered as an intravenous (IV; into a vein) injection only in a medical setting.

If you miss a dose of Trasylol, contact your doctor immediately.

Ask your health care provider any questions you may have about how to use Trasylol.

Important safety information:

Lab tests, including kidney function and blood clotting tests, may be performed while you use Trasylol. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.

Trasylol should not be used in CHILDREN; safety and effectiveness in children have not been confirmed.

PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Trasylol while you are pregnant. It is not known if Trasylol is found in breast milk. If you are or will be breast-feeding while you use Trasylol, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Trasylol:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; diarrhea; difficulty urinating; infection (eg, fever, chills, sore throat); lightheadedness; sleeplessness; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); asthma; chest pain; confusion; decreased urination; fast or irregular heartbeat; lung disorder; nausea; numbness of an arm or leg; one-sided weakness; severe stomach pain; sudden severe headache, dizziness, fainting, or vomiting; sudden weight gain; swelling of the hands, legs, or feet; vision or speech changes.

See also: Trasylol side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800 -222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Trasylol:

Trasylol is usually handled and stored by a health care provider. Keep Trasylol out of the reach of children and away from pets.

General information:

If you have any questions about Trasylol, please talk with your doctor, pharmacist, or other health care provider.

Trasylol is to be used only by the patient for whom it is prescribed. Do not share it with other people.

If your symptoms do not improve or if they become worse, check with your doctor.

Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Trasylol. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

More Trasylol resources

Trasylol Side Effects (in more detail)
Trasylol Use in Pregnancy & Breastfeeding
Trasylol Drug Interactions
Trasylol Support Group
0 Reviews for Trasylol - Add your own review/rating

Trasylol Prescribing Information (FDA)

Trasylol Monograph (AHFS DI)

Compare Trasylol with other medications

Bleeding Disorder

Trasylol

aprotinin bovine

Dosage Form: injection

Trasylol® administration may cause fatal anaphylactic or anaphylactoid reactions. Fatal reactions have occurred with an initial (test) dose as well as with any of the components of the dose regimen. Fatal reactions have also occurred in situations where the initial (test) dose was tolerated. The risk for anaphylactic or anaphylactoid reactions is increased among patients with prior aprotinin exposure and a history of any prior aprotinin exposure must be sought prior to Trasylol® administration. The risk for a fatal reaction appears to be greater upon re-exposure within 12 months of the most recent prior aprotinin exposure. Trasylol® should be administered only in operative settings where cardiopulmonary bypass can be rapidly initiated. The benefit of Trasylol® to patients undergoing primary CABG surgery should be weighed against the risk of anaphylaxis associated with any subsequent exposure to aprotinin. (See CONTRAINDICATIONS, WARNINGS and PRECAUTIONS.)

Trasylol Description

Trasylol® (aprotinin injection), C284H432N84O79S7, is a natural proteinase inhibitor obtained from bovine lung. Aprotinin (molecular weight of 6512 daltons), consists of 58 amino acid residues that are arranged in a single polypeptide chain, cross-linked by three disulfide bridges. It is supplied as a clear, colorless, sterile isotonic solution for intravenous administration. Each milliliter contains 10,000 KIU (Kallikrein Inhibitor Units) (1.4 mg/mL) and 9 mg sodium chloride in water for injection. Hydrochloric acid and/or sodium hydroxide is used to adjust the pH to 4.5-6.5.

Trasylol - Clinical Pharmacology

Mechanism of Action:

Aprotinin is a broad spectrum protease inhibitor which modulates the systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB) surgery. SIR results in the interrelated activation of the hemostatic, fibrinolytic, cellular and humoral inflammatory systems. Aprotinin, through its inhibition of multiple mediators [e.g., kallikrein, plasmin] results in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation.

Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis. In platelets, aprotinin reduces glycoprotein loss (e.g., GpIb, GpIIb/IIIa), while in granulocytes it prevents the expression of pro-inflammatory adhesive glycoproteins (e.g., CD11b).

The effects of aprotinin use in CPB involves a reduction in inflammatory response which translates into a decreased need for allogeneic blood transfusions, reduced bleeding, and decreased mediastinal re-exploration for bleeding.

Pharmacokinetics:

The studies comparing the pharmacokinetics of aprotinin in healthy volunteers, cardiac patients undergoing surgery with cardiopulmonary bypass, and women undergoing hysterectomy suggest linear pharmacokinetics over the dose range of 50,000 KIU to 2 million KIU. After intravenous (IV) injection, rapid distribution of aprotinin occurs into the total extracellular space, leading to a rapid initial decrease in plasma aprotinin concentration. Following this distribution phase, a plasma half-life of about 150 minutes is observed. At later time points, (i.e., beyond 5 hours after dosing) there is a terminal elimination phase with a half-life of about 10 hours.

Average steady state intraoperative plasma concentrations were 137 KIU/mL (n=10) after administration of the following dosage regimen: 1 million KIU IV loading dose, 1 million KIU into the pump prime volume, 250,000 KIU per hour of operation as continuous intravenous infusion (Regimen B). Average steady state intraoperative plasma concentrations were 250 KIU/mL in patients (n=20) treated with aprotinin during cardiac surgery by administration of Regimen A (exactly double Regimen B): 2 million KIU IV loading dose, 2 million KIU into the pump prime volume, 500,000 KIU per hour of operation as continuous intravenous infusion.

Following a single IV dose of radiolabelled aprotinin, approximately 25-40% of the radioactivity is excreted in the urine over 48 hours. After a 30 minute infusion of 1 million KIU, about 2% is excreted as unchanged drug. After a larger dose of 2 million KIU infused over 30 minutes, urinary excretion of unchanged aprotinin accounts for approximately 9% of the dose. Animal studies have shown that aprotinin is accumulated primarily in the kidney. Aprotinin, after being filtered by the glomeruli, is actively reabsorbed by the proximal tubules in which it is stored in phagolysosomes. Aprotinin is slowly degraded by lysosomal enzymes. The physiological renal handling of aprotinin is similar to that of other small proteins, e.g., insulin.

Clinical Trials

Repeat Coronary Artery Bypass Graft Patients:

Four placebo-controlled, double-blind studies of Trasylol® were conducted in the United States; of 540 randomized patients undergoing repeat coronary artery bypass graft (CABG) surgery, 480 were valid for efficacy analysis. The following treatment regimens were used in the studies:

Trasylol® Regimen A (2 million KIU IV loading dose, 2 million KIU into the pump prime volume, and 500,000 KIU per hour of surgery as a continuous intravenous infusion); Trasylol® Regimen B (1 million KIU IV loading dose, 1 million KIU into the pump prime volume, and 250,000 KIU per hour of surgery as a continuous intravenous infusion); a pump prime regimen (2 million KIU into the pump prime volume only); and a placebo regimen (normal saline). All patients valid for efficacy in the above studies were pooled by treatment regimen for analyses of efficacy.

In this pooled analysis, fewer patients receiving Trasylol®, either Regimen A or Regimen B, required any donor blood compared to the pump prime only or placebo regimens. The number of units of donor blood required by patients, the volume (milliliters) of donor blood transfused, the number of units of donor blood products transfused, the thoracic drainage rate, and the total thoracic drainage volumes were also reduced in patients receiving Trasylol® as compared to placebo.

Efficacy Variables: Repeat CABG Patients Mean (S.D.) or % of Patients
VARIABLE	PLACEBO REGIMEN N=156	Trasylol® PUMP PRIME REGIMEN† N=68	Trasylol® REGIMEN B** N=113	Trasylol® REGIMEN A** N=143
† The pump prime regimen was evaluated in only one study in patients undergoing repeat CABG surgery. Note: The pump prime only regimen is not an approved dosage regimen.
* Significantly different from placebo, p<0.05 (Transfusion variables analyzed via ANOVA on ranks)
** Differences between Regimen A (high dose) and Regimen B (low dose) in efficacy and safety are not statistically significant.
a Excludes patients who required reoperation
% OF REPEAT CABG PATIENTS WHO REQUIRED DONOR BLOOD	76.3%	72.1%	48.7%	46.9%

UNITS OF DONOR BLOOD TRANSFUSED	3.7 (4.4)	2.5 (2.4)	2.2 (5.0)*	1.6 (2.9)*

mL OF DONOR BLOOD TRANSFUSED	1132 (1443)	756 (807)	723 (1779)*	515 (999)*

PLATELETS TRANSFUSED (Donor Units)	5.0 (10.0)	2.1 (4.6)*	1.3 (4.6)*	0.9 (4.3)*

CRYOPRECIPITATE TRANSFUSED (Donor Units)	0.9 (3.5)	0.0 (0.0)*	0.5 (4.0)	0.1 (0.8)*

FRESH FROZEN PLASMA TRANSFUSED (Donor Units)	1.3 (2.5)	0.5 (1.4)*	0.3 (1.1)*	0.2 (0.9)*

THORACIC DRAINAGE RATE (mL/hr)	89 (77)	73 (69)	66 (244)	40 (36)*

TOTAL THORACIC DRAINAGE VOLUME (mL)a	1659 (1226)	1561 (1370)	1103 (2001)*	960 (849)*

REOPERATION FOR DIFFUSE BLEEDING	1.9%	2.9%	0%	0%

Primary Coronary Artery Bypass Graft Patients:

Four placebo-controlled, double-blind studies of Trasylol® were conducted in the United States; of 1745 randomized patients undergoing primary CABG surgery, 1599 were valid for efficacy analysis. The dosage regimens used in these studies were identical to those used in the repeat CABG studies described above (Regimens A, B, pump prime, and placebo). All patients valid for efficacy were pooled by treatment regimen.

In this pooled analysis, fewer patients receiving Trasylol® Regimens A, B, and pump prime required any donor blood in comparison to the placebo regimen. The number of units of donor blood required by patients, the volume of donor blood transfused, the number of units of donor blood products transfused, the thoracic drainage rate, and total thoracic drainage volumes were also reduced in patients receiving Trasylol® as compared to placebo.

Efficacy Variables: Primary CABG Patients Mean (S.D.) or % of Patients
VARIABLE	PLACEBO REGIMEN N=624	Trasylol® PUMP PRIME REGIMEN† N=159	Trasylol® REGIMEN B** N=175	Trasylol® REGIMEN A** N=641
† The pump prime regimen was evaluated in only one study in patients undergoing primary CABG surgery. Note: The pump prime only regimen is not an approved dosage regimen.
* Significantly different from placebo, p<0.05 (Transfusion variables analyzed via ANOVA on ranks)
** Differences between Regimen A (high dose) and Regimen B (low dose) in efficacy and safety are not statistically significant.

% OF PRIMARY CABG PATIENTS WHO REQUIRED DONOR BLOOD	53.5%	32.7%*	37.1%*	36.8%*


UNITS OF DONOR BLOOD TRANSFUSED	1.7 (2.4)	0.9 (1.6)*	1.0 (1.6)*	0.9 (1.4)*

mL OF DONOR BLOOD TRANSFUSED	584 (840)	286 (518)*	313 (505)*	295 (503)*

PLATELETS TRANSFUSED (Donor Units)	1.3 (3.7)	0.5 (2.4)*	0.3 (1.6)*	0.3 (1.5)*

CRYOPRECIPITATE TRANSFUSED (Donor Units)	0.5 (2.2)	0.0 (0.0)*	0.1 (0.8)*	0.0 (0.0)*

FRESH FROZEN PLASMA TRANSFUSED (Donor Units)	0.6 (1.7)	0.2 (1.7)*	0.2 (0.8)*	0.2 (0.9)*

THORACIC DRAINAGE RATE (mL/hr)	87 (67)	51 (36)*	45 (31)*	39 (32)*

TOTAL THORACIC DRAINAGE VOLUME (mL)	1232 (711)	852 (653)*	792 (465)*	705 (493)*

REOPERATION FOR DIFFUSE BLEEDING	1.4%	0.6%	0%	0%*

Additional subgroup analyses showed no diminution in benefit with increasing age. Male and female patients benefited from Trasylol® with a reduction in the average number of units of donor blood transfused. Although male patients did better than female patients in terms of the percentage of patients who required any donor blood transfusions, the number of female patients studied was small.

A double-blind, randomized, Canadian study compared Trasylol® Regimen A (n=28) and placebo (n=23) in primary cardiac surgery patients (mainly CABG) requiring cardiopulmonary bypass who were treated with aspirin within 48 hours of surgery. The mean total blood loss (1209.7 mL vs. 2532.3 mL) and the mean number of units of packed red blood cells transfused (1.6 units vs 4.3 units) were significantly less (p<0.008) in the Trasylol® group compared to the placebo group.

In a U.S. randomized study of Trasylol® Regimen A and Regimen B versus the placebo regimen in 212 patients undergoing primary aortic and/or mitral valve replacement or repair, no benefit was found for Trasylol® in terms of the need for transfusion or the number of units of blood required.

Indications and Usage for Trasylol

Trasylol® is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion.

Contraindications

Hypersensitivity to aprotinin.

Administration of Trasylol® to patients with a known or suspected previous aprotinin exposure during the last 12 months is contraindicated. For patients with known or suspected history of exposure to aprotinin greater than 12 months previously, see WARNINGS. Aprotinin may also be a component of some fibrin sealant products and the use of these products should be included in the patient history.

Warnings

Anaphylactic or anaphylactoid reactions have occurred with Trasylol® administration, including fatal reactions in association with the initial (test) dose. The initial (test) dose does not fully predict a patient’s risk for a hypersensitivity reaction, including a fatal reaction. Fatal hypersensitivity reactions have occurred among patients who tolerated an initial (test) dose.

Hypersensitivity reactions often manifest as anaphylactic/anaphylactoid reactions with hypotension the most frequently reported sign of the hypersensitivity reaction. The hypersensitivity reaction can progress to anaphylactic shock with circulatory failure. If a hypersensitivity reaction occurs during injection or infusion of Trasylol®, administration should be stopped immediately and emergency treatment should be initiated. Even when a second exposure to aprotinin has been tolerated without symptoms, a subsequent administration may result in severe hypersensitivity/anaphylactic reactions.

Trasylol® should be administered only in operative settings where cardiopulmonary bypass can be rapidly initiated. Before initiating treatment with Trasylol®, the recommendations below should be followed to manage a potential hypersensitivity or anaphylactic reaction: 1) Have standard emergency treatments for hypersensitivity or anaphylactic reactions readily available in the operating room (e.g., epinephrine, corticosteroids). 2) Administration of the initial (test) dose and loading dose should be done only when the patient is intubated and when conditions for rapid cannulation and initiation of cardiopulmonary bypass are present. 3) Delay the addition of Trasylol® into the pump prime solution until after the loading dose has been safely administered.

Re-exposure to aprotinin: Administration of aprotinin, especially to patients who have received aprotinin in the past, requires a careful risk/benefit assessment because an allergic reaction may occur (see CONTRAINDICATIONS). Although the majority of cases of anaphylaxis occur upon re-exposure within the first 12 months, there are also case reports of anaphylaxis occurring upon re-exposure after more than 12 months.

In a retrospective review of 387 European patient records with documented re-exposure to Trasylol®, the incidence of hypersensitivity/anaphylactic reactions was 2.7%. Two patients who experienced hypersensitivity/anaphylactic reactions subsequently died, 24 hours and 5 days after surgery, respectively. The relationship of these 2 deaths to Trasylol® is unclear. This retrospective review also showed that the incidence of a hypersensitivity or anaphylactic reaction following re-exposure is increased when the re-exposure occurs within 6 months of the initial administration (5.0% for re-exposure within 6 months and 0.9% for re-exposure greater than 6 months). Other smaller studies have shown that in case of re-exposure, the incidence of hypersensitivity/anaphylactic reactions may reach the five percent level.

An analysis of all spontaneous reports from the Bayer Global database covering a period from 1985 to March 2006 revealed that of 291 possibly associated spontaneous cases of hypersensitivity (fatal: n=52 and non-fatal: n=239), 47% (138/291) of hypersensitivity cases had documented previous exposure to Trasylol®. Of the 138 cases with documented previous exposure, 110 had information on the time of the previous exposure. Ninety-nine of the 110 cases had previous exposure within the prior 12 months.

Renal Dysfunction: Trasylol® administration increases the risk for renal dysfunction and may increase the need for dialysis in the perioperative period. This risk may be especially increased for patients with pre-existing renal impairment or those who receive aminoglycoside antibiotics or drugs that alter renal function. Data from Bayer’s global pool of placebo-controlled studies in patients undergoing coronary artery bypass graft (CABG) surgery showed that the incidence of serum creatinine elevations >0.5 mg/dL above pre-treatment levels was statistically higher at 9.0% (185/2047) in the high-dose aprotinin (Regimen A) group compared with 6.6% (129/1957) in the placebo group. In the majority of instances, post-operative renal dysfunction was not severe and was reversible. However, renal dysfunction may progress to renal failure and the incidence of serum creatinine elevations >2.0 mg/dL above baseline was slightly higher in the high-dose aprotinin group (1.1% vs. 0.8%). Careful consideration of the balance of benefits versus potential risks is advised before administering Trasylol® to patients with impaired renal function (creatinine clearance < 60 mL/min) or those with other risk factors for renal dysfunction (such as perioperative administration of aminogylcoside or products that alter renal function). (See PRECAUTIONS and ADVERSE REACTIONS: Laboratory Findings: Serum Creatinine.)

Precautions

General:

Initial (Test) Dose: All patients treated with Trasylol® should first receive an initial (test) dose to minimize the extent of Trasylol® exposure and to help assess the potential for allergic reactions. Initiation of this initial (test) dose should occur only in operative settings where cardiopulmonary bypass can be rapidly initiated. The initial (test) dose of 1 mL Trasylol® should be administered intravenously at least 10 minutes prior to the loading dose and the patient should be observed for manifestations of possible hypersensitivity reaction. However, even after the uneventful administration of the initial 1 mL (test) dose, any subsequent dose may cause an anaphylactic reaction. If this happens, the infusion of Trasylol® should immediately be stopped and standard emergency treatment for anaphylaxis applied. It should be noted that serious, even fatal, hypersensitivity/anaphylactic reactions can also occur with administration of the initial (test) dose (see WARNINGS).

Allergic Reactions: Patients with a history of allergic reactions to drugs or other agents may be at greater risk of developing a hypersensitivity or anaphylactic reaction upon exposure to Trasylol® (see WARNINGS).

Loading Dose: The loading dose of Trasylol® should be given intravenously to patients in the supine position over a 20-30 minute period. Rapid intravenous administration of Trasylol® can cause a transient fall in blood pressure (see DOSAGE AND ADMINISTRATION).

Renal Dysfunction: Bayer’s global pool of placebo-controlled studies in patients undergoing CABG showed aprotinin administration was associated with elevations of serum creatinine values > 0.5 mg/dL above baseline. Careful consideration of the balance of benefits and risks is advised before administering aprotinin to patients with pre-existing impaired renal function or those with other risk factors for renal dysfunction. Serum creatinine should be monitored regularly following Trasylol® administration (see WARNINGS: Renal Dysfunction).

Use of Trasylol® in patients undergoing deep hypothermic circulatory arrest: Two U.S. case control studies have reported contradictory results in patients receiving Trasylol® while undergoing deep hypothermic circulatory arrest in connection with surgery of the aortic arch.

The first study showed an increase in both renal failure and mortality compared to age-matched historical controls. Similar results were not observed, however, in a second case control study. The strength of this association is uncertain because there are no data from randomized studies to confirm or refute these findings.

Drug Interactions:

Trasylol® is known to have antifibrinolytic activity and, therefore, may inhibit the effects of fibrinolytic agents.

In study of nine patients with untreated hypertension, Trasylol® infused intravenously in a dose of 2 million KIU over two hours blocked the acute hypotensive effect of 100mg of captopril.

Trasylol®, in the presence of heparin, has been found to prolong the activated clotting time (ACT) as measured by a celite surface activation method. The kaolin activated clotting time appears to be much less affected. However, Trasylol® should not be viewed as a heparin sparing agent (see Laboratory Monitoring of Anticoagulation During Cardiopulmonary Bypass).

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Long-term animal studies to evaluate the carcinogenic potential of Trasylol® or studies to determine the effect of Trasylol® on fertility have not been performed.

Results of microbial in vitro tests using Salmonella typhimurium and Bacillus subtilis indicate that Trasylol® is not a mutagen.

Pregnancy: Teratogenic Effects: Pregnancy Category B:

Reproduction studies have been performed in rats at intravenous doses up to 200,000 KIU/kg/day for 11 days, and in rabbits at intravenous doses up to 100,000 KIU/kg/day for 13 days, 2.4 and 1.2 times the human dose on a mg/kg basis and 0.37 and 0.36 times the human mg/m2 dose. They have revealed no evidence of impaired fertility or harm to the fetus due to Trasylol®. 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.

Nursing Mother:

Not applicable.

Pediatric Use:

Safety and effectiveness in pediatric patient(s) have not been established.

Geriatric Use:

Of the total of 3083 subjects in clinical studies of Trasylol®, 1100 (35.7 percent) were 65 and over, while 297 (9.6 percent) were 75 and over. Of patients 65 years and older, 479 (43.5 percent) received Regimen A and 237 (21.5 percent) received Regimen B. No overall differences in safety or effectiveness were observed between these subjects and younger subjects for either dose regimen, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Laboratory Monitoring of Anticoagulation during Cardiopulmonary Bypass:

Trasylol® prolongs whole blood clotting times by a different mechanism than heparin. In the presence of aprotinin, prolongation is dependent on the type of whole blood clotting test employed. If an activated clotting time (ACT) is used to determine the effectiveness of heparin anticoagulation, the prolongation of the ACT by aprotinin may lead to an overestimation of the degree of anticoagulation, thereby leading to inadequate anticoagulation. During extended extracorporeal circulation, patients may require additional heparin, even in the presence of ACT levels that appear adequate.

In patients undergoing CPB with Trasylol® therapy, one of the following methods may be employed to maintain adequate anticoagulation:

1): ACT - An ACT is not a standardized coagulation test, and different formulations of the assay are affected differently by the presence of aprotinin. The test is further influenced by variable dilution effects and the temperature experienced during cardiopulmonary bypass. It has been observed that Kaolin-based ACTs are not increased to the same degree by aprotinin as are diatomaceous earth-based (celite) ACTs. While protocols vary, a minimal celite ACT of 750 seconds or kaolin-ACT of 480 seconds, independent of the effects of hemodilution and hypothermia, is recommended in the presence of aprotinin. Consult the manufacturer of the ACT test regarding the interpretation of the assay in the presence of Trasylol®.
2): Fixed Heparin Dosing - A standard loading dose of heparin, administered prior to cannulation of the heart, plus the quantity of heparin added to the prime volume of the CPB circuit, should total at least 350 IU/kg. Additional heparin should be administered in a fixed-dose regimen based on patient weight and duration of CPB.
3): Heparin Titration - Protamine titration, a method that is not affected by aprotinin, can be used to measure heparin levels. A heparin dose response, assessed by protamine titration, should be performed prior to administration of aprotinin to determine the heparin loading dose. Additional heparin should be administered on the basis of heparin levels measured by protamine titration. Heparin levels during bypass should not be allowed to drop below 2.7 U/mL (2.0 mg/kg) or below the level indicated by heparin dose response testing performed prior to administration of aprotinin.

Protamine Administration - In patients treated with Trasylol®, the amount of protamine administered to reverse heparin activity should be based on the actual amount of heparin administered, and not on the ACT values.

Adverse Reactions

Studies of patients undergoing CABG surgery, either primary or repeat, indicate that Trasylol® is generally well tolerated. The adverse events reported are frequent sequelae of cardiac surgery and are not necessarily attributable to Trasylol® therapy. Adverse events reported, up to the time of hospital discharge, from patients in US placebo-controlled trials are listed in the following table. The table lists only those events that were reported in 2% or more of the Trasylol® treated patients without regard to causal relationship.

INCIDENCE RATES OF ADVERSE EVENTS (> = 2%) BY BODY SYSTEM AND TREATMENT FOR ALL PATIENTS FROM US PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse Event	Aprotinin (n = 2002) values in %	Placebo (n = 1084) values in %
Any Event	76	77
Body as a Whole
Fever	15	14
Infection	6	7
Chest Pain	2	2
Asthenia	2	2
Cardiovascular
Atrial Fibrillation	21	23
Hypotension	8	10
Myocardial Infarct	6	6
Atrial Flutter	6	5
Ventricular Extrasystoles	6	4
Tachycardia	6	7
Ventricular Tachycardia	5	4
Heart Failure	5	4
Pericarditis	5	5
Peripheral Edema	5	5
Hypertension	4	5
Arrhythmia	4	3
Supraventricular Tachycardia	4	3
Atrial Arrhythmia	3	3
Digestive
Nausea	11	9
Constipation	4	5
Vomiting	3	4
Diarrhea	3	2
Liver Function Tests Abnormal	3	2
Hemic and Lymphatic
Anemia	2	8
Metabolic & Nutritional
Creatine Phosphokinase Increased	2	1
Musculoskeletal
Any Event	2	3
Nervous
Confusion	4	4
Insomnia	3	4
Respiratory
Lung Disorder	8	8
Pleural Effusion	7	9
Atelectasis	5	6
Dyspnea	4	4
Pneumothorax	4	4
Asthma	2	3
Hypoxia	2	1
Skin and Appendages
Rash	2	2
Urogenital
Kidney Function Abnormal	3	2
Urinary Retention	3	3
Urinary Tract Infection	2	2

In comparison to the placebo group, no increase in mortality in patients treated with Trasylol® was observed. Additional events of particular interest from controlled US trials with an incidence of less than 2%, are listed below:

EVENT	Percentage of patients treated with Trasylol® N = 2002	Percentage of patients treated with Placebo N = 1084
Thrombosis	1.0	0.6
Shock	0.7	0.4
Cerebrovascular Accident	0.7	2.1
Thrombophlebitis	0.2	0.5
Deep Thrombophlebitis	0.7	1.0
Lung Edema	1.3	1.5
Pulmonary Embolus	0.3	0.6
Kidney Failure	1.0	0.6
Acute Kidney Failure	0.5	0.6
Kidney Tubular Necrosis	0.8	0.4

Listed below are additional events, from controlled US trials with an incidence between 1 and 2%, and also from uncontrolled, compassionate use trials and spontaneous post-marketing reports. Estimates of frequency cannot be made for spontaneous post-marketing reports (italicized).

Body as a Whole: Sepsis, death, multi-system organ failure, immune system disorder, hemoperitoneum.

Cardiovascular: Ventricular fibrillation, heart arrest, bradycardia, congestive heart failure, hemorrhage, bundle branch block, myocardial ischemia, ventricular tachycardia, heart block, pericardial effusion, ventricular arrhythmia, shock, pulmonary hypertension.

Digestive: Dyspepsia, gastrointestinal hemorrhage, jaundice, hepatic failure.

Hematologic and Lymphatic: Although thrombosis was not reported more frequently in aprotinin versus placebo-treated patients in controlled trials, it has been reported in uncontrolled trials, compassionate use trials, and spontaneous post-marketing reporting. These reports of thrombosis encompass the following terms: thrombosis, occlusion, arterial thrombosis, pulmonary thrombosis, coronary occlusion, embolus, pulmonary embolus, thrombophlebitis, deep thrombophlebitis, cerebrovascular accident, cerebral embolism. Other hematologic events reported include leukocytosis, thrombocytopenia, coagulation disorder (which includes disseminated intravascular coagulation), decreased prothrombin.

Metabolic and Nutritional: Hyperglycemia, hypokalemia, hypervolemia, acidosis.

Musculoskeletal: Arthralgia.

Nervous: Agitation, dizziness, anxiety, convulsion.

Respiratory: Pneumonia, apnea, increased cough, lung edema.

Skin:Skin discoloration.

Urogenital: Oliguria, kidney failure, acute kidney failure, kidney tubular necrosis.

Myocardial Infarction: In the pooled analysis of all patients undergoing CABG surgery, there was no significant difference in the incidence of investigator-reported myocardial infarction (MI) in Trasylol® treated patients as compared to placebo treated patients. However, because no uniform criteria for the diagnosis of myocardial infarction were utilized by investigators, this issue was addressed prospectively in three later studies (two studies evaluated Regimen A, Regimen B and Pump Prime Regimen; one study evaluated only Regimen A), in which data were analyzed by a blinded consultant employing an algorithm for possible, probable or definite MI. Utilizing this method, the incidence of definite myocardial infarction was 5.9% in the aprotinin-treated patients versus 4.7% in the placebo treated patients. This difference in the incidence rates was not statistically significant. Data from these three studies are summarized below.

Incidence of Myocardial Infarctions by Treatment Group Population: All CABG Patients Valid for Safety Analysis
Treatment	Definite MI %	Definite or Probable MI %	Definite, Probable or Possible MI %
Pooled Data from Three Studies that Evaluated Regimen A
Trasylol® Regimen A n = 646	4.6	10.7	14.1
Placebo n = 661	4.7	11.3	13.4
Pooled Data from Two Studies that Evaluated Regimen B and Pump Prime Regimen
Trasylol® Regimen B n = 241	8.7	15.9	18.7
Trasylol® Pump Prime Regimen n = 239	6.3	15.7	18.1
Placebo n = 240	6.3	15.1	15.8

Graft Patency: In a recently completed multi-center, multi-national study to determine the effects of Trasylol® Regimen A vs. placebo on saphenous vein graft patency in patients undergoing primary CABG surgery, patients were subjected to routine postoperative angiography. Of the 13 study sites, 10 were in the United States and three were non-U.S. centers (Denmark (1), Israel (2)). The results of this study are summarized below.

Incidence of Graft Closure, Myocardial Infarction and Death by Treatment Group
	Overall Closure Rates*		Incidence of MI**	Incidence of Death***
	All Centers n = 703 %	U.S. Centers n = 381 %	All Centers n = 831 %	All Centers n = 870 %
Trasylol®	15.4	9.4	2.9	1.4
Placebo	10.9	9.5	3.8	1.6
CI for the Difference (%) (Drug - Placebo)	(1.3, 9.6)†	(-3.8, 5.9)†	-3.3 to 1.5‡	-1.9 to 1.4‡
* Population: all patients with assessable saphenous vein grafts
** Population: all patients assessable by blinded consultant
*** All patients
† 90%; per protocol
‡ 95%; not specified in protocol

Although there was a statistically significantly increased risk of graft closure for Trasylol® treated patients compared to patients who received placebo (p=0.035), further analysis showed a significant treatment by site interaction for one of the non-U.S. sites vs. the U.S. centers. When the analysis of graft closures was repeated for U.S. centers only, there was no statistically significant difference in graft closure rates in patients who received Trasylol® vs. placebo. These results are the same whether analyzed as the proportion of patients who experienced at least one graft closure postoperatively or as the proportion of grafts closed. There were no differences between treatment groups in the incidence of myocardial infarction as evaluated by the blinded consultant (2.9% Trasylol® vs. 3.8% placebo) or of death (1.4% Trasylol® vs. 1.6% placebo) in this study.

Hypersensitivity and Anaphylaxis: See CONTRAINDICATI