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Trental

Trental(pentoxifylline) – Sanofi-Aventis

THERAPEUTIC CLASS

Blood viscosity reducer

INDICATIONS

Treatment of intermittent claudication on the basis of chronic occlusive arterial disease of the limbs.

ADULT DOSAGE

Adults: Usual: 400mg tid with meals for at least 8 weeks. Reduce to 400mg bid if digestive and CNS side effects occur; d/c if side effects persist. Elderly: Start at lower end of dosing range.

HOW SUPPLIED

Tab, Extended-Release: 400mg

CONTRAINDICATIONS

Recent cerebral and/or retinal hemorrhage, intolerance to methylxanthines (eg, caffeine, theophylline, theobromine).

WARNINGS/PRECAUTIONS

Not intended to replace more definitive therapy (eg, surgical bypass, removal of arterial obstructions) when treating peripheral vascular disease. D/C at the 1st sign of anaphylactic/anaphylactoid reaction. Angina, hypotension, and arrhythmia occasionally reported in patients with concurrent coronary artery and cerebrovascular diseases. Perform periodic exams for bleeding (eg, Hgb, Hct) in patients with risk factors complicated by hemorrhage (eg, recent surgery, peptic ulceration, cerebral/retinal bleeding). Caution in elderly.

ADVERSE REACTIONS

Belching/flatus/bloating, dyspepsia, N/V, dizziness, headache.

DRUG INTERACTIONS

Bleeding and/or prolonged PT reported with and without anticoagulants or platelet aggregation inhibitors; frequently monitor PT if on warfarin. May increase theophylline levels; monitor for signs of toxicity and adjust theophylline dose PRN. Small decreases in BP observed with concomitant nifedipine or captopril; periodically monitor BP in patients receiving antihypertensive therapy and reduce antihypertensive agent dose if indicated. Increased anticoagulant activity with vitamin K antagonists; monitor anticoagulant activity.

PREGNANCY

Category C, not for use in nursing.

MECHANISM OF ACTION

Blood viscosity reducer; not established. Increases blood flow to affected microcirculation and enhances tissue oxygenation. Produces dose-related hemorrheologic effects, lowers blood viscosity, improves erythrocyte flexibility, increases leukocyte deformability, and inhibits neutrophil adhesion and activation.

PHARMACOKINETICS

Absorption: Tmax=2-4 hrs. Distribution: Found in breast milk. Metabolism: 1st pass; metabolites (major): Metabolite 1 (1-[5-hydroxyhexyl]-3,7-dimethylxanthine); Metabolite V (1-[3-carboxypropyl]-3,7-dimethylxanthine). Elimination: Urine (major), feces (<4%); T1/2=0.4-0.8 hrs; 1-1.6 hrs (metabolites).

ASSESSMENT

Assess for risk factors for hemorrhage, intolerance to drug or methylxanthines (eg, caffeine, theophylline, theobromine), renal impairment, pregnancy/nursing status, and possible drug interactions.

MONITORING

Monitor for signs/symptoms of anaphylactic/anaphylactoid reaction, angina, arrhythmia, and hypotension. Monitor anticoagulant activity if treated concomitantly with vitamin K antagonists. Perform periodic exams for bleeding (eg, Hgb, Hct) with risk factors complicated by hemorrhage. Monitor BP with concomitant antihypertensive therapy. Monitor renal function.

PATIENT COUNSELING

Inform of risks and benefits of therapy. Counsel to report if any digestive (eg, bloating, dyspepsia, N/V) or CNS (eg, headaches, dizziness) side effects develop. Instruct to notify physician if taking other drugs, pregnant or planning to become pregnant. Advise not to breastfeed while on therapy.

ADMINISTRATION/STORAGE

Administration: Oral route. Storage: 15-30°C (59-86°F).


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    Trental

    Trental

    Pronunciation Generic Name: pentoxifylline (PEN-tox-IF-i-lin)

    Brand Name: Trental

    OverviewSide EffectsInteractionsFor ProfessionalsMore…

    Trental is used for:

    Treating intermittent claudication in certain patients to reduce pain, cramping, numbness, or weakness in the arms or legs. It may also be used for other conditions as determined by your doctor.

    Trental is a xanthine derivative. It works by making red blood cells more flexible, which helps to improve blood flow.

    Do NOT use Trental if:

    • you are allergic to any ingredient in Trental or to methylxanthines (eg, theophylline, caffeine, theobromine)
    • you have had recent bleeding in the brain or eye

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

    Before using Trental:

    Some medical conditions may interact with Trental. 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 stomach or bowel ulcers, blood vessel problems (eg, in the heart or brain), heart problems (eg, chest pain, irregular heartbeat), high or low blood pressure, kidney problems, or a history of bleeding in the brain or eye
    • if you have recently had surgery
    • if you take medicine for high blood pressure

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

    • Anticoagulants (eg, warfarin) or antiplatelet medicines (eg, clopidogrel) because the risk of bleeding may be increased
    • Theophylline because the risk of its side effects may be increased by Trental

    This may not be a complete list of all interactions that may occur. Ask your health care provider if Trental 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 Trental:

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

    • Take Trental by mouth with a meal.
    • Swallow Trental whole. Do not break, crush, or chew before swallowing.
    • Continue to take Trental even if you feel well. Do not miss any doses.
    • If you miss a dose of Trental, 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 Trental.

    Important safety information:

    • Trental may cause dizziness or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Trental with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.
    • Tell your doctor or dentist that you take Trental before you receive any medical or dental care, emergency care, or surgery.
    • It may take 2 to 4 weeks to notice improvement in your condition, and up to 8 weeks for maximum relief. Do NOT take more than the recommended dose, change your dose, or take Trental for longer than prescribed without checking with your doctor.
    • Trental should be used with extreme caution 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 Trental while you are pregnant. Trental is found in breast milk. Do not breast-feed while taking Trental.

    Possible side effects of Trental:

    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:

    Belching; bloating; dizziness; flushing; gas; indigestion; nausea; stomach discomfort or upset; 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); blurred vision or other vision changes; chest pain; fainting; irregular heartbeat; severe or persistent dizziness or light-headedness; stomach pain; unusual bruising or bleeding; unusual tiredness or weakness; yellowing of the skin or eyes.

    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.

    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 agitation; drowsiness; fainting; fever; flushing; loss of consciousness; seizures; severe dizziness.

    Proper storage of Trental: Store Trental at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Trental out of the reach of children and away from pets.

    General information:

    • If you have any questions about Trental, please talk with your doctor, pharmacist, or other health care provider.
    • Trental 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 should not be used to decide whether or not to take Trental or any other medicine. Only your health care provider has the knowledge and training to decide which medicines are right for you. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Trental. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Trental. This information is not specific medical advice and does not replace information you receive from your health care provider. You must talk with your healthcare provider for complete information about the risks and benefits of using Trental.

    Issue Date: March 6, 2013 Database Edition 13.1.1.003 Copyright © 2013 Wolters Kluwer Health, Inc.

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    Trental

    Trental

    Pronunciation Generic Name: pentoxifylline (Oral route)

    pen-tox-IF-i-lin

    OverviewSide EffectsInteractionsFor ProfessionalsMore…

    Commonly used brand name(s)

    In the U.S.

    • Pentopak
    • Pentoxil
    • Trental

    Available Dosage Forms:

    • Tablet, Extended Release

    Therapeutic Class: Hemorheologic

    Chemical Class: Methylxanthine

    Uses For Trental

    Pentoxifylline improves the flow of blood through blood vessels. It is used to reduce leg pain caused by poor blood circulation. Pentoxifylline makes it possible to walk farther before having to rest because of leg cramps.

    Pentoxifylline is available only with your doctor’s prescription.

    Before Using Trental

    In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

    Allergies

    Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

    Pediatric

    Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of pentoxifylline in children with use in other age groups.

    Geriatric

    Side effects may be more likely to occur in the elderly, who are usually more sensitive than younger adults to the effects of pentoxifylline.

    Pregnancy

    Pregnancy Category Explanation
    All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

    Breast Feeding

    There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

    Interactions with Medicines

    Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

    Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

    • Aceclofenac
    • Acemetacin
    • Alclofenac
    • Benoxaprofen
    • Bromfenac
    • Bufexamac
    • Carprofen
    • Clometacin
    • Clonixin
    • Dexketoprofen
    • Diclofenac
    • Diflunisal
    • Dipyrone
    • Droxicam
    • Etodolac
    • Etofenamate
    • Felbinac
    • Fenbufen
    • Fenoprofen
    • Fentiazac
    • Floctafenine
    • Flufenamic Acid
    • Flurbiprofen
    • Ibuprofen
    • Indomethacin
    • Indoprofen
    • Isoxicam
    • Ketoprofen
    • Ketorolac
    • Lornoxicam
    • Meclofenamate
    • Mefenamic Acid
    • Meloxicam
    • Nabumetone
    • Naproxen
    • Niflumic Acid
    • Nimesulide
    • Oxaprozin
    • Oxyphenbutazone
    • Phenylbutazone
    • Pirazolac
    • Piroxicam
    • Pirprofen
    • Propyphenazone
    • Proquazone
    • Sulindac
    • Suprofen
    • Tenidap
    • Tenoxicam
    • Tiaprofenic Acid
    • Tolmetin
    • Zomepirac

    Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

    • Cimetidine
    • Dicumarol
    • Theophylline

    Interactions with Food/Tobacco/Alcohol

    Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

    Other Medical Problems

    The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

    • Any condition in which there is a risk of bleeding (e.g., recent stroke)—Pentoxifylline may make the condition worse
    • Kidney disease or
    • Liver disease—The chance of side effects may be increased

    Proper Use of pentoxifylline

    This section provides information on the proper use of a number of products that contain pentoxifylline. It may not be specific to Trental. Please read with care.

    Swallow the tablet whole. Do not crush, break, or chew it before swallowing.

    Pentoxifylline should be taken with meals to lessen the chance of stomach upset. Taking an antacid with the medicine may also help.

    Dosing

    The dose of this medicine will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

    The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

    • For oral dosage form (extended-release tablets):
      • For peripheral vascular disease (circulation problems):
        • Adults—400 milligrams (mg) two to three times a day, taken with meals.
        • Children—Use must be determined by your doctor.

    Missed Dose

    If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

    Storage

    Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

    Keep out of the reach of children.

    Do not keep outdated medicine or medicine no longer needed.

    Precautions While Using Trental

    It may take several weeks for this medicine to work. If you feel that pentoxifylline is not working, do not stop taking it on your own. Instead, check with your doctor.

    Smoking tobacco may worsen your condition since nicotine may further narrow your blood vessels. Therefore, it is best to avoid smoking.

    Trental Side Effects

    Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

    Check with your doctor as soon as possible if any of the following side effects occur:

    Rare

    • Chest pain
    • irregular heartbeat

    Signs and symptoms of overdose (in the order in which they may occur)

    • Drowsiness
    • flushing
    • faintness
    • unusual excitement
    • convulsions (seizures)

    Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

    Less common

    • Dizziness
    • headache
    • nausea or vomiting
    • stomach discomfort

    Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

    Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

    See also: Trental side effects (in more detail)

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    Trental

    Trental

    Pronunciation Generic Name: pentoxifylline (pen tox I fi leen)

    Brand Name: TRENtal

    OverviewSide EffectsDosageInteractionsFor ProfessionalsMore…

    What is Trental (pentoxifylline)?

    Pentoxifylline causes changes in your blood that help improve blood flow. This also helps your blood carry oxygen to your tissues and organs.

    Pentoxifylline is used to improve blood flow and reduce certain symptoms of a condition called intermittent claudication (IN-ter-MIT-ent KLOD-ih-KAY-tion). Pentoxifylline is not a cure for this condition.

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

    What is the most important information I should know about Trental (pentoxifylline)?

    You should not use this medication if you are allergic to pentoxifylline, or if you are allergic to caffeine or theophylline (Elixophyllin, Theo-24, Theo-Dur, Slo-Bid, Theochron, Theolair, Uniphyl, and others).

    You also should not use pentoxifylline if you are breast-feeding a baby, or if you have recently had any type of bleeding in your brain or the retina of your eye.

    Before you take pentoxifylline, tell your doctor if you have angina (chest pain), a heart rhythm disorder, high blood pressure, a stomach or intestinal ulcer, kidney disease, or if you have recently had surgery.

    Tell your doctor about all other medicines you use, especially warfarin (Coumadin, Jantoven), theophylline (Elixophyllin, Theo-24, Theo-Dur, Slo-Bid, Theochron, Theolair, Uniphyl, and others), or blood pressure medication.

    Take pentoxifylline with food.

    Stop taking this medication and get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

    What should I discuss with my healthcare provider before taking Trental (pentoxifylline)?

    You should not use this medication if you are allergic to pentoxifylline, or if you are allergic to caffeine or theophylline (Elixophyllin, Theo-24, Theo-Dur, Slo-Bid, Theochron, Theolair, Uniphyl, and others).

    You also should not use pentoxifylline if you have recently had any type of bleeding in your brain or the retina of your eyes.

    To make sure you can safely take pentoxifylline, tell your doctor if you have other medical conditions, especially:

    • angina (chest pain);

    • a heart rhythm disorder;
    • high blood pressure (hypertension);
    • a stomach or intestinal ulcer;
    • kidney disease; or
    • if you have recently had surgery.

    FDA pregnancy category C. It is not known whether pentoxifylline will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

    Pentoxifylline can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using pentoxifylline.

    How should I take Trental (pentoxifylline)?

    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.

    Pentoxifylline is usually taken 3 times each day, with meals. Follow your doctor’s instructions.

    Do not crush, chew, or break an extended-release tablet. Swallow it whole. Breaking the pill may cause too much of the drug to be released at one time.

    It may take up to 4 weeks before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve after 8 weeks of treatment.

    Store at room temperature away from moisture, heat, and light.

    See also: Trental 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 symptoms may include severe drowsiness, agitation, fever, flushing (warmth, redness, or tingly feeling), fainting, or seizure.

    What should I avoid while taking Trental (pentoxifylline)?

    Follow your doctor’s instructions about any restrictions on food, beverages, or activity.

    Trental (pentoxifylline) side effects

    Stop taking this medication and get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

    Call your doctor at once if you have a serious side effect such as:

    • chest pain,

    • pounding heartbeats or fluttering in your chest;
    • feeling like you might pass out;
    • red or pink urine;
    • bloody, black, or tarry stools; or
    • coughing up blood or vomit that looks like coffee grounds.

    Less serious side effects may include:

    • dizziness, headache;

    • blurred vision;
    • flushing (warmth, redness, or tingly feeling);
    • gas, bloating, upset stomach; or
    • nausea, vomiting, diarrhea.

    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.

    See also: Trental side effects (in more detail)

    What other drugs will affect Trental (pentoxifylline)?

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

    • a blood thinner such as warfarin (Coumadin, Jantoven);

    • theophylline (Elixophyllin, Theo-24, Theo-Dur, Slo-Bid, Theochron, Theolair, Uniphyl, and others); or
    • blood pressure medication, especially nifedipine (Nifedical, Procardia) or captopril (Capoten, Capozide).

    This list is not complete and other drugs may interact with pentoxifylline. 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.

    Next Page → Side Effects

    More Trental resources

    • Side Effects
    • Recommended Dosage
    • Pregnancy Warnings
    • Drug Images
    • Drug Interactions
    • Support Group
    • 2 Reviews - Add your own review/rating
    • Generic Availability
    • Trental MedFacts Consumer Leaflet (Wolters Kluwer)
    • Trental Prescribing Information (FDA)
    • Trental Advanced Consumer (Micromedex) – Includes Dosage Information
    • Pentoxifylline Prescribing Information (FDA)
    • Pentoxifylline Professional Patient Advice (Wolters Kluwer)
    • Pentoxifylline Monograph (AHFS DI)
    • Pentoxil Prescribing Information (FDA)

    Compare Trental with other medications

    • Intermittent Claudication

    Where can I get more information?

    • Your pharmacist can provide more information about pentoxifylline.

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    Trental

    Trental

    Pronunciation Generic Name: pentoxifylline

    Dosage Form: tablet, film coated, extended release

    For ProfessionalsSide EffectsDosageInteractionsMore…

    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

    At the first sign of anaphylactic/anaphylactoid reaction, Trental must be discontinued.

    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 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 plus nifedipine or captopril; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced.

    Postmarketing cases of increased anticoagulant activity have been reported in patients concomitantly treated with pentoxifylline and vitamin K antagonists. Monitoring of anticoagulant activity in these patients is recommended when pentoxifylline is introduced or the dose is changed.

    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. Digestive — hepatitis, jaundice, cholestasis, increased liver enzymes; and Hemic and Lymphatic — decreased serum fibrinogen, pancytopenia, aplastic anemia, leukemia, purpura, thrombocytopenia. Immune system disorders — anaphylactic reaction, anaphylactoid reaction, anaphylactic shock.

    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. July 2010

    sanofi-aventis U.S. LLC

    Bridgewater, NJ 08807

    ©2010 sanofi-aventis U.S. LLC

    PRINCIPAL DISPLAY PANEL – Label

    NDC 0039-0078-10

    Trental®

    pentoxifylline

    Tablets

    400mg

    100 Tablets

    sanofi aventis

    Trental 

    pentoxifylline tablet, film coated, extended release

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: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  
    hypromelloses  
    magnesium stearate  
    polyethylene glycols  
    povidone  
    talc  
    titanium dioxide  
    Product Characteristics
    Color PINK Score no score
    Shape OVAL (capsule-shaped) Size 17mm
    Flavor Imprint Code Trental
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:0039-0078-10 100 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE
    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
    Valeant Pharmaceuticals International Inc. 248902996 MANUFACTURE(0039-0078), ANALYSIS(0039-0078), LABEL(0039-0078), PACK(0039-0078)

    Revised: 06/2012   Sanofi-Aventis U.S. LLC

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