TRENTAL® (pentoxifylline) tablets for oral administration contain 400 mg of the active drug and the following inactive ingredients: D&C Red No. 27 Aluminum Lake or FD&C Red No. 3, hypromellose USP, magnesium stearate NF, polyethylene glycol NF, povidone USP, talc USP, titanium dioxide USP, and other ingredients in a controlled-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 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.

The usual dosage of TRENTAL in controlled-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.

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), and Unit Dose Packs of 100 (NDC 0039-0078-11). Store between 59 and 86° F (15 and 30° C). Dispense in well-closed, light-resistant containers. Protect blisters from light.

Rx only.
Rev. May 2003

US Patents 3,737,433 & 4,189,469
US Patent 3,737,433 patent term has been extended.

Manufactured by:
Patheon Pharmaceuticals Inc.
Cincinnati, OH 45215 USA

Manufactured for:
Aventis Pharmaceuticals NJ
Bridgewater, NJ 08807 USA

©2002 Aventis Pharmaceuticals Inc.

TRE-MAY03-F-A
Revised April 2005

Clinical trials were conducted using either controlled-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 controlled-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 controlled-release tablets were conducted outside the U.S.
The table indicates that in the tablet studies few patients discontinued because of adverse effects.

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.
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.

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.

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.

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

See DRUG INTERACTIONS section.

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.

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.

No information provided.

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, but AUC was increased and elimination rate decreased in an older population (60-68 years) compared to younger individuals (22-30 years).

After administration of the 400 mg controlled-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 C_max and AUC by about 28% and 13% for pentoxifylline, respectively. C_max for metabolite 1 also increased by about 20%. The controlled release of pentoxifylline from the tablet eliminates peaks and troughs in plasma levels for improved gastrointestinal tolerance.

See WARNINGS and PRECAUTIONS.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

PENTOXIFYLLINE SUSTAINED-ACTION - ORAL

(pen-tox-IF-ill-een)

COMMON BRAND NAME(S): Trental

USES: This medication is used to improve the symptoms of a certain blood flow problem in the legs/arms (intermittent claudication due to occlusive artery disease). Pentoxifylline can decrease the muscle aching/pain/cramps with exercise, including walking, that occur with intermittent claudication. Pentoxifylline belongs to a class of drugs known as hemorrheologic agents. It works by helping blood flow more easily through narrowed arteries. This increases the amount of oxygen that can be delivered by the blood when the muscles need more (e.g., during exercise).

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used for decreased blood flow to the brain (cerebrovascular insufficiency), to improve blood flow problems in chronic heart failure, and to treat kidney problems from diabetes.

HOW TO USE: Take this medication by mouth with food, usually 3 times daily or as directed by your doctor. Do not crush or chew the tablets. Doing so can destroy the long action of the drug and may increase side effects.

Dosage is based on your medical condition, kidney function, and response to therapy.

Use this medication regularly in order to get the most benefit from it. To help you remember, take it at the same times each day. It is important to continue taking this medication even if you feel well. Do not stop this medication without your doctor's permission. Improvement in symptoms can occur in 2-4 weeks, but it may take up to 8 weeks to get the full benefit.

Inform your doctor if your condition persists or worsens (e.g., muscle cramps/pain/aching do not improve or worsen).

SIDE EFFECTS: Nausea, vomiting, gas, belching, and dizziness may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these rare but very serious side effects occur: unusual sweating, fast/irregular heartbeat, fainting, new/severe tiredness, weakness, bluish fingernails/lips, pale skin, cough, loss of appetite, weight loss, new diarrhea, signs of infection (e.g., fever, chills, persistent sore throat), persistent nausea, stomach/abdominal pain, dark urine, yellowing eyes/skin, easy bruising/bleeding.

Seek immediate medical attention if this rare but very serious side effect occurs: chest pain.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking pentoxifylline, tell your doctor or pharmacist if you are allergic to it; or to caffeine, theophylline, or theobromine; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: recent stroke (cerebral hemorrhage), recent retinal bleeding (hemorrhage).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney problems, chest pain (angina), heart rhythm problems, recent major surgery, stomach ulcer, problems with the retina (e.g., retinopathy due to HIV or diabetes).

This drug may rarely make you dizzy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug, especially dizziness.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

This medication passes into breast milk and may cause undesirable effects in a nursing infant. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medication because very serious interactions may occur: ketorolac.

If you are currently using the medication listed above, tell your doctor or pharmacist before starting pentoxifylline.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: theophylline, warfarin, any medicine for blood pressure (e.g., nifedipine, atenolol, enalapril, hydrochlorothiazide).

If you are taking warfarin, your blood clotting ability may need to be followed more closely.

In rare cases, pentoxifylline has caused small decreases in blood pressure. If you are taking a medicine for high blood pressure, your dose may need to be decreased. Consult your doctor.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting pentoxifylline.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., blood counts, blood pressure) should be performed from time to time to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember unless it is within 2 hours of your next dose. In that case, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store tablets at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.