TRENtal

Pentoxifylline may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• upset stomach
• vomiting
• gas
• dizziness
• headache

If you experience either of the following symptoms, call your doctor immediately:

• chest pain
• fast heartbeat

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

The recommended dose of pentoxifylline is 400 mg three times daily with meals. The dose may be reduced to 400 mg twice daily to reduce adverse effects.

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.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

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

While using pentoxifylline, you may need frequent blood tests.

Do not crush, chew, or break an extended-release tablet. Swallow it whole.

It may take up to 4 weeks before your symptoms improve. Keep using the medicine 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.

Stop taking pentoxifylline 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:

• chest pain;

• pounding heartbeats or fluttering in your chest;

• red or pink urine;

• a light-headed feeling, like you might pass out; or

• signs of stomach bleeding--bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds.

Common side effects may include:

• dizziness, headache;

• nausea, vomiting;

• diarrhea, gas; or

• bloating, upset stomach.

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.

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.

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:

• Chest pain
• irregular heartbeat

• 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:

• 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.

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:

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.

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.