PENTOXIFYLLINE

Pentoxifylline Extended-Release Tablets USP for oral administration contain 400 mg of the active drug and the following inactive ingredients: hypromellose, povidone, talc, magnesium stearate, maltodextrin, polyethylene glycol, titanium dioxide, triacetin, D&C yellow #10 aluminum lake and FD&C yellow #6 in an extended-release formulation. Pentoxifylline is a tri-substituted xanthine derivative designated chemically as 3,7-Dihydro-3,7-dimethyl-1-(5-oxohexyl)-1 H ‑purine-2,6-dione 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 chemical structure is: Pentoxifylline Extended-Release Tablets USP comply with USP dissolution test 7. Structure

Pentoxifylline Extended-Release Tablets are indicated for the treatment of patients with intermittent claudication on the basis of chronic occlusive arterial disease of the limbs. Pentoxifylline Extended-Release Tablets 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 pentoxifylline in extended-release tablet form is one tablet (400 mg) three times a day with meals. While the effect of pentoxifylline 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 pentoxifylline should be discontinued. In patients with severe renal impairment (creatinine clearance below 30 mL/min) reduce dose to 400 mg once a day. Dosing information cannot be provided for patients with hepatic impairment.

Pentoxifylline Extended-Release Tablets 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.

Clinical trials were conducted using either extended-release pentoxifylline tablets for up to 60 weeks or immediate-release pentoxifylline capsules for up to 24 weeks. Dosage ranges in the tablet studies were 400 mg bid to tid and in the capsule studies, 200 to 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 pentoxifylline tablets, immediate-release pentoxifylline 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 Pentoxifylline Placebo Pentoxifylline 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 Pentoxifylline 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. To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Bleeding has been reported in patients treated with pentoxifylline with or without concomitant NSAIDs, anticoagulants, or platelet aggregation inhibitors. Increased prothrombin time has 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. Concomitant administration of pentoxifylline and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Monitor theophylline levels when starting pentoxifylline or changing dose. Concomitant administration of strong CYP1A2 inhibitors (including e.g. ciprofloxacin or fluvoxamine) may increase the exposure to pentoxifylline (see ADVERSE REACTIONS ). Pentoxifylline has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; 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. Concomitant administration with cimetidine is reported to increase the average steady state plasma concentration of pentoxifylline (~25%) and the Metabolite I (~30%).