Pentoxifylline

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.

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.

GENERAL PRECAUTIONS At the first sign of anaphylactic/anaphylactoid reaction, pentoxifylline extended-release tablets must be discontinued. Patients with chronic occlusive arterial disease of the limbs frequently show other manifestations of arteriosclerotic disease. Pentoxifylline extended-release tablets have 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 pentoxifylline extended-release tablets cause 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. In patients with hepatic or renal impairment, the exposure to pentoxifylline and/or active metabolites is increased. The consequences of the increase in drug exposure are not known (see Pharmacokinetics and Metabolism and DOSAGE AND ADMINISTRATION). DRUG INTERACTIONS Bleeding has been reported in patients treated with pentoxifylline extended-release tablets 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 extended-release tablets and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Monitor theophylline levels when starting pentoxifylline extended-release tablets 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 extended-release tablets have 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 extended-release tablets; 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%). CARCINOGENESIS & MUTAGENESIS & 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: Teratogenicity studies have been performed in rats and rabbits using oral doses up to 576 mg/kg 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. Pentoxifylline extended-release tablets 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 pentoxifylline extended-release tablets 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 V 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.

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 mg 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 Pentoxifylline extended-release tablets have 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 Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. pentoxifyllinetable.jpg

Bleeding has been reported in patients treated with pentoxifylline extended-release tablets 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 extended-release tablets and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Monitor theophylline levels when starting pentoxifylline extended-release tablets 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 extended-release tablets have 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 extended-release tablets; 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%).

Teratogenicity studies have been performed in rats and rabbits using oral doses up to 576 mg/kg 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. Pentoxifylline extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of pentoxifylline extended-release tablets 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 V 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.