decreases in blood pressure have been observed in some patients treated with pentoxifylline 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. concomitant administration with cimetidine is reported to increase the average steady state plasma concentration of pentoxifylline (~25%) and the metabolite i (~30%).

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 ).

xtended-release tablets immediate- release capsules commercially available used only for controlled clinical trials pentoxifylline placebo pentoxifylline placebo (number 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.

decreases in blood pressure have been observed in some patients treated with pentoxifylline 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. concomitant administration with cimetidine is reported to increase the average steady state plasma concentration of pentoxifylline (~25%) and the metabolite i (~30%).

tion 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 i (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 i 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 pentoxifylline auc was increased and elimination rate decreased in an older population (60 to 68 years, n=6) compared to younger individuals (22 to 30 years, n=6) (see precautions , geriatric use ). after administration of the 400 mg extended-release pentoxifylline 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 pentoxifylline extended-release tablets with meals resulted in an increase in mean auc and c max of about 1.1 and 1.3 fold for pentoxifylline, respectively. c max for metabolite i also increased about 1.2 fold. the extended release of pentoxifylline from the tablet eliminates peaks and troughs in plasma levels for improved gastrointestinal tolerance. patients with hepatic impairment in patients with mild to moderate liver impairment auc and c max of pentoxifylline increased 6.5 and 7.5 fold, respectively, after a single 400 mg dose of pentoxifylline extended-release tablet auc and c max of the active metabolite i also increased 6.9 and 8.2 fold, respectively, in hepatic impaired subjects. pentoxifylline extended-release tablet has not been studied in patients with severe hepatic failure. patients with renal impairment in patients with mild, moderate, or severe renal impairment the exposure to pentoxifylline and its active metabolite i are not increased. in contrast, auc 0-tss and c max of the active metabolite v in patients with mild to moderate renal impairment increased 2.4 and 2.1 fold, respectively, with a 400 mg tid regimen of pentoxifylline extended-release tablet. in severe renal impairment auc 0 to tss and c max of the active metabolite v increased 12.9 and 10.6 fold, respectively, with a 400 mg pentoxifylline extended-release tablet tid regimen. the increase in exposure to metabolite v is only slightly smaller in both renal impairment groups if pentoxifylline extended-release tablet is administered bid.

ivation. it was also negative in the in vivo mouse micronucleus test.