PENTOXIFYLLINE EXTENDED-RELEASE TABLETS, USP 400MG RX only

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.

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 mg 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 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 pentoxifylline extended-release 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 1 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.  AUC and C_max of the active Metabolite l also increased 6.9- and 8.2-fold, respectively, in hepatic impaired subjects.

Pentoxifylline 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 l 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 three times daily regimen of pentoxifylline.  In severe renal impairment AUC_0-tss and C_max of the active Metabolite V increased 12.9- and 10.6-fold, respectively, with a 400 mg pentoxifylline three times daily regimen.  The increase in exposure to Metabolite V is only slightly smaller in both renal impairment groups if pentoxifylline is administered twice daily.

At the first sign of anaphylactic/anaphylactoid reaction, pentoxifylline must be discontinued.

Patients with chronic occlusive arterial disease of the limbs frequently show other manifestations of arteriosclerotic disease. Pentoxifylline 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 pentoxifylline 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.

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 CLINICAL PHARMACOLOGY:  Pharmacokinetics and Metabolism and DOSAGE AND ADMINISTRATION).

Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with pentoxifylline 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 pentoxifylline 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.

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.

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.

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 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.