Pentoxifylline Information
Pentoxifylline () Description
Each extended-release tablet, for oral administration, contains 400 mg of Pentoxifylline () and the following inactive ingredients: D&C Red #30 Aluminum Lake, FD&C Blue #2 Aluminum Lake, FD&C Yellow #6 Aluminum Lake, hydroxyethyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, titanium dioxide and triacetin in an extended-release formulation. Pentoxifylline () 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 structural formula is:
Pentoxifylline () Extended-release Tablets, USP meet .
Pentoxifylline () Clinical Pharmacology
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 1 (1-[5-hydroxyhexyl]-3,7-di-methylxanthine) 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 1 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 pharmacokinetics and metabolism of Pentoxifylline () have not been studied in patients with renal and/or hepatic dysfunction, but AUC was increased and elimination rate decreased in an older population (60 to 68 years) compared to younger individuals (22 to 30 years).
After administration of a 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 C and AUC by about 28% and 13% for Pentoxifylline () , respectively. C for Metabolite 1 also increased by about 20%. The controlled release of Pentoxifylline () from the tablet eliminates peaks and troughs in plasma levels for improved gastrointestinal tolerance.
Pentoxifylline () Indications And Usage
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 () 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 () Contraindications
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.
Pentoxifylline () Precautions
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 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.
Pentoxifylline () Adverse Reactions
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.
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:
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: –angina, arrhythmia, tachycardia, anaphylactoid reaction; –hepatitis, jaundice, increased liver enzymes; and –decreased serum fibrinogen, pancytopenia, aplastic anemia, leukemia, purpura, thrombocytopenia.
Pentoxifylline () Overdosage
Overdosage with Pentoxifylline () 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 to 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.
Pentoxifylline () Dosage And Administration
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.
Pentoxifylline () How Supplied:
Pentoxifylline () Extended-release Tablets, USP are available as film coated, lavender, unscored, capsule-shaped tablets, each containing 400 mg of Pentoxifylline () . The tablet is debossed with on one side and on the other side. It is available as follows:
NDC 51079-889-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
NDC 51079-889-19 - Robot Ready blister packages of 25 (25 cards of 1 tablet each).
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Protect from light.
Manufactured by:Mylan Pharmaceuticals Inc.Morgantown, WV 26505
Distributed by:UDL Laboratories, Inc.Rockford, IL 61103
S-6727 R87/10
Pentoxifylline () Prinicpal Display Panel
Pentoxifylline () Extended-Release Tablets, USP
400 mg
10 Tablets
