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pentoxifylline er 400 mg tab

In stock Manufacturer OCEANSIDE PHARM 68682010150
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Uses

Peripheral Vascular Disease

Pentoxifylline is used for the symptomatic treatment of intermittent claudication associated with peripheral vascular disease (i.e., chronic occlusive arterial disease of the extremities). Although pentoxifylline may provide some improvement in function of the extremities and symptoms of the disease, management of intermittent claudication with the drug should not replace more definitive therapy for peripheral vascular disease such as smoking cessation, weight loss, exercise therapy, or surgical bypass or removal of arterial obstructions when indicated.

Intermittent claudication is a symptom complex that is associated with an inadequate arterial blood supply to contracting muscles and that occurs principally in patients with peripheral vascular disease in whom the supply of arterial blood is diminished during exercise. Symptoms of intermittent claudication include aching, cramping, tiredness, or tightness in the affected extremity(ies) and are exercise induced; symptoms never occur at rest or with weight bearing alone and are induced more quickly by an increased rate of exercise. A constant amount of exercise will usually gradually induce increased discomfort; however, a sudden progression of discomfort indicates acute occlusion of the main or collateral vessels. Symptoms of intermittent claudication generally are completely relieved in a few minutes following cessation of exercise.

Evidence from hemorrheologic studies indicates that blood flow is impaired in patients with various hematologic (e.g., polycythemia, multiple myeloma, sickle cell disease) and cardiovascular (e.g., acute myocardial infarction, hypertension, Raynaud's syndrome) diseases, and that, in addition to vascular components, blood flow also depends on blood viscosity and the coagulation system, including platelet function and coagulation factors in the blood. Hemorrheologic abnormalities, including increased erythrocyte and platelet aggregation and impaired erythrocyte flexibility, are generally present in patients with peripheral vascular disease and are associated with a secondary hyperviscosity syndrome, which correlates directly with the severity of vascular disease and tissue ischemia. Tissue hypoxia increases blood vessel wall permeability and intensifies the local influx of vasoactive substances and coagulation factors into the blood, which subsequently leads to increased local hemoconcentration and erythrocyte rigidity as a result of release of catabolites produced by anoxic parenchymal metabolism. These intravascular changes enhance intravascular coagulation and result in further impairment of blood flow in the already decompensated microcirculation in patients with peripheral vascular disease.

In patients with intermittent claudication, pentoxifylline therapy has been shown to provide some improvement in walking distance and duration as measured by standardized treadmill or walking distance testing. However, the efficacy of pentoxifylline compared with other forms of therapy (e.g., exercise) has not been elucidated. Results from well-designed, controlled clinical studies indicate that pentoxifylline is more effective than placebo in increasing initial (tolerable) and absolute (intolerable) claudication distances. Pentoxifylline also has been reported to produce greater reductions in severity and occurrence of paresthesia and trophic ulcers than does placebo; however, the drug does not appear to be more effective than placebo in relieving other symptoms associated with claudication such as cramping, tiredness, tightness, and pain during exercise.

Clinical evaluations of pentoxifylline in the management of intermittent claudication and in vitro studies have shown that pentoxifylline therapy increases erythrocyte flexibility, muscle oxygen pressure (PO2), and blood flow and decreases whole blood viscosity in patients with peripheral vascular disease. The results of these findings suggest that the efficacy of pentoxifylline in the management of intermittent claudication results from the drug's effects on improving blood flow via changes in erythrocyte flexibility and subsequent increase in tissue oxygenation.

Cerebrovascular Disease

Pentoxifylline has been used for the management of acute and chronic cerebrovascular insufficiency in a limited number of patients. Pentoxifylline therapy has improved regional and hemispheric cerebral blood flow, particularly in ischemic areas where microcirculation is impaired, and has been associated with measurable increases in oxygen and glucose supply, elimination or reduction of perivascular edema, and enhancement of cellular function in some patients with cerebrovascular insufficiency. Improvement in cerebral blood flow has been observed following acute or chronic and oral or IV administration of the drug. Clinical evaluation of patients receiving pentoxifylline indicates that the drug can improve psychopathologic symptoms of cerebrovascular insufficiency (e.g., those associated with aging, stroke, transient ischemic attacks), including memory loss, disorientation, constructional apraxia, impaired practical reasoning, motor impairment, and dizziness. In addition, pentoxifylline therapy has reduced the incidence of recurrence of transient ischemic attacks. Additional studies to determine the efficacy of pentoxifylline in patients with cerebrovascular insufficiency are currently under way.

Other Uses

Pentoxifylline has been used prophylactically in at least one patient for the management of sickle cell disease. The drug appeared to prevent sickle cell crises and related pain without reducing hemolysis, and there reportedly was a correlation between clinical improvement and improvement in microrrheologic parameters including normalization of erythrocyte flexibility. Additional studies to determine the role, if any, of pentoxifylline in the management of this disease are currently under way.

There is some evidence that pentoxifylline may have beneficial effects in patients with diabetes mellitus. The drug has improved hemorrheology in diabetic patients, and has reduced urinary albumin and total proteinexcretion and increased creatinine clearance in some diabetic patients, including a limited number with nephropathy. Subjective improvement in peripheral neuropathy also has been reported in a limited number of diabetic patients receiving the drug. In at least one patient, pentoxifylline therapy reportedly improved healing of cutaneous ulcers associated with necrobiosis lipoidica diabeticorum.

Pentoxifylline has been used IV in combination with dextran 40 and cortisone for the treatment of Bell's palsy (idiopathic facial paralysis). In a limited number of patients, this combination regimen has reportedly been more effective than cortisone alone or surgical facial nerve decompression as evidenced by an increased percentage of patients achieving complete recovery according to clinical and neurophysiologic (e.g., electromyographic) evaluation. Additional study to determine the efficacy, if any, of pentoxifylline alone or in combination with other drugs in the treatment of Bell's palsy is necessary.

Pentoxifylline has been used in a limited number of patients for the treatment of male fertility disorders, including asthenospermia and idiopathic oligospermia. Pentoxifylline has been reported to increase the duration of activity of ejaculated spermatozoa and, in one study, several males with asthenospermia successfully impregnated their wives during therapy with the drug. However, in another study comparing the effectiveness of pentoxifylline with that of placebo, clomiphene citrate, mesterolone, or testosterone rebound therapy for the treatment of idiopathic oligospermia, pentoxifylline therapy did not result in a clinically important increase in mean sperm count nor in successful pregnancy in the sexual partners. In this study, clinically important increases in mean sperm concentration and successful pregnancy only occurred in association with clomiphene citrate therapy. Further study is needed to adequately determine the role, if any, of pentoxifylline in the treatment of male fertility disorders.

Dosage and Administration

Administration

Pentoxifylline is administered orally, preferably with meals.

Dosage

For the management of intermittent claudication associated with peripheral vascular disease (i.e., chronic occlusive arterial disease), the usual adult dosage of pentoxifylline as extended-release tablets is 400 mg 3 times daily. If adverse GI and/or CNS effects develop, dosage should be reduced to 400 mg twice daily; if adverse effects persist at this lower dosage, the manufacturer recommends that the drug be discontinued. Although symptomatic relief may occur in some patients within 2-4 weeks following initiation of pentoxifylline therapy, the manufacturer recommends that treatment with the drug be continued for at least 8 weeks to determine efficacy. Although longer term therapy may be necessary, the manufacturer states that efficacy of the drug to date has been established in well-controlled studies up to 6-months' duration.

Cautions

Adverse reactions to pentoxifylline generally involve the GI tract and CNS. Evidence from initial clinical studies in patients with peripheral vascular disease receiving pentoxifylline dosages of 600 mg to 1.2 g daily as conventional capsules (not commercially available in the US) for up to 24 weeks suggests that the incidence of pentoxifylline-induced adverse GI and CNS effects is related to dosage. During controlled clinical studies, the overall incidence of adverse effects was higher in patients receiving pentoxifylline as conventional capsules than in those receiving the drug as the commercially available extended-release tablets. If patients develop adverse GI or CNS effects during pentoxifylline therapy, dosage of the drug should be reduced; if the adverse effect persists following a reduction in dosage, the manufacturer recommends that the drug be discontinued. (See Dosage and Administration: Dosage.) Adverse reactions requiring discontinuance of the drug occur in less than 5% of patients.

GI Effects

The most frequent adverse effects of pentoxifylline involve the GI tract. Dyspepsia, nausea, and vomiting occur in about 1-3% of patients receiving the drug as extended-release tablets; during clinical studies, nausea occurred in almost 30% of patients receiving the drug as conventional capsules. Belching, flatus, and/or bloating occur in less than 1% of patients. Abdominal discomfort and diarrhea also have been reported in patients receiving the drug as conventional capsules. Anorexia, cholecystitis, constipation, dry mouth, and thirst have been reported rarely in patients receiving pentoxifylline, but these adverse effects have not been directly attributed to the drug.

CNS Effects

Adverse CNS effects of pentoxifylline include dizziness in about 2% of patients receiving extended-release tablets and, less frequently, headache, and tremor. Dizziness or headache occurred in about 12% or about 6%, respectively, of patients receiving the drug as conventional capsules during clinical studies. A few cases of agitation, nervousness, drowsiness, blurred vision, and insomnia also have been reported in patients receiving the drug as conventional capsules. Other adverse CNS effects that have been reported in less than 1% of patients receiving pentoxifylline and for which a causal relationship has not been definitely established include anxiety, confusion, depression, and seizures.

Cardiovascular Effects

Adverse cardiovascular effects of pentoxifylline occur in less than 1% of patients receiving the drug as extended-release tablets and include angina and chest pain; although a causal relationship has not been established, arrhythmia, tachycardia, palpitation, flushing, dyspnea, edema, and hypotension also have occurred. Adverse cardiovascular effects have been reported more frequently in patients receiving conventional capsules of the drug. Flushing and palpitation have also been reported in patients receiving conventional capsules.(See Cautions: Precautions and Contraindications.)

Other Adverse Effects

Epistaxis, flu-like symptoms, laryngitis, nasal congestion, conjunctivitis, blurred vision, scotoma, earache, bad taste, excessive salivation, sore throat, swollen neck glands, malaise, weight change, brittle fingernails, pruritus, rash, urticaria, anaphylactoid reaction, and angioedema have reportedly occurred in patients receiving pentoxifylline; however, a definite causal relationship has not been established. Hepatitis, increased hepatic enzymes, jaundice, decreased serum fibrinogen concentration, leukopenia, pancytopenia, leukemia, purpura, and thrombocytopenia also have occurred in some patients receiving the drug, but these adverse effects have not been directly attributed to the drug. Fatal aplastic anemia has been reported in at least 2 patients receiving pentoxifylline, although a causal relationship to the drug has not been clearly established.

Precautions and Contraindications

Patients with chronic occlusive arterial disease of the extremities frequently exhibit other manifestations of arteriosclerotic disease. Although pentoxifylline has been used safely for the management of peripheral vascular disease in patients with concomitant coronary artery and/or cerebrovascular disease, there have been occasional reports of angina, hypotension, and arrhythmia in these patients. Evidence from controlled clinical studies indicates that pentoxifylline does not cause these adverse effects more frequently than placebo; however, since pentoxifylline is a xanthine derivative, the possibility that such effects may occur should be considered.

Pentoxifylline is contraindicated in patients who have a history of intolerance to the drug or to xanthine derivatives such as caffeine, theophylline, or theobromine.

Pediatric Precautions

Safety and efficacy of pentoxifylline in children younger than 18 years of age have not been established.

Mutagenicity and Carcinogenicity

It is not known if pentoxifylline is mutagenic or carcinogenic in humans. In vitro tests (Ames test) have not shown pentoxifylline to be mutagenic.

No evidence of carcinogenesis was seen in mice receiving oral pentoxifylline dosages up to 570 mg/kg daily for 18 months. An increased number of benign mammary fibroadenomas was observed in female rats receiving pentoxifylline dosages up to 570 mg/kg daily for 18 months; however, the clinical importance of this finding has been questioned since benign mammary fibroadenomas commonly occur spontaneously in aged rats.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using oral pentoxifylline dosages up to about 25 and 10 times the maximum human dosage, respectively, have not revealed evidence of fetal malformation; however, an increased incidence of fetal resorption was observed in pregnant rats receiving oral pentoxifylline dosages 25 times the maximum human dosage. There are no adequate and controlled studies to date using pentoxifylline in pregnant women, and the drug should be used during pregnancy only when clearly needed.

Fertility

Although the effect of pentoxifylline on fertility in humans has not been conclusively determined, the drug has been shown to increase the duration of activity of spermatozoa in the ejaculate of males receiving the drug for treatment of infertility. Studies to further evaluate the effect of pentoxifylline on fertility are under way.

Lactation

Pentoxifylline and its metabolites are distributed into milk. Because of the tumorigenic potential exhibited by pentoxifylline in rats, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Anticoagulants and Platelet-aggregation Inhibitors

Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin times in patients receiving pentoxifylline alone or concomitantly with anticoagulants or drugs that inhibit platelet aggregation. Patients receiving concomitant therapy with pentoxifylline and an oral anticoagulant (e.g., warfarin) should have more frequent prothrombin time determinations. Periodic examination for signs of bleeding, including hemoglobin and hematocrit determinations, should be performed in patients receiving pentoxifylline who have risk factors potentially complicated by hemorrhage (e.g., recent surgery, peptic ulceration, cerebral and/or retinal bleeding).

Antacids

Concomitant oral administration of an aluminum and magnesium hydroxides antacid and pentoxifylline does not appear to substantially affect the rate or extent of pentoxifylline absorption. Although oral bioavailability of 2 metabolites of the drug may be reduced by concomitant antacid administration, this reduction is not clinically important. Therefore, an aluminum and magnesium hydroxides antacid can be administered concomitantly with pentoxifylline (e.g., in an attempt to reduce intolerable GI effects).

Other Drugs

Clinically important interactions have not occurred in patients receiving pentoxifylline concurrently with β-adrenergic blocking agents, cardiac glycosides, diuretics, antidiabetic agents, and/or antiarrhythmic agents. Although clinically important interactions have not been reported to date, periodic monitoring of systemic blood pressure is recommended in patients receiving pentoxifylline and antihypertensive therapy concomitantly, and, if indicated, dosage of the hypotensive agent(s) should be reduced since small decreases in blood pressure have occurred in some patients receiving pentoxifylline alone.

Pharmacokinetics

Although pentoxifylline is commercially available as extended-release tablets, most pharmacokinetic data have been derived from studies using other dosage forms (e.g., aqueous solutions, conventional capsules) of the drug.

Absorption

Pentoxifylline is rapidly and almost completely absorbed from the GI tract following oral administration, but the drug undergoes extensive first-pass metabolism in the liver.(See Pharmacokinetics: Elimination.) Limited data indicate that about 10-30 and 10-50% of a dose of pentoxifylline reaches systemic circulation unchanged following oral administration of extended-release tablets and conventional capsules of the drug, respectively. Initial pharmacokinetic studies using other oral dosage forms (e.g., conventional capsules) suggested that the rate but not the extent of absorption of the drug was affected by the presence of food. In these studies, when pentoxifylline was taken shortly after ingestion of food, there was a decrease in peak plasma concentration of the drug and a lengthening of the time to reach the peak, but the extent of absorption was not altered. Although a correlation between dosage and plasma pentoxifylline concentrations reportedly exists, the areas under the plasma concentration-time curves (AUCs) for pentoxifylline and the 5-hydroxyhexyl metabolite increase nonlinearly with dose.

Following oral administration of pentoxifylline as an aqueous solution, peak plasma concentrations of the drug and its metabolites occur within 1 hour and exhibit wide interpatient variation. Following oral administration of a single 400-mg dose of the drug as two 200-mg conventional capsules in healthy adults in one study, mean peak plasma pentoxifylline concentrations of 1289 and 433 ng/mL occurred at an average of 0.8 and 2.6 hours after ingestion in the fasted and nonfasted state, respectively. In the same study, peak plasma 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (the principal metabolite in blood) concentrations of 1841 and 980 ng/mL occurred at an average of 1.3 and 2.9 hours after ingestion in the fasted and nonfasted state, respectively. In one study, following oral administration of a single 400-mg dose of the drug as an extended-release tablet, peak plasma pentoxifylline concentrations of approximately 100 ng/mL occurred within 2-4 hours and reached a plateau of about 60 ng/mL at 4-8 hours. Peak plasma concentrations of the 5-hydroxyhexyl metabolite in this study averaged approximately 300 ng/mL within 2-4 hours and reached a plateau of about 200 ng/mL at 4-8 hours. Plasma concentrations of the 5-hydroxyhexyl metabolite generally exceed those of pentoxifylline after 1 hour, suggesting rapid metabolism of the parent drug. Following oral administration of a single 400-mg dose in healthy, fasted adults in another study, mean peak plasma pentoxifylline concentrations of about 1100 or 300 ng/mL occurred at an average of about 1 or 3.3 hours after ingestion of two 200-mg conventional capsules or one extended-release tablet of the drug, respectively. In this study, mean peak plasma concentrations of the 5-hydroxyhexyl metabolite of about 1940 or 340 ng/mL occurred at an average of about 1.8 or 3.2 hours after ingestion of conventional capsules or extended-release tablets, respectively.

Peak plasma concentrations of pentoxifylline and its 5-hydroxyhexyl metabolite were substantially higher in adults with hepatic cirrhosis than in healthy men, averaging approximately 413 and 1177 ng/mL, respectively, in adults with cirrhosis and 55 and 143 ng/mL, respectively, in healthy men following administration of a single 400-mg oral dose as an extended-release tablet. In addition, mean time to peak concentration of pentoxifylline was substantially prolonged (6.6 versus 2 hours, respectively) and mean absolute bioavailability substantially increased (71 versus 33%, respectively) in patients with cirrhosis compared with healthy men.

The therapeutic range for plasma pentoxifylline concentrations and the relationship of plasma concentrations to clinical response and toxicity have not been established.

Distribution

Distribution of pentoxifylline and its metabolites into body tissues and fluids has not been fully characterized. Limited evidence suggests that the volume of distribution of pentoxifylline is not altered substantially in patients with hepatic cirrhosis.

Evidence from in vitro studies indicate that pentoxifylline is 45% bound to the erythrocyte membrane where it is rapidly metabolized to the 5-hydroxyhexyl metabolite which is about 40% bound to the membrane. Plasma concentrations of pentoxifylline and the 5-hydroxyhexyl metabolite are in equilibrium with the amounts bound to the erythrocyte membrane.(See Pharmacokinetics: Elimination.)

It is not known if pentoxifylline or its metabolites cross the placenta. The drug and its metabolites are distributed into milk.

Elimination

Plasma concentrations of pentoxifylline appear to decline in a biphasic manner. Following IV infusion of a single 200-mg dose of the drug, the half-life of pentoxifylline in the initial distribution phase (t½α) is about 0.3 hours and the half-life in the terminal elimination phase (t½β) is about 1.6 hours. Following oral administration of extended-release tablets of the drug in adults with normal renal and hepatic function, the apparent plasma half-life of pentoxifylline has been reported to be 0.4-0.8 hours. The elimination half-life of pentoxifylline is nonlinearly related to dose, increasing with increasing doses of the drug. The manufacturer states that pentoxifylline does not accumulate in plasma following administration of multiple oral doses of the drug in patients with normal renal function.

Elimination of pentoxifylline appears to be prolonged substantially in adults with hepatic disease (cirrhosis). Following IV infusion of a single 100-mg dose of pentoxifylline, elimination half-life of pentoxifylline averaged 0.8 or 2.1 hours in healthy men or patients with hepatic cirrhosis, respectively; plasma clearance was substantially reduced in patients with cirrhosis.

Although the exact metabolic fate of pentoxifylline is not clearly established, it appears that the drug is extensively metabolized in erythrocytes and the liver, principally via reduction, oxidation, and demethylation. The major metabolites found in blood are the 5-hydroxyhexyl and the 3-carboxypropyl derivatives; plasma concentrations of these metabolites are 5 and 8 times greater, respectively, than those of pentoxifylline. Following absorption, pentoxifylline appears to be rapidly metabolized by erythrocytes to the 5-hydroxyhexyl metabolite via reduction of the oxohexyl substituent at position 1 of the xanthine nucleus. In vitro studies in whole blood indicate that erythrocytes are principally responsible for formation of the 5-hydroxyhexyl metabolite found in blood. Four other metabolites, including the 3-carboxypropyl derivative, are formed in the liver via reduction and oxidation of the oxohexyl substituent at position 1 of the xanthine nucleus. Pentoxifylline and the 5-hydroxyhexyl derivative are further metabolized in the liver via oxidation of the oxohexyl substituent at the 1 position and demethylation at the 7 position of the xanthine moiety to form 2 additional metabolites. The two major metabolites (i.e., the 5-hydroxyhexyl and 3-carboxypropyl derivatives) are pharmacologically active and contribute to the hemorrheologic effects observed following administration of the drug; the pharmacologic potency of the 5-hydroxyhexyl metabolite is equivalent to that of pentoxifylline. The elimination half-life of the 5-hydroxyhexyl metabolite is nonlinearly related to dose, increasing with increasing doses of the drug; however, the 3-carboxypropyl metabolite (the major metabolite excreted in urine) does not exhibit a dose-dependent elimination profile. Pentoxifylline does not appear to induce its own metabolism following oral administration of multiple doses of the drug.

Pentoxifylline and its metabolites are excreted in urine and feces. In adults with normal renal and hepatic function, approximately 95% of an oral dose of the drug is excreted in urine within 24 hours, principally as metabolites. About 50-80% of an oral dose is excreted in urine as the 3-carboxypropyl metabolite and about 20% as other metabolites; only trace amounts of a dose are excreted unchanged. Less than 4% of an oral dose of the drug is excreted in feces.

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