VA Class:CV900
Pentoxifylline, a synthetic xanthine derivative, is a hemorrheologic agent.1, 2, 3, 4
Pentoxifylline is used for the symptomatic treatment of intermittent claudication associated with peripheral vascular disease (i.e., chronic occlusive arterial disease of the extremities).1, 2, 4, 6, 7, 8, 9, 13, 14, 16, 18, 21, 27, 32, 52, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 120, 121 Although pentoxifylline may provide some improvement in function of the extremities and symptoms of the disease,1, 2, 4, 6, 7, 8, 9, 13, 14, 16, 18, 21, 27, 32, 52, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 103, 120, 121 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,18, 103, 107, 108, 121 or surgical bypass or removal of arterial obstructions when indicated.1
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.4, 103 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.4, 103 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.4 Symptoms of intermittent claudication generally are completely relieved in a few minutes following cessation of exercise.4
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,72 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.7, 8 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.6, 7, 8 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.7, 8 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.7, 8
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.2, 4, 6, 7, 8, 13, 14, 27, 32, 35, 52, 57, 59, 60, 61, 62, 63, 64, 65, 68, 69, 71, 119, 120, 121 However, the efficacy of pentoxifylline compared with other forms of therapy (e.g., exercise) has not been elucidated.103 Results from well-designed, controlled clinical studies indicate that pentoxifylline is more effective than placebo in increasing initial (tolerable) and absolute (intolerable) claudication distances.8, 57, 59, 62, 63, 64, 68, 119, 120, 121 Pentoxifylline also has been reported to produce greater reductions in severity and occurrence of paresthesia6, 7, 8, 57, 59, 62, 63, 64, 68, 121 and trophic ulcers6, 7, 8, 109, 110, 121 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.57, 59, 62, 63, 64, 68
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.6, 7, 14, 121 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.3, 6, 7, 14, 121
Pentoxifylline has been used for the management of acute73, 76, 81, 83, 121 and chronic cerebrovascular insufficiency†73, 74, 75, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 121 in a limited number of patients. Pentoxifylline therapy has improved regional and hemispheric cerebral blood flow, particularly in ischemic areas where microcirculation is impaired,73, 74, 75, 76, 77, 78, 79, 81, 82, 83, 84, 85, 86, 87 and has been associated with measurable increases in oxygen and glucose supply, elimination or reduction of perivascular edema, and enhancement of cellular function77, 82, 87 in some patients with cerebrovascular insufficiency.121 Improvement in cerebral blood flow has been observed following acute73, 75, 85, 86, 87 or chronic73, 74, 75, 76, 77, 78, 79, 81, 82, 83, 84, 87 and oral73, 74, 75, 77, 79, 81, 82, 84, 87 or IV73, 75, 76, 77, 78, 81, 83, 84, 85, 86, 87 administration of the drug. Clinical evaluation of patients receiving pentoxifylline indicates that the drug can improve psychopathologic symptoms of cerebrovascular insufficiency74, 81, 87, 121 (e.g., those associated with aging, stroke, transient ischemic attacks), including memory loss, disorientation, constructional apraxia, impaired practical reasoning, motor impairment, and dizziness.74, 81, 87 In addition, pentoxifylline therapy has reduced the incidence of recurrence of transient ischemic attacks.87, 121 Additional studies to determine the efficacy of pentoxifylline in patients with cerebrovascular insufficiency are currently under way.102, 103
Pentoxifylline has been used prophylactically in at least one patient for the management of sickle cell disease†.93, 94, 102, 121 The drug appeared to prevent sickle cell crises and related pain without reducing hemolysis,93, 94 and there reportedly was a correlation between clinical improvement and improvement in microrrheologic parameters including normalization of erythrocyte flexibility.93 Additional studies to determine the role, if any, of pentoxifylline in the management of this disease are currently under way.102, 103
There is some evidence that pentoxifylline may have beneficial effects in patients with diabetes mellitus†.113, 114, 115, 116, 118, 121 The drug has improved hemorrheology in diabetic patients,113, 114, 115 and has reduced urinary albumin113, 114, 115, 121 and total protein113, 114, 115, 121 excretion and increased creatinine clearance113 in some diabetic patients, including a limited number with nephropathy.113 Subjective improvement in peripheral neuropathy also has been reported in a limited number of diabetic patients receiving the drug.116, 121 In at least one patient, pentoxifylline therapy reportedly improved healing of cutaneous ulcers associated with necrobiosis lipoidica diabeticorum.118
Pentoxifylline has been used IV in combination with dextran 40 and cortisone for the treatment of Bell's palsy† (idiopathic facial paralysis).88, 89, 121 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.88, 89 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.102, 103
Pentoxifylline has been used in a limited number of patients for the treatment of male fertility disorders†, including asthenospermia†90, 92, 121 and idiopathic oligospermia†.91, 92, 121 Pentoxifylline has been reported to increase the duration of activity of ejaculated spermatozoa90, 95 and, in one study, several males with asthenospermia successfully impregnated their wives during therapy with the drug.90 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.91 In this study, clinically important increases in mean sperm concentration and successful pregnancy only occurred in association with clomiphene citrate therapy.91 Further study is needed to adequately determine the role, if any, of pentoxifylline in the treatment of male fertility disorders.91
Pentoxifylline is administered orally, preferably with meals.1
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.1, 2, 4, 8, 13, 18, 59, 60, 61, 63, 64, 65, 68, 69, 71 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.1 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.1 Although longer term therapy may be necessary,102 the manufacturer states that efficacy of the drug to date has been established in well-controlled studies up to 6-months' duration.1
Adverse reactions to pentoxifylline generally involve the GI tract and CNS.1, 2, 4, 59 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.1 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.1 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.1, 4
The most frequent adverse effects of pentoxifylline involve the GI tract.1, 2, 4, 18, 59 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.1 Belching, flatus, and/or bloating occur in less than 1% of patients.1 Abdominal discomfort and diarrhea also have been reported in patients receiving the drug as conventional capsules.1 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.1
Adverse CNS effects of pentoxifylline include dizziness in about 2% of patients receiving extended-release tablets and, less frequently, headache, and tremor.1, 59 Dizziness or headache occurred in about 12% or about 6%, respectively, of patients receiving the drug as conventional capsules during clinical studies.1 A few cases of agitation, nervousness, drowsiness, blurred vision, and insomnia also have been reported in patients receiving the drug as conventional capsules.1 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.1
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.1 Adverse cardiovascular effects have been reported more frequently in patients receiving conventional capsules of the drug.1 Flushing and palpitation have also been reported in patients receiving conventional capsules.1 (See Cautions: Precautions and Contraindications.)
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.1 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.1 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.1, 112
Precautions and Contraindications
Patients with chronic occlusive arterial disease of the extremities frequently exhibit other manifestations of arteriosclerotic disease.1 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.1 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.1
Pentoxifylline is contraindicated in patients who have a history of intolerance to the drug or to xanthine derivatives such as caffeine, theophylline, or theobromine.1
Safety and efficacy of pentoxifylline in children younger than 18 years of age have not been established.1
Mutagenicity and Carcinogenicity
It is not known if pentoxifylline is mutagenic or carcinogenic in humans.102, 103 In vitro tests (Ames test) have not shown pentoxifylline to be mutagenic.1
No evidence of carcinogenesis was seen in mice receiving oral pentoxifylline dosages up to 570 mg/kg daily for 18 months.1 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.1
Pregnancy, Fertility, and Lactation
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.1 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.1
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†.90, 95 Studies to further evaluate the effect of pentoxifylline on fertility are under way.
Pentoxifylline and its metabolites are distributed into milk.1, 102, 104 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.1
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.1 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).1
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.117 Although oral bioavailability of 2 metabolites of the drug may be reduced by concomitant antacid administration, this reduction is not clinically important.117 Therefore, an aluminum and magnesium hydroxides antacid can be administered concomitantly with pentoxifylline (e.g., in an attempt to reduce intolerable GI effects).117
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.1 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.1
The manufacturer states that overdosage of pentoxifylline has been reported in adults and children.1 Data collected by a poison control center on 44 cases of acute pentoxifylline overdosage with enteric-coated tablets (not commercially available in the US) indicated that symptoms usually occurred within 4-5 hours and persisted for about 12 hours following ingestion; symptoms appeared to be dose related.1, 102 However, this time course may not exist following acute overdosage with the commercially available extended-release tablets.102 Acute ingestion of single pentoxifylline doses up to 80 mg/kg has been associated with complete recovery.1 Flushing, hypotension, seizures, somnolence, loss of consciousness, fever, and agitation have been the principal effects reported.1 One patient who intentionally ingested 4-6 g of pentoxifylline experienced severe bradycardia (30-40 beats/minute), first- and second-degree atrioventricular (AV) block, and hypokalemia; first-degree AV block persisted for 18 hours following overdosage.96 In addition, the patient experienced abdominal cramps, nausea, vomiting, and severe excitation.96
Treatment of pentoxifylline overdosage generally involves symptomatic and supportive care;1 there is no specific antidote for pentoxifylline intoxication.102, 103 In acute pentoxifylline overdose, the stomach should be emptied immediately by gastric lavage.1 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric material.101 Administration of activated charcoal after gastric lavage may be useful in preventing absorption of pentoxifylline.1 Although data currently are not available, some clinicians suggest that administration of a carthartic may be useful in facilitating elimination of unabsorbed extended-release tablet fragments.103 Appropriate therapy should be instituted if hypotension or seizures occur.1
The pharmacology of pentoxifylline is complex and its mechanism(s) of action has not been fully elucidated.1, 3, 4, 6, 7, 8 The principal pharmacologic activity of pentoxifylline involves effects on erythrocytes.1, 2, 3, 4, 6, 7, 8 Unlike other currently available xanthine derivatives, pentoxifylline has hemorrheologic effects.1, 3
Pentoxifylline has several effects on erythrocytes.3, 4, 6, 7, 8, 11, 13, 18, 21 The principal hemorrheologic effects of pentoxifylline in patients with peripheral vascular disease appear to be an increase in erythrocyte flexibility (deformability)1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 18, 19, 20, 21 and a secondary reduction in viscosity of whole blood;1, 2, 3, 4, 6, 7, 16, 17, 20, 21 these effects are associated with a decrease in total systemic vascular resistance3, 4 and subsequent improvement in blood flow, particularly in the microcirculation,1, 2, 3, 18 and with increased tissue oxygenation.1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 In patients with peripheral vascular disease, oral or IV administration of pentoxifylline produces improvement of poststenotic blood flow in relatively poorly perfused tissue, while in healthy tissue or areas with mild vascular insufficiency, the drug produces only a transient (persisting for a few minutes) increase in blood flow similar to that produced by other vasoactive substances.6, 7, 26, 27, 30, 31, 32 Evidence from capillary muscle circulation studies in patients with peripheral vascular disease receiving oral pentoxifylline dosages of 1.2-1.6 g daily for 6-8 weeks indicates that the pentoxifylline-induced increase in capillary perfusion is more pronounced in extremities with more severe initial circulatory disturbances than in extremities with normal capillary circulation.27
Pentoxifylline-induced improvements in resting blood flow and reactive hyperemia have been demonstrated objectively using venous occlusion plethysmography.26, 31 In patients with peripheral vascular disease, pentoxifylline increases peak flow of reactive hyperemia in the extremities indicating an increase in reserve blood flow which is associated with some increase in walking distance in these patients.31 Objective evidence of pentoxifylline-induced improvement in peripheral blood flow has also been determined in some patients with this disease via radiolabeled xenon clearance, rheography, Doppler ultrasound, in vivo microscopy, Achilles tendon reflex, ergometry, and oscillography studies.6, 7, 8 IV pentoxifylline has also been shown to increase blood flow to the brain, retina, and liver.6, 7
Although the exact mechanism for the pentoxifylline-induced increase in erythrocyte flexibility has not been conclusively determined, the drug appears to facilitate the ability of erythrocytes to maintain their integrity, apparently by modulating the phosphorylation/dephosphorylation reactions of membrane proteins that are involved in maintaining erythrocyte shape and deformability.24 The drug increases intraerythrocytic phosphoprotein concentrations and decreases intraerythrocytic calcium concentrations via effects on several enzyme systems, but the principal effect for increasing erythrocyte flexibility has not been determined.4 Increases in intraerythrocytic phosphoprotein concentrations [e.g., cyclic 3',5'-adenosine monophosphate (cAMP), adenosine triphosphate (ATP)] apparently result from competitive inhibition by pentoxifylline of cAMP phosphodiesterase3, 4, 6, 7, 22, 23, 24 and calcium-dependent ATPase activity.24, 25 Increased intracellular cAMP enhances the activity of cAMP-dependent protein kinase in erythrocytes, resulting in increased protein phosphorylation.24 Pentoxifylline also increases protein phosphorylation by decreasing intraerythrocytic calcium concentration which results in inhibition of phosphoprotein phosphatase (an enzyme that hydrolyzes phosphoproteins) and in stimulation of protein kinase (an enzyme involved in membrane protein phosphorylation).24 Stabilization and destabilization of the erythrocyte cell membrane, which is manifested by altered hemolysis, is associated with a selective, biphasic, concentration-dependent pattern of phosphorylation of membrane proteins in erythrocytes.24 At low concentrations (140-695 mcg/mL) in vitro, pentoxifylline enhances phosphorylation of membrane proteins in intact erythrocytes and is associated with a decrease in hemolysis, while at high concentrations (1390 mcg/mL), the drug inhibits phosphorylation of membrane proteins.24 Limited data indicate that low concentrations of pentoxifylline that reduce intracellular calcium concentration inhibit erythrocytic calcium-dependent transglutaminase, an enzyme involved in membrane protein cross-linking, while higher concentrations of the drug increase the enzyme's activity.24
In addition to effects on erythrocytic phosphoproteins, pentoxifylline has effects on the electrolyte balance of erythrocytes which may improve erythrocyte flexibility and blood flow.6, 7, 29 Following oral administration of pentoxifylline (600 mg daily) for 4 weeks in patients with ischemic heart disease, the drug has produced a stabilizing effect on erythrocyte membranes as evidenced by an increased intraerythrocytic potassium/sodium ratio.6, 7 This erythrocyte membrane stabilizing effect was also associated with a reduction in age-induced potassium efflux from erythrocytes following incubation with pentoxifylline.29
Following administration of pentoxifylline in animals, the drug-induced increase in erythrocyte phosphoproteins is apparent almost immediately;22 however, in animals and in humans with peripheral vascular disease, there is an apparent latent period of about 2-4 weeks before therapeutic hemorrheologic effects can be demonstrated.1, 3 These findings suggest that the drug's therapeutic hemorrheologic effects result principally from an action on newly formed erythrocytes rather than on circulating mature erythrocytes.3 Additional study is needed to determine whether the pentoxifylline-induced increase in erythrocyte flexibility is a homogeneous effect on all erythrocytes during their life cycle or an effect on one specific age group of erythrocytes.28
Pentoxifylline also enhances blood flow in patients with peripheral vascular disease through correction of pathologically altered platelet reactivity.3, 4, 6, 7, 16, 18, 32, 33, 34, 35, 36 Platelets in patients with this disease exhibit increased reactivity characterized by a greater aggregation tendency and increased release of platelet factor 3.6, 7 Following oral or IV administration, pentoxifylline exhibits inhibitory effects on platelet aggregation and disseminated intravascular coagulation6, 7, 16, 34, 35, 38 which are associated with a concomitant reduction in blood viscosity.7 The drug has been shown to produce a dose-dependent inhibition of ADP- and serotonin-induced platelet aggregation in monkeys.34 In addition to decreasing spontaneous and induced platelet aggregation and fragmentation, pentoxifylline reduces pseudopodia formation and release of platelet factor 3.7, 37
Pentoxifylline stimulates the synthesis and release of prostacyclin (epoprostenol, PGI2) from human vascular tissue in vitro,39, 40 which subsequently results in increased platelet cAMP concentrations via activation of platelet adenyl cyclase.41 Pentoxifylline also inhibits cAMP phosphodiesterase in platelet membranes, thereby resulting in a further increase in intracellular cAMP concentration.7, 36, 42 Since prostacyclin inhibits platelet aggregation and causes vasodilation, it appears to oppose the effects of thromboxane A2 (and prostaglandin endoperoxides) on hemostasis;7, 41 however, pentoxifylline-induced formation of prostacyclin does not appear to inhibit platelet deposition on the blood vessel wall and, therefore, does not affect primary hemostasis or prolong bleeding time.40 Increased platelet cAMP concentrations inhibit cyclooxygenase in circulating platelets and thus reduce the synthesis of thromboxane A2;41 however, pentoxifylline has little, if any, effect on platelet aggregation in vitro and no effect on arachidonic acid-induced synthesis or release of thromboxane A2.40 Therefore, it has been suggested that the effects of pentoxifylline on platelets in vivo may be mediated principally via stimulation of prostacyclin release from vascular tissue.40 However, the clinical importance of these effects on platelets has not been elucidated.40
Effects on Fibrinogen and Fibrinolysis
Pentoxifylline reduces plasma fibrinogen concentration and increases fibrinolytic activity,3, 4, 6, 7, 18, 43, 44, 45, 46 subsequently resulting in a greater anticoagulant potential and decreased erythrocyte aggregation and plasma viscosity;3, 7 these effects contribute to an overall reduction in viscosity of whole blood.16, 17, 44 Following administration of pentoxifylline in patients with peripheral vascular disease, increased fibrinolytic activity appears to result from increased plasma concentrations of plasminogen activator and decreased antiplasmin activity.37, 46 Pentoxifylline-induced reduction in plasma fibrinogen concentration is reversible and has not been reported to cause appreciable bleeding in patients receiving therapeutic doses of the drug.3
Cardiovascular effects of pentoxifylline differ following oral and IV administration.3 Improvement in blood flow induced by orally administered drug in patients with peripheral vascular disease does not appear to be mediated via a direct cardiovascular mechanism (e.g., vasodilation), but rather via complex hemorrheologic effects.1, 3, 4, 6, 7, 8 (See Pharmacology: Hemorrheologic Effects.)
Hemodynamic studies in animals indicate that IV pentoxifylline has positive chronotropic and inotropic effects similar to, but less potent than, those of theophylline.3, 47, 48, 49, 50, 51 The cardiac effects of IV pentoxifylline, like those of theophylline, are mediated via purinergic receptors, increased intracellular concentrations of cAMP, and intracellular translocation of ionized calcium.3, 105 IV pentoxifylline causes a transient increase in cardiac output and a decrease in total systemic vascular resistance; however, unlike IV theophylline, which causes a more marked increase in cardiac output and a direct general vasodilation, pentoxifylline causes a slight initial increase in cardiac output and reflex systemic vasodilation.3
Following oral administration of pentoxifylline in patients with peripheral vascular disease, the drug generally has no effect on heart rate, cardiac function, or systemic arterial blood pressure;3, 47, 48, 52 however, a decrease in blood pressure may occur in some hypertensive patients during long-term oral therapy with the drug.1, 4, 6
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.1, 3, 4, 54
Pentoxifylline is rapidly and almost completely absorbed from the GI tract following oral administration,1, 2, 3, 4, 53, 54, 55 but the drug undergoes extensive first-pass metabolism in the liver.1, 53, 55, 100, 122 (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.100, 122 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.1, 54 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.54 Although a correlation between dosage and plasma pentoxifylline concentrations reportedly exists,3 the areas under the plasma concentration-time curves (AUCs) for pentoxifylline and the 5-hydroxyhexyl metabolite increase nonlinearly with dose.1
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.1 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.54 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.54 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.53 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.53 Plasma concentrations of the 5-hydroxyhexyl metabolite generally exceed those of pentoxifylline after 1 hour, suggesting rapid metabolism of the parent drug.3, 53, 122 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.100 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.100
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.122 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.122
The therapeutic range for plasma pentoxifylline concentrations and the relationship of plasma concentrations to clinical response and toxicity have not been established.102, 103
Distribution of pentoxifylline and its metabolites into body tissues and fluids has not been fully characterized.102, 103 Limited evidence suggests that the volume of distribution of pentoxifylline is not altered substantially in patients with hepatic cirrhosis.122
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.4, 102 Plasma concentrations of pentoxifylline and the 5-hydroxyhexyl metabolite are in equilibrium with the amounts bound to the erythrocyte membrane.4 (See Pharmacokinetics: Elimination.)
It is not known if pentoxifylline or its metabolites cross the placenta.102, 103 The drug and its metabolites are distributed into milk.102, 104
Plasma concentrations of pentoxifylline appear to decline in a biphasic manner.5, 100 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.100 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.1, 53, 55 The elimination half-life of pentoxifylline is nonlinearly related to dose, increasing with increasing doses of the drug.1 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.1
Elimination of pentoxifylline appears to be prolonged substantially in adults with hepatic disease (cirrhosis).122 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.122
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.3, 4, 53, 55 The major metabolites found in blood are the 5-hydroxyhexyl and the 3-carboxypropyl derivatives;1, 53, 55, 100 plasma concentrations of these metabolites are 5 and 8 times greater, respectively, than those of pentoxifylline.1 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.3, 4, 53 In vitro studies in whole blood indicate that erythrocytes are principally responsible for formation of the 5-hydroxyhexyl metabolite found in blood.3 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.3 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.4 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;3, 4, 53 the pharmacologic potency of the 5-hydroxyhexyl metabolite is equivalent to that of pentoxifylline.3 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.1 Pentoxifylline does not appear to induce its own metabolism following oral administration of multiple doses of the drug.1, 102
Pentoxifylline and its metabolites are excreted in urine and feces.1, 3, 4, 53, 55 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.3, 4, 53, 55 About 50-80% of an oral dose is excreted in urine as the 3-carboxypropyl metabolite and about 20% as other metabolites;3, 4, 53 only trace amounts of a dose are excreted unchanged.1, 3, 4, 53 Less than 4% of an oral dose of the drug is excreted in feces.1, 3, 4, 53, 55
Pentoxifylline, a synthetic xanthine derivative, is a hemorrheologic agent.1, 2, 3, 4 The drug is a trisubstituted xanthine derivative which is structurally related to other xanthine derivatives (e.g., caffeine, theobromine, theophylline).3, 4 Pentoxifylline is a dimethylxanthine derivative which differs structurally from caffeine or theobromine by the presence of a 5-oxohexyl group rather than a methyl group or hydrogen atom, respectively, at position 1.3
Pentoxifylline occurs as a white, odorless, crystalline powder4, 5 with a bitter taste.5, 97 The drug has solubilities of approximately 77 mg/mL in water at 25°C4, 97, 98 and 63 mg/mL in alcohol at 22°C.4, 102 The drug has a pKa of 0.28.102
Commercially available pentoxifylline extended-release tablets should be stored in well-closed, light-resistant containers at 15-30°C.1
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, extended-release, film-coated | 400 mg* | ||
Pentoxil® (scored) | ||||
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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