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.

This is indicated in-

• Peripheral arterial occlusive disease (PAOD) of arteriosclerotic or diabetic origin (e.g. with intermittent claudication and rest pain)
• Trophic lesions (e.g. leg ulcers and gangrene)
• Cerebral vascular diseases 
• Circulatory disturbances of the eye in conjunction with degenerative vascular disorders.

In principle, dosage is based on the type and severity of the circulatory disorders and on how the individual patient tolerates the drug. Usual dosage is 400 mg pentoxifylline 2 to 3 times daily. Tablets are to be swallowed whole during or shortly after a meal with sufficient amounts of liquid (approx. ½ glass).

Interaction

• Precautions for use: The blood-sugar-lowering effect of insulin or oral antidiabetics may be potentiated. Therefore it is recommended that patients under medication for diabetes mellitus be carefully monitored. Post-marketing cases of increased anti-coagulant activity have been reported in patients concomitantly treated with pentoxifylline and anti-vitamin K. Monitoring of anti-coagulant activity in these patients is recommended when pentoxifylline is introduced or the dose is changed.
• Take into account: The blood-pressure-lowering efect of antihypertensive agents and other drugs with blood-pressure-lowering potential may be increased by Pentoxifylline.
• Concomitant administration of pentoxifylline and theophylline may increase theophylline levels in some patients. Therefore, there may be an increase in and intensifcation of adverse reactions from theophylline.
• Concomitant administration with ciprofoxacin may increase the serum concentration of pentoxifylline in some patients. Therefore, there may be an increase in and intensifcation of adverse reactions associated with co-administration.
• Potential additive efect with platelet aggregation inhibitors: Because of the increased risk of bleeding, the concomitant administration of a platelet aggregation inhibitor (such as clopidogrel, eptifibatide, tirofiban, epoprostenol, iloprost, abciximab, anagrelide, NSAIDs other than selective COX-2 inhibitors, acetylsalicylates [ASA/LAS], ticlopidine, dipyridamole) with pentoxifylline should be undertaken with caution.
• Concomitant administration with cimetidine may increase the plasma concentration of pentoxifylline and the active Metabolite.

Pentoxifylline must not be used:

• in patients with hypersensitivity to pentoxifylline, other methylxanthines or any of the excipients of Pentoxifylline.
• in patients with massive bleeding (risk of increased bleeding).
• in patients with extensive retinal bleeding (risk of increased bleeding).

These adverse reactions have been reported in clinical trials or post-marketing-

• Investigations: Transaminases increased (Transaminase elevation), Blood pressure decreased (Fall in blood pressure)
• Cardiac disorders: Arrhythmia (Cardiac arrhythmia), Tachycardia, Angina Pectoris
• Blood and lymphatic system disorders: Thrombocytopenia (Thrombopenia), Leucopenia/neutropenia
• Nervous system disorders: Dizziness, headache, meningitis aseptic (Aseptic meningitis)
• Gastrointestinal disorders: Gastrointestinal disorder (Gastrointestinal complaints), Epigastric discomfort (Gastric pressure), Abdominal distension (Fullness), Nausea, Vomiting, Diarrhoea, Constipation, Hypersalivation
• Skin and subcutaneous tissue disorders: Pruritus, Erythema (Reddening of the skin), Urticaria, Rash
• Vascular disorders: Hot fush (Flushes), Haemorrhage (Bleedings)
• Immune system disorders: Anaphylactic reaction, Anaphylactoid reaction, Angioedema (Angioneurotic edema), Bronchospasm, Anaphylactic shock (shock)
• Hepatobiliary disorders: Cholestasis (Intrahepatic cholestasis)
• Psychiatric disorders: Agitation, Sleep disorder (Sleep disturbances)

Overdose Effects

Initial symptoms of acute overdose with pentoxifylline may be nausea, dizziness, tachycardia or a fall in blood pressure. Furthermore, signs such as fever, agitation, flush, loss of consciousness, areflexia, tonic -clonic convulsions and as a sign of gastrointestinal bleeding - coffee-ground vomiting may occur. No specific antidote is known. If ingestion has only just taken place, attempts may be made to prevent further systemic absorption of the active ingredient by primary elimination of the toxin (e.g. gastric lavage) or by delaying its absorption (e.g. activated charcoal).

At the first signs of an anaphylactic/anaphylactoid reaction, Pentoxifylline must be discontinued or the infusion be halted immediately, and a physician must be informed. Particularly careful monitoring is required:

• in patients with severe cardiac arrhythmias
• in patients with myocardial infarction
• in hypotensive patients
• in patients with impaired renal function (creatinine clearance below 30 ml/min)
• in patients with severely impaired liver function
• in patients with increased bleeding
• in patients treated concomitantly with pentoxifylline and anti-vitamin K or platelet aggregation inhibitors
• in patients treated concomitantly with pentoxifylline and antidiabetic agents
• in patients treated concomitantly with pentoxifylline and ciprofoxacin
• in patients treated concomitantly with pentoxifylline and theophylline

Use in Special Populations

Hepatic impairment: A dose reduction- guided by individual tolerance- is necessary in patients with severely impaired liver function.

Renal impairment: In patients with impairment of renal function (creatinine clearance below 30 mL/min) a dose reduction by approx. 30% to 50% may be necessary guided by individual tolerance.

Other: Treatment must be started at low-dose levels in hypotensive patients or patients whose circulation is unstable as well as in patients, who would be at particular risk from a reduction in blood pressure (e.g. patients with severe coronary heart disease or relevant stenoses of blood vessels supplying the brain); in such cases, the dose must only be increased gradually.

Pregnancy & Lactation

Insufficient experience has been gained concerning use in pregnancy. Therefore, it is recommended that Pentoxifylline is not used during pregnancy. Pentoxifylline passes into breast milk in minute quantities. Because insufficient experience has been gained, the physician must carefully weigh the possible risks and benefits before administering Pentoxifylline in breast-feeding women.