Pentoxifylline (pentoxifylline)

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.

Pentoxifylline is administered orally, preferably with meals.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Pentoxifylline/Ketorolac

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Ketorolac affects platelet function.(1) Pentoxifylline affects blood viscosity.(2)

CLINICAL EFFECTS: Concurrent use of ketorolac and pentoxifylline may result in an increased risk of bleeding.(1-3)

PREDISPOSING FACTORS: Concomitant use of other medications known to increase risk of bleeds (anticoagulants, aspirin, other NSAIDs, probenecid, lithium).(1-3) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding.

PATIENT MANAGEMENT: The US manufacturers of ketorolac(1) and pentoxifylline(2) states that concurrent use of these agents is contraindicated. The Australian manufacturer of ketorolac recommends careful monitoring if ketorolac is administered concomitantly with other medications that affect hemostasis such as pentoxifylline.(3) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: When ketorolac is administered with pentoxifylline, there is an increased tendency to bleeding.(1)

Xanthine Derivatives/Adenosine; Hexobendine; Regadenoson

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Xanthine derivatives may antagonize the effects of endogenous(1) and exogenous adenosine,(2,3) regadenoson,(4) and hexobendine.(5)

CLINICAL EFFECTS: Concurrent use of a xanthine derivative use may result in decreased effectiveness of adenosine, hexobendine and regadenoson. Aminophylline may increase the risk of adenosine-induced seizures.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with adenosine and a xanthine derivative should be monitored for decreased effectiveness of adenosine. The dosage of adenosine may need to be increased. Whenever possible, withhold xanthine derivatives for 5 half-lives prior to using adenosine in cardiac stress tests.(6) Methylxanthines should not be used to reverse the effects of adenosine in patients who experience adenosine-induced seizures.(3) Concurrent therapy with hexobendine and a xanthine oxidase derivative should also be monitored for decreased effectiveness of hexobendine.(5) The US manufacturer of regadenoson recommends that patients avoid methylxanthines (e.g. caffeine, pentoxifylline, and theophylline) for 12 hours prior to regadenoson administration. Aminophylline may be used to attenuate severe and/or persistent adverse reactions to regadenoson.(4)

DISCUSSION: In a study in six healthy subjects, theophylline significantly reduced the heart-rate response to adenosine. In addition, theophylline reduced the amount of abdominal and chest discomfort reported by subjects, allowing significantly higher infusion rates of adenosine.(7) Theophylline has also been reported to antagonize the vasorelaxant action of adenosine in human forearm arterioles.(8) In a study in five subjects, theophylline decreased the amounts of adenosine-induced side effects, including chest pain. There was no change in blood pressure or respiratory rate during concurrent adenosine and theophylline.(9) In a study in ten dog and twelve human subjects, the administration of adenosine after hexobendine increased coronary sinus blood flow. Aminophylline administration significantly decreased the coronary vasodilation response to adenosine and hexobendine.(5) In a study in ten healthy subjects, caffeine reduced the mean adenosine-induced increases in systolic blood pressure by 7.2 mmHg and heart rate by 8.4 beats/min when compared to placebo.(2) In another study in ten healthy subjects, caffeine was shown to lower the adenosine-induced response of blood pressure and heart rate.(3) Caffeine has also been reported to reduced adenosine-induced changes in minute ventilation and tidal volume.(3) Aminophylline has been shown to shorten the duration of coronary blood flow response to regadenoson.(3) Coronary flow reserve was 8% lower in patients who received caffeine (200 mg single dose) 2 hours prior to regadenoson administration when compared to subjects who received placebo instead of caffeine.(4)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Theophylline Derivatives/Cimetidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cimetidine inhibits the metabolism of theophylline by CYP1A2.(1-10) The duration of cimetidine's inhibitory action is uncertain. Short-term cimetidine therapy appears to reverse rapidly(2) but may persist in prolonged therapy. Increased pentoxifylline serum levels may be the result of an increase in the oral bioavailability of pentoxifylline.(11)

CLINICAL EFFECTS: Concurrent cimetidine and theophylline derivative therapy may result in elevated theophylline derivative concentration levels, prolonged elimination half-life, and decreased clearance.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Theophylline derivative blood levels should be very closely monitored if cimetidine therapy is to be initiated, changed, or discontinued. Theophylline has a narrow therapeutic range; therefore, dosage reductions up to 30-50%(4) should be considered to prevent intoxication when cimetidine therapy is started. Antacids, famotidine, or possibly ranitidine might be more judicious choices than cimetidine in patients receiving theophylline derivatives.

DISCUSSION: It is well documented that cimetidine impairs the elimination of theophylline when the two agents are co-administered to patients.(1-10, 12-22) This interaction has been noted by a variety of routes including continuous intravenous infusion.(22) Reports indicate that with concurrent cimetidine, theophylline plasma concentrations increase, theophylline half-life is prolonged from 29% to 73%(1-3;9,12-14) and theophylline clearance is decreased by 18.5% to 46%.(1-3,9,13,23) Age and smoking do not appear to affect the magnitude of the interaction.(17,18,20) Significant changes can be seen within 24 hours(3,5) and may progress as co-therapy continues.(3) A study involving ten healthy patients demonstrated that concomitant administration of cimetidine significantly decreased the plasma clearance of oxtriphylline.(24) Aminophylline is involved in a similar interaction as theophylline as seen in one case report.(25) In one report cimetidine also decreased the clearance and prolonged the half-life of caffeine.(26,27) A study demonstrated that cimetidine caused a significant increase in plasma levels of pentoxifylline.(11) Information on ranitidine is conflicting. Several studies have shown that ranitidine does not influence theophylline.(9,15,16,19,28,29) One case report noted toxic theophylline levels after ranitidine;(30) however, this case report has been challenged.(31) In another case report, theophylline levels rose from 16.6 mcg/ml to 39.7 mcg/ml(32) when the patient was given ranitidine. Other reports have also noted a reduction in theophylline elimination by ranitidine.(33,34) Famotidine has shown to have no effect on theophylline metabolism in a clinical trial;(35) however, there is one case report of decreased theophylline clearance during famotidine therapy.(36) Dyphylline, a theophylline derivative that is not converted to theophylline in vivo, is not to be expected to interact with cimetidine. A study showed that cimetidine increased the average steady state plasma concentration of pentoxifylline and its metabolite by 25% and 30%, respectively.(37)

Theophyllines/Selected Quinolones

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Quinolones may inhibit the hepatic microsomal enzymes responsible for the metabolism of theophyllines.

CLINICAL EFFECTS: May see an increase in the pharmacologic and toxic effects of theophylline due to elevated serum levels. Fatalities have been reported.

PREDISPOSING FACTORS: Older age.

PATIENT MANAGEMENT: Monitor theophylline serum levels and observe the patient for symptoms of theophylline toxicity (e.g, nausea, seizure). Adjust the dose of theophylline as needed.

DISCUSSION: Several studies have demonstrated that quinolones (e.g., ciprofloxacin, enoxacin, norfloxacin) may increase serum theophylline levels and decrease theophylline clearance. In addition, ciprofloxacin has been reported to increase the half-life and volume of distribution of theophylline. Theophylline toxicity has been associated with concurrent administration of quinolone antibiotics. Some studies indicate that norfloxacin does not interact with theophyllines.

There are no moderate interactions for this drug.

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• Intracranial bleeding
• Retinal hemorrhage

• Acute myocardial infarction
• Peptic ulcer

• Coronary artery disease
• Disease of liver
• Increased risk of bleeding
• Kidney disease with reduction in glomerular filtration rate (GFr)

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Rare or Very Rare

• Abnormal hepatic function tests
• Anaphylaxis
• Angioedema
• Aplastic anemia
• Cardiac arrhythmia
• Chest pain
• Cholecystitis
• Cholestasis
• Hepatitis
• Hypofibrinogenemia
• Jaundice
• Leukopenia
• Non-infective meningitis
• Pancytopenia
• Purpura
• Seizure disorder
• Thrombocytopenic disorder

More Frequent

• Dizziness
• Dyspepsia
• Eructation
• Nausea

Less Frequent

• Abdominal distension
• Acute abdominal pain
• Agitation
• Blurred vision
• Diarrhea
• Flushing
• Headache disorder
• Insomnia
• Palpitations
• Vomiting

Rare or Very Rare

• Acute cognitive impairment
• Anorexia
• Conjunctivitis
• Depression
• Dysgeusia
• Dyspnea
• Earache
• Edema
• Epistaxis
• Flu-like symptoms
• Hypotension
• Laryngitis
• Malaise
• Nasal congestion
• Nervousness
• Onychia sicca
• Pruritus of skin
• Scotomata
• Sialorrhea
• Skin rash
• Sore throat
• Symptoms of anxiety
• Tachycardia
• Urticaria
• Xerostomia

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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.

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.

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