Pentoxifylline

Pharmacologic Category

Dosing: Adult

Alcoholic hepatitis (severe) (Maddrey Discriminant Function [MDF] score ≥32, especially when corticosteroids contraindicated) (off-label use): Oral: 400 mg 3 times daily for 4 weeks (AASLD [O’Shea 2010], ACG [Singal 2018]).

Intermittent claudication: Oral: 400 mg 3 times daily; maximal therapeutic benefit may take 2 to 4 weeks to develop; recommended to maintain therapy for at least 8 weeks. May reduce to 400 mg twice daily if GI or CNS side effects occur; discontinue if side effects persist.

Note: Use for the treatment of intermittent claudication refractory to exercise therapy (and smoking cessation) has been discouraged by The American College of Chest Physicians (ACCP) (Guyatt 2012).

Venous leg ulcer (off-label use): Oral: 400 mg 3 times daily (with compression therapy) (Jull 2012; Robson 2006).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

Manufacturer's labeling:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling. However, exposure to one of pentoxifylline’s the active metabolites (metabolite V) is increased with renal impairment; use with caution.

CrCl <30 mL/minute: 400 mg once daily.

The following guidelines have been used by some clinicians:

Aronoff 2007:

CrCl >50 mL/minute: 400 mg every 8 to 12 hours.

CrCl 10-50 mL/minute: 400 mg every 12 to 24 hours.

CrCl <10 mL minute: 400 mg every 24 hours.

Hemodialysis: supplemental postdialysis dose is not necessary.

Peritoneal dialysis: 400 mg every 24 hours.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling. However, pentoxifylline exposure is increased with hepatic impairment; use with caution.

Dosing: Pediatric

Kawasaki disease; adjunctive: Limited data available, efficacy results variable (Nash 1996); AHA recommendations do not address pentoxifylline for the treatment of Kawasaki disease (AHA [McCrindle 2017]): Infants ≥2 months and Children: Oral: 20 mg/kg/day in 3 divided doses in combination with standard IV immunoglobulin and aspirin therapy; specific role in disease management undefined; data suggests use in patients with high serum concentrations of TNF may be appropriate (Best 2003; Furukawa 1994); the initial trial (n=22, mean age: 2 years, youngest: 6 months) reported a lower incidence of coronary artery lesions in patient receiving pentoxifylline compared to those who did not; all patients received aspirin and IV gamma globulin therapy (Furukawa 1994).

Dosing: Renal Impairment: Pediatric

Use with caution; monitor for enhanced therapeutic and toxic effects; Note: Pentoxifylline is not eliminated unchanged in the urine; however, the pharmacologically active metabolite (M-V) is; M-V may accumulate in patients with renal impairment and add to pharmacologic and toxic effects. Based on experience in adult patients, dosing adjustment suggested.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in manufacturer's labeling; use with caution.

Calculations

Use: Labeled Indications

Intermittent claudication: Treatment of intermittent claudication on the basis of chronic occlusive arterial disease of the limbs.

Limitations of use: May improve function and symptoms, but not intended to replace more definitive therapy. Note: The American College of Chest Physicians (ACCP) discourages the use of pentoxifylline for the treatment of intermittent claudication refractory to exercise therapy (and smoking cessation) (Guyatt, 2012).

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Alcoholic hepatitis (severe)Level of Evidence [G]

Based on the American College of Gastroenterology for Alcoholic Liver Disease guideline, existing evidence does not support the use of pentoxifylline in the management of severe alcoholic hepatitis; however, certain patient subgroups, such as those with concomitant renal failure, may benefit. The American Association for the Study for Liver Disease Practice Guideline recommends that pentoxifylline be considered in patients with severe alcoholic hepatitis, especially if there are contraindications to steroid therapy.

Venous leg ulcers (with compression therapy)Level of Evidence [A]

Based on a meta-analysis of trials evaluating the treatment of venous leg ulcers with compression therapy, the use of pentoxifylline was shown to be safe and effective Ref.

Level of Evidence Definitions

Level of Evidence Scale

Clinical Practice Guidelines

Severe Alcoholic Liver Disease:

ACG, “American College of Gastroenterology Clinical Guideline: Alcoholic Liver Disease,” January 2018

American Association for the Study of Liver Diseases (AASLD) Practice Guideline, Alcoholic Liver Disease, 2010

Other:

AHA, "The Postthrombotic Syndrome: Evidence-Based Prevention, Diagnosis, and Treatment Strategies,” October 2014

Administration: Oral

Administer with food. Swallow whole; do not chew, crush, or divide.

Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. No alternative formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, if pentoxifylline extended release is continued, close clinical monitoring is advised in the immediate postoperative phase for the theoretical circumstance of reduced absorption after bariatric surgery.

Administration: Pediatric

Oral: Administer with food or antacids to decrease GI upset. Do not crush, break, or chew extended or controlled release tablet, swallow whole.

Dietary Considerations

May be taken with meals.

Storage/Stability

Store between 20°C to 25°C (68°F to 77°F); protect from light.

Extemporaneously Prepared

A 20 mg/mL oral suspension may be made using tablets. Crush ten 400 mg tablets and reduce to a fine powder. Add a small amount of purified water and mix to a uniform paste; mix while adding purified water to almost 200 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 200 mL. Label "shake well" and "refrigerate". Stable 91 days.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to ease pain, numbness, and tingling in the legs.

• It is used to treat certain blood vessel problems.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Burping

• Bloating

• Dizziness

• Passing gas

• Headache

• Vomiting

• Nausea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Chest pain

• Arrhythmia

• Severe dizziness

• Passing out

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

Contraindications

Patients previously exhibiting intolerance to pentoxifylline, xanthines (eg, caffeine, theophylline), or any component of the formulation; recent cerebral and/or retinal hemorrhage

Canadian labeling: Additional contraindications (not in US labeling): Acute MI, severe coronary artery disease when myocardial stimulation might prove harmful, peptic ulcers (current or recent)

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis/anaphylactoid reactions: Discontinue at first sign of anaphylaxis or anaphylactoid reaction.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with mild to moderate hepatic impairment; the bioavailability of pentoxifylline and metabolite I is increased. Has not been studied in patients with severe hepatic disease.

• Renal impairment: Use with caution in patients with renal impairment; bioavailability of active metabolite V may be increased.

Special populations:

• Elderly: Use with caution in the elderly due to the potential for cardiac, hepatic, or renal impairment.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Pentoxifylline's value in the treatment of intermittent claudication is controversial. Walking distance improved statistically in some clinical trials, but the actual distance was minimal when applied to improving physical activity. Dose adjustment in moderate and severe kidney impairment has been recommended based on accumulation of two active metabolites. However, these doses have not been studied for clinical or safety outcomes.

Reproductive Considerations

Pentoxifylline may be used to test sperm viability when evaluating nonfertile males (ASRM 2015). It has also been evaluated for the treatment of infertility due to endometriosis, but use for this purpose is not currently recommended (Lu 2012).

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies.

Breast-Feeding Considerations

Pentoxifylline and its metabolites are present in breast milk.

Five breastfeeding women (~6 weeks' postpartum) were given a single dose of pentoxifylline 400 mg and maternal milk and serum samples were measured 2 and 4 hours later. The mean M/P ratio of pentoxifylline was 0.87 at 4 hours; actual milk concentrations ranged from below the limit of detection to 67.4 ng/mL. Three metabolites were also measured in breast milk, with mean M/P ratios ranging from 0.54 to 1.13 at 4 hours (Witter 1985). Due to the potential for serious adverse reactions in the breastfeeding infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, considering the importance of treatment to the mother.

Briggs' Drugs in Pregnancy & Lactation

Pentoxifylline

Adverse Reactions

1% to 10%: Gastrointestinal: Nausea (2%), vomiting (1%)

<1%, postmarketing, and/or case reports: Anaphylactic shock, anaphylactoid reaction, anaphylaxis, angioedema, angina pectoris, anorexia, anxiety, aplastic anemia, aseptic meningitis, bloating, blurred vision, cardiac arrhythmia, chest pain, cholecystitis, confusion, conjunctivitis, constipation, decreased serum fibrinogen, depression, dysgeusia, dyspnea, edema, epistaxis, eructation, flatulence, flu-like symptoms, hallucination, hepatitis, hypotension, increased liver enzymes, jaundice, laryngitis, leukemia, leukopenia, malaise, nail disease (brittle fingernails), nasal congestion, otalgia, pancytopenia, pruritus, purpura, scotoma, seizure, sialorrhea, skin rash, sore throat, tachycardia, thrombocytopenia, tremor, urticaria, weight changes, xerostomia

* See Cautions in AHFS Essentials for additional information.

Metabolism/Transport Effects

Substrate of CYP1A2 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions Open Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Pentoxifylline may enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Blood Pressure Lowering Agents: Pentoxifylline may enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Cimetidine: May increase the serum concentration of Pentoxifylline. Risk C: Monitor therapy

CYP1A2 Inhibitors (Moderate): May increase the serum concentration of Pentoxifylline. Risk C: Monitor therapy

CYP1A2 Inhibitors (Strong): May increase the serum concentration of Pentoxifylline. Risk C: Monitor therapy

Heparin: Pentoxifylline may enhance the anticoagulant effect of Heparin. Risk C: Monitor therapy

Heparins (Low Molecular Weight): Pentoxifylline may enhance the anticoagulant effect of Heparins (Low Molecular Weight). Risk C: Monitor therapy

Ketorolac (Nasal): May enhance the adverse/toxic effect of Pentoxifylline. Specifically, the risk of bleeding may be increased. Risk X: Avoid combination

Ketorolac (Systemic): May enhance the adverse/toxic effect of Pentoxifylline. Specifically, the risk of bleeding may be increased with this combination. Risk X: Avoid combination

Theophylline Derivatives: Pentoxifylline may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Pentoxifylline may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Food Interactions

Food may decrease rate but not extent of absorption. Pentoxifylline peak serum levels may be decreased if taken with food.

Test Interactions

Concomitant administration increases theophylline levels

Monitoring Parameters

Renal function; hemoglobin/hematocrit (especially in high risk patients)

Advanced Practitioners Physical Assessment/Monitoring

Assess efficacy of therapy objectively.

Nursing Physical Assessment/Monitoring

For claudication: Monitor ability to increase walking distance without discomfort.

For liver disease: Monitor improvement of liver disease.

Tell prescriber if patient has renal dysfunction; dose adjustment may be required.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet Extended Release, Oral:

Generic: 400 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet Extended Release, Oral:

Generic: 400 mg

Anatomic Therapeutic Chemical (ATC) Classification

C04AD03

Generic Available (US)

Yes

Pricing: US

Tablet, controlled release (Pentoxifylline ER Oral)

400 mg (per each): $0.43 - $1.50

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Pentoxifylline increases blood flow to the affected microcirculation. Although the precise mechanism of action is not well-defined, blood viscosity is lowered, erythrocyte flexibility is increased, leukocyte deformability is increased, and neutrophil adhesion and activation are decreased. Overall, tissue oxygenation is significantly increased.

Pharmacodynamics/Kinetics

Onset of action: 2 to 4 weeks with multiple doses

Absorption: Well absorbed

Metabolism: Hepatic to multiple metabolites; undergoes extensive first-pass effect; Pentoxifylline undergoes reduction to metabolite I (active), and oxidation to form metabolite V (active) (Ward 1987); Note: Plasma concentrations of M-1 and M-V are 5 and 8 times greater, respectively, than pentoxifylline

Half-life elimination: Parent drug: 24 to 48 minutes; Metabolites: 60 to 96 minutes

Time to peak, serum: 2 to 4 hours

Excretion: Urine (0% as unchanged, 50% to 80% as M-V metabolite, 20% as other metabolites); feces (<4%)

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: In patients with mild to moderate renal impairment, AUC0-tss and Cmax of the active Metabolite V increased 2.4- and 2.1-fold, respectively. In patients with severe renal impairment, the AUC0-tss and Cmax of active Metabolite V increased 12.9- and 10.6-fold, respectively. Twice daily administration increased the exposure to metabolite V only slightly in both groups.

Hepatic function impairment: Following a single dose of pentoxifylline, the AUC increased 6.5-fold and the Cmax increased 7.5-fold in patients with mild to moderate hepatic impairment. The AUC and Cmax of active Metabolite I also increased 6.9- and 8.2-fold, respectively. Studies were not conducted in patients with severe hepatic failure.

Geriatric: Pentoxifylline: Increased AUC and decreased elimination rate (60 to 68 years of age).

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

No significant effects or complications reported

Effects on Bleeding

Pentoxifylline is a methylxanthine derivative with potent hemorrheologic properties. Pentoxifylline has been shown to decrease platelet aggregation and adhesion, and enhances plasminogen activator while decreasing fibrinogen and alpha2-antiplasmin.

Related Information

Oral Medications That Should Not Be Crushed or Altered

Index Terms

Oxpentifylline; Trental

FDA Approval Date

August 30, 1984

References

Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007.

Aronoff SC, Quinn FJ, Carpenter LS, et al, “Effects of Pentoxifylline on Sputum Neutrophil Elastase and Pulmonary Function in Patients With Cystic Fibrosis: Preliminary Observations,” J Pediatr, 1994, 125(6 Pt 1):992-7.[PubMed 7996376]

Berman W Jr, Berman N, Pathak D, et al, “Effects of Pentoxifylline (Trental®) on Blood Flow, Viscosity, and Oxygen Transport in Young Adults With Inoperable Cyanotic Congenital Heart Disease,” Pediatr Cardiol, 1994, 15(2):66-70.[PubMed 7997416]

Best BM, Burns JC, DeVincenzo J, et al. Pharmacokinetic and tolerability assessment of a pediatric oral formulation of pentoxifylline in kawasaki disease. Curr Ther Res Clin Exp. 2003;64(2):96-115.[PubMed 24944359]

Furukawa S, Matsubara T, Umezawa Y, et al, “Pentoxifylline and Intravenous Gamma Globulin Combination Therapy for Acute Kawasaki Disease,” Eur J Pediatr, 1994, 153(9):663-7.[PubMed 7957426]

Guyatt GH, Akl EA, Crowther M, et al, “Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines,” Chest, 2012, 141(2 Suppl):7-47.

Jull AB, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev. 2012;12:CD001733.[PubMed 23235582]

Lauterbach R, “Pentoxifylline Treatment of Persistent Pulmonary Hypertension of Newborn,” Eur J Pediatr, 1993, 152(5):460. (I.V. use)[PubMed 8319723]

Lauterbach R, Pawlik D, Tomaszczyk B, et al, “Pentoxifylline Treatment of Sepsis of Premature Infants; Preliminary Clinical Observations,” Eur J Pediatr, 1994, 153(9):672-4. (I.V. use)[PubMed 7957428 ]

Lu D, Song H, Li Y, et al, "Pentoxifylline for Endometriosis," Cochrane Database Syst Rev, 2012, 1:CD007677.[PubMed 22258970]

Luke DR, Rocci ML Jr, and Hoholick C, "Inhibition of Pentoxifylline Clearance by Cimetidine," J Pharm Sci, 1986, 75(2):155-7.[PubMed 3958924]

MacDonald MJ, Shahidi NT, Allen DB, et al, “Pentoxifylline in the Treatment of Children With New-Onset Type I Diabetes Mellitus,” JAMA, 1994, 271(1):27-8.[PubMed 8258882]

Mauro VF, Mauro LS, and Hageman JH, "Alteration of Pentoxifylline Pharmacokinetics by Cimetidine," Clin Pharmacol, 1988, 28(7):649-54.

McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017;135(17):e927-e999.[PubMed 28356445]

Nash MC, Wade AM. No evidence for use of pentoxifylline in acute Kawasaki disease. Eur J Pediatr. 1996;155(3):258.[PubMed 8929744]

O’Shea R, Dasarathy S, McCullough A, et al, “Alcoholic Liver Disease,” Hepatology, 2010, 51(1):307-28.[PubMed 20034030]

Paap CM, Simpson KS, Horton MW, et al, “Multiple-Dose Pharmacokinetics of Pentoxifylline and its Metabolites During Renal Insufficiency,” Ann Pharmacother, 1996, 30(7-8):724-9.[PubMed 8826548]

Pentoxifylline [prescribing information]. Bridgewater, NJ: Oceanside Pharmaceuticals; November 2019.

Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril. 2015;103(6):e44-e50.[PubMed 25936238]

Robson MC, Cooper DM, Aslam R, et al, “Guidelines for the Treatment of Venous Ulcers,” Wound Repair Regen, 2006, 14(6):649-62.[PubMed 17199831]

Singal AK, Bataller R, Ahn J, et al. ACG Clinical Guideline: alcoholic liver disease. Am J Gastroenterol. 2018;113(2):175-194. doi: 10.1038/ajg.2017.469.[PubMed 29336434]

Trental (pentoxifylline) [prescribing information]. Parsippany, NJ: Validus; January 2016.

Ward A and Clissold SP, “Pentoxifylline: A Review of Its Pharmacodynamic and Pharmacokinetic Properties and Its Therapeutic Efficacy,” Drugs, 1987, 34(1):50-97.[PubMed 3308412]

Witter FR and Smith RV, "The Excretion of Pentoxifylline and Its Metabolites Into Human Breast Milk," Am J Obstet Gynecol, 1985, 151(8):1094-7.[PubMed 3985069]

Brand Names: International

Agapurin (HU, PK, UA, VN); Angiopurin (HU); Artal (FI); Artelife (MX); Cental (TW); Cerator (HK, MY, TH); Ceretal (TW); Chinotal (HU); Circulaid (JO); Clem (PY); Dartelin (HR); Duplat (CR, DO, GT, HN, MX, NI, PA, SV); Elorgan (ES); Fixoten (MX); Flexital CR (TH); Fylin (TW); Hemovas (ES); Ipentol (TW, VN); Kentadin (MX); Latren (UA); Nelorpin (ES); Oxiflux (RO); Oxopurin 400 SR (IL); Penphylline (TW); Pental (EG); Pentamon (HR); Pentilin (HR, LV); Pentolin (BD); Pentox (EG, PH); Pentox von ct (LU); Pentoxal (PH); Pentoxi (CH); Pentoxifilina (CO); Pentoxifyllin AL (HU); Pentoxifyllin Pharmavit (HU); Pentoxifyllin-B (HU); Pentoxifyllin-ratiopharm (LU); Pentoxin SR (KR); Pentoxine (JO, QA); Pentyllin (AE, CY, IQ, IR, JO, KW, LB, LY, OM, SA, SY, YE); Perencal (KR); Peridane (MX); Pexal (BM, BZ, GY, SR); Pexol (PE); Platof (ID); Profiben (MX); Qiquan (CN); Rentylin (LU); Sufisal (CR, DO, GT, HN, MX, NI, PA, SV); Tarontal (GR, ID, TR); Torental (BE, FR, LU); Trenfyl (ID); Trenlin (HK); Trenlin SR (SG); Trental (AE, AR, AT, AU, BB, BD, BG, BM, BO, BR, BS, BZ, CH, CL, CO, CU, CY, CZ, DE, DK, EC, EE, EG, FI, GB, GY, HK, HR, HU, ID, IN, IQ, IR, IS, IT, JM, JO, JP, KR, KW, LB, LT, LV, LY, MT, MX, MY, NL, NO, NZ, OM, PE, PH, PK, PL, PR, PT, PY, QA, RU, SA, SE, SG, SI, SK, SR, SY, TH, TR, TT, TW, UA, UY, VE, YE); Trental SR (BH, EG); Trental-400 (LK); Vantoxyl (CR, DO, GT, HN, MX, NI, PA, SV); Vasolax (BD); Vasonit (AT, RO, UA); Vasonit Retard (LV); Vasopentox (PE); Vasotal (EG); Xipen (MX)

Last Updated 4/14/20

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