Pentoxifylline

C04A - Peripheral vasodilators ATC C04AD03 Small molecule approved 1984 Oral Natural product

JFDA label: Pentoxine S.R Tab

Mechanism of Action

Antagonist of Adenosine A2 receptor — Adenosine A2 receptor antagonist; Inhibitor of 3',5'-cyclic phosphodiesterase — 3',5'-cyclic phosphodiesterase inhibitor

Target	Action	Gene / class
3',5'-cyclic phosphodiesterase efficacy	INHIBITOR
Adenosine A2 receptor efficacy	ANTAGONIST

Indications

Approved

Intermittent claudication

Off-label

Severe alcoholic liver disease
Venous leg ulcers (with compression therapy)

Contraindications

Source: Lexicomp

Additional contraindications (not in U.S. labeling): Acute MI, severe coronary artery disease when myocardial stimulation might prove harmful, peptic ulcers (current or recent) Absolute
Patients previously exhibiting intolerance to pentoxifylline, xanthines (eg, caffeine, theophylline), or any component of the formulation Absolute
recent cerebral and/or retinal hemorrhage Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Other (2)

Common Gastrointestinal: Nausea · vomiting

Dosing

Source: Lexicomp

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). Severe alcoholic hepatitis (Maddrey Discriminant Function [MDF] score ≥32, especially when corticosteroids contraindicated) (off-label use): Oral: 400 mg 3 times daily for 4 weeks (O’Shea, 2010) Venous leg ulcer (off-label use): Oral: 400 mg 3 times daily (with compression therapy) (Jull, 2002; Robson, 2006)

Refer to adult dosing.

Manufacturer's labeling: CrCl The following guidelines have been used by some clinicians: Aronoff, 2007: Adults: CrCl >50 mL/minute: 400 mg every 8 to 12 hours CrCl 10-50 mL/minute: 400 mg every 12 to 24 hours CrCl Hemodialysis: supplemental postdialysis dose is not necessary. Peritoneal dialysis: 400 mg every 24 hours Paap, 1996: Adults: Moderate renal impairment (CrCl ~60 mL/minute): 400 mg twice daily. Severe renal impairment (CrCl ~20 mL/minute): 400 mg once daily; further reduction may be required; Paap suggests 200 mg once daily, but with current products (extended or controlled release; unscored) may require adaptation to 400 mg once every other day.

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

Warnings & Precautions

Source: Lexicomp

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.

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events have been observed in animal reproduction studies. Information related to use in pregnant women has not been located. Pentoxifylline may be used to test sperm viability when evaluating nonfertile males (ASRM, 2012). It has also been evaluated for the treatment of infertility due to endometriosis, but use for this purpose is not currently recommended (Lu, 2012).

Lactation

Pentoxifylline and its metabolites are excreted into breast milk. Five nursing 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 0.54-1.13 at 4 hours (Witter, 1985). Due to

Monitoring

Clinical pearl	Renal function; hemoglobin/hematocrit in patients with risk factors for hemorrhage

Chemistry & Properties

Formula	C13H18N4O3
Molecular weight	278.31 g/mol
IUPAC name	3,7-dimethyl-1-(5-oxohexyl)purine-2,6-dione
CAS	6493-05-6
PubChem CID	4740
InChIKey	`BYPFEZZEUUWMEJ-UHFFFAOYSA-N`
logP	0.19 (XLogP 0.3)
Polar surface area	78.89 Å²
H-bond acceptors / donors	7 / 0
Drug-likeness (QED)	0.73
Lipinski violations	0

SMILES

CC(=O)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Inhibitor	—
CYP1A2	Substrate	—
CYP2B6	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 1)

Target	Action	Affinity
A2B receptor (ADORA2B)	Antagonist	pKi 5.3

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Acalabrutinib	major
Inotersen	major
Ketorolac	major
Abametapir (topical)	moderate
Abciximab	moderate
Acebutolol	moderate
Acetohexamide	moderate
Acetylsalicylic acid	moderate
Alfuzosin	moderate
Aliskiren	moderate
Alprostadil	moderate
Alteplase	moderate
Ambrisentan	moderate
Amiloride	moderate
Aminophylline	moderate
Amlodipine	moderate
Amyl Nitrite	moderate
Anagrelide	moderate
Anisindione	moderate
Anistreplase	moderate
Antithrombin Alfa	moderate
Antithrombin III human	moderate
Apixaban	moderate
Ardeparin	moderate
Argatroban	moderate
Atenolol	moderate
Avanafil	moderate
Azilsartan medoxomil	moderate
Benazepril	moderate
Bendroflumethiazide	moderate
Benzthiazide	moderate
Bepridil	moderate
Betaxolol	moderate
Betrixaban	moderate
Bisoprolol	moderate
Bivalirudin	moderate
Bosentan	moderate
Bromfenac	moderate
Bumetanide	moderate
Cangrelor	moderate

Showing 40 of 100+.

Registered Products (6)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Pentoxine S.R Tab	Tablet 400 mg	20 tab pack varies	Hayat Pharmaceutical Industries CO.PLC/JORDAN	3.360
Circulaid Tab.	Tablet 400 mg	20 tab	THE JORDANIAN PHARMACEUTICAL MANUFACTURING COMPANY/JORDAN	3.640
Pentyllin S.R	Tablet 400 mg	20 tab pack varies	Pharma International Company/ Jordan	3.640
Trental	Tablet 400 mg	20 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	4.200
Pentoxine S.R Tab	Tablet 400 mg	500 tab pack varies	Hayat Pharmaceutical Industries CO.PLC/JORDAN	71.400
Pentyllin S.R	Tablet 400 mg	500 tab pack varies	Pharma International Company/ Jordan	77.350