Forflow

Uses

Forflow is used for the treatment of peripheral vascular disease evident as intermittent claudication, venous leg ulcers, Forflow can improve function and symptoms but is not intended to replace more definitive therapy, such as surgical bypass, or removal of arterial obstructions when treating peripheral vascular disease.

Forflow is also used to associated treatment for these conditions: Intermittent Claudication, Venous Leg Ulcer (VLU), Severe alcoholic liver disease

How Forflow works

Patients with peripheral arterial disease (PAD) may suffer from intermittent claudication, exertional leg pain that resolves upon rest, which is underscored by a complex etiology including vascular dysfunction (reduced limb perfusion, angiogenesis, and microcirculatory flow), systemic inflammation, and skeletal muscle dysfunction. Forflow (PTX), (3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione) or 1-(5-oxohexyl)-3,7-­dimethylxanthine, is a methyl-xanthine derivative that acts to lower blood viscosity by increasing erythrocyte flexibility, reducing plasma fibrinogen, inhibiting neutrophil activation, and suppressing erythrocyte/platelet aggregation; it also has antioxidant and anti-inflammatory effects. Although the precise mechanism of action has yet to be elucidated, numerous studies have suggested several effects of PTX.

The classical interpretation of PTX's broad effects is due to its ability to act, in vitro, as a non-specific cyclic-3',5'-phosphodiesterase (PDE) inhibitor at millimolar concentrations; specifically, it has been proposed that inhibition of PDE type III and IV isozymes leads to elevated cyclic adenosine monophosphate (cAMP) levels, which mediate diverse downstream effects. This view has been challenged, specifically by observing those plasma concentrations of PTX in routine clinical use are typically only around 1μM, far lower than those used to inhibit PDEs in vitro. Instead, several studies have suggested that PTX can modulate adenosine receptor function, specifically the Gα-coupled A2A receptor (A2AR). Whether PTX acts directly as an A2AR agonist is unclear, although it can clearly increase the response of A2AR to adenosine. A2AR activation activates adenylyl cyclase, which increases intracellular cAMP levels; this observation may explain PTX's ability to increase intracellular cAMP in a PDE-independent fashion.

Elevated cAMP levels have numerous downstream effects. cAMP-mediated activation of protein kinase A (PKA) suppresses nuclear translocation of NF-κB, which suppresses transcription of pro-inflammatory cytokines such as tumour necrosis factor (TNF-α), interleukin-1 (IL-1), and IL-6 as well as TNF-induced molecules such as adhesion molecules (ICAM1 and VCAM1) and the C-reactive protein (CRP). PTX has also been shown to prevent the downstream phosphorylation of p38 MAPK and ERK, which are responsible for assembling the NADPH oxidase involved in the neutrophil oxidative burst. This effect is due to a PKA-independent decrease in Akt phosphorylation and a PKA-dependent decrease in phosphorylation of p38 MAPK and ERK. This transcriptional regulation at least partially explains the anti-inflammatory and anti-oxidative properties of PTX.

Also, activated PKA can activate the cAMP response element-binding protein (CREB), which itself blocks SMAD-driven gene transcription, effectively disrupting transforming growth factor (TGF-β1) signalling. This results in lower levels of fibrinogenic molecules such as collagens, fibronectin, connective tissue growth factor, and alpha-smooth muscle actin. Hence, disruption of TGF-β1 signalling may explain the anti-fibrotic effects of PTX, including at least some of the decrease in blood viscosity.

The picture is complicated by the observation that PTX metabolites M1, M4, and M5 have been shown to inhibit C5 Des Arg- and formyl-methionylleucylphenylalanine-induced superoxide production in neutrophils and M1 and M5 significantly contribute to PTX's observed hemorheological effects. Overall, PTX administration is associated with decreased pro-inflammatory molecules, an increase in anti-inflammatory molecules such as IL-10, and decreased production of fibrinogenic and cellular adhesion molecules.

Dosage

Forflow dosage

The usual dosage of Forflow tablet is one tablet (400 mg) two to three times a day with meals. While the effect of Forflow tablet may be seen within 2 to 4 weeks, it is recommended that treatment be continued for at least 8 weeks.

Digestive and central nervous system side effects are dose related. If patients develop these effects it is recommended that the dosage be lowered to one tablet twice a day (800 mg/day). If side effects persist at this lower dosage, the administration of Forflow tablet should be discontinued.

Side Effects

Cardiovascular- dyspnea, edema, hypotension.

Digestive- anorexia, cholecystitis, constipation, dry mouth/thirst.

Nervous- anxiety, confusion, depression, seizures.

Respiratory- epistaxis, flu-like symptoms, laryngitis, nasal congestion.

Skin and Appendages- brittle fingernails, pruritus, rash, urticaria, angioedema.

Special Senses- blurred vision, conjunctivitis, earache, scotoma.

Miscellaneous- bad taste, excessive salivation, leukopenia, malaise, sore throat/swollen neck glands, weight change.

Toxicity

Overdoses of pentoxifylline have been reported with symptoms including agitation, fever, flushing, hypotension, convulsions, somnolence, and loss of consciousness beginning 4-5 hours following ingestion and lasting up to 12 hours. Symptomatic treatment is recommended, specifically pertaining to maintaining proper respiration, blood pressure, and controlling convulsions. Activated charcoal may prove useful in absorbing excess pentoxifylline in overdose cases. Patients have recovered from overdose even at doses as high as 80 mg/kg.

Precaution

Patients on warfarin should have frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration, cerebral and/or retinal bleeding) should have periodic examinations for bleeding including, hematocrit and/or hemoglobin.

Interaction

Patients on warfarin should have frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of Forflow and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. Forflow has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with Forflow; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced.

Food Interaction

• Limit caffeine intake.
• Take with food. Administration with food may reduce irritation. Co-administration with food modestly increases the mean pentoxifylline AUC and maximum plasma concentrations (1.1- and 1.3-fold, respectively) achieved with an extended-release tablet.

Forflow Drug Interaction

Moderate: aspirin, aspirin, omega-3 polyunsaturated fatty acids, furosemide, metoprolol, metoprolol, clopidogrelUnknown: fluticasone / salmeterol, rosuvastatin, duloxetine, atorvastatin, pregabalin, esomeprazole, acetaminophen / hydrocodone, tiotropium, acetaminophen, cyanocobalamin, ascorbic acid, ergocalciferol, cholecalciferol

Forflow Disease Interaction

Major: cerebral or retinal hemorrhageModerate: cardiovascular dysfunction, hepatic/renal

Volume of Distribution

Forflow has a volume of distribution of 4.15 ± 0.85 following a single intravenous 100 mg dose in healthy subjects.

Elimination Route

Oral pentoxifylline (PTX) is almost completely absorbed but has low bioavailability of 20-30% due to extensive first-pass metabolism; three of the seven known metabolites, M1, M4, and M5 are present in plasma and appear soon after dosing. Single oral doses of 100, 200, and 400 mg of pentoxifylline in healthy males produced a mean t_max of 0.29-0.41 h, a mean C_max of 272-1607 ng/mL, and a mean AUC_0-∞ of 193-1229 ng*h/mL; corresponding ranges for metabolites 1, 4, and 5 were 0.72-1.15, 114-2753, and 189-7057. Single administration of a 400 mg extended-release tablet resulted in a heightened t_max of 2.08 ± 1.16 h, lowered C_max of 55.33 ± 22.04 ng/mL, and a comparable AUC_0-t of 516 ± 165 ng*h/mL; all these parameters were increased in cirrhotic patients.

Smoking was associated with a decrease in the C_max and AUC_steady-state of metabolite M1 but did not dramatically affect the pharmacokinetic parameters of pentoxifylline or other measured metabolites. Renal impairment increases the mean C_max, AUC, and ratio to parent compound AUC of metabolites M4 and M5, but has no significant effect on PTX or M1 pharmacokinetics. Finally, similar to cirrhotic patients, the C_max and t_max of PTX and its metabolites are increased in patients with varying degrees of chronic heart failure.

Overall, metabolites M1 and M5 exhibit plasma concentrations roughly five and eight times greater than PTX, respectively. PTX and M1 pharmacokinetics are approximately dose-dependent, while those of M5 are not. Food intake before PTX ingestion delays time to peak plasma concentrations but not overall absorption. Extended-release forms of PTX extend the t_max to between two and four hours but also serves to ameliorate peaks and troughs in plasma concentration over time.

Half Life

Overall, pentoxifylline has an elimination half-life of between 0.39 and 0.84 hours, while its primary metabolites have elimination half-lives of between 0.96 and 1.61 hours.

Clearance

Forflow given as a single 100 mg intravenous infusion has a clearance of 3.62 ± 0.75 L/h/kg in healthy subjects, which decreased to 1.44 ± 0.46 L/h/kg in cirrhotic patients. In another study, the apparent clearance of either 300 or 600 mg of pentoxifylline given intravenously (median and range) was 4.2 (2.8-6.3) and 4.1 (2.3-4.6) L/min, respectively. It is important to note that, due to the reversible extra-hepatic metabolism of the parent compound and metabolite 1, the true clearance of pentoxifylline may be even higher than the measured values.

Elimination Route

Forflow is eliminated almost entirely in the urine and predominantly as M5, which accounts for between 57 and 65 percent of the administered dose. Smaller amounts of M4 are recovered, while M1 and the parent compound account for less than 1% of the recovered dose. The fecal route accounts for less than 4% of the administered dose.

Pregnancy & Breastfeeding use

Forflow should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Forflow and its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for pentoxifylline in rats, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Forflow should not be used in patients with recent cerebral and/or retinal hemorrhage or in patients who have previously exhibited intolerance to this product or methylxanthines such as caffeine, theophylline, and theobromine.

Special Warning

Pediatric use: Safety and effectiveness in pediatric patients have not been established.

Acute Overdose

Overdosage with Forflow has been reported in children and adults. Symptoms appear to be dose related. Flushing, hypotension, convulsions, somnolence, loss of consciousness, fever, and agitation occurred. In addition to symptomatic treatment special attention must be given to supporting respiration, maintaining systemic blood pressure, and controlling convulsions. Activated charcoal has been used to absorb Forflow in patients who have overdosed.

Storage Condition

Store in a cool and dry place, away from light. Keep out of reach of children.

Innovators Monograph

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