Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of Action Trental (pentoxifylline) is a xanthine derivative. It belongs to a group of vasoactive drugs which improve peripheral blood flow and thus enhance peripheral tissue oxygenation. The mechanism by which Trental achieves this effect has not been determined, but it is likely that the following factors are involved: Trental, as with other xanthine derivatives, relaxes certain smooth muscles including those of the peripheral vessels, thus causing vasodilatation or preventing spasm. This action, however, may have a limited role in patients with chronic obstructive arterial disease when peripheral vessels are already maximally dilated. Trental improves flexibility of red blood cells. This increase in the flexibility of red blood cells probably contributes to the improvement of the ability of blood to flow through peripheral vessels (haemorheologic action). This property was seen during in vitro and in vivo experiments with Trental but the correlation between it and the clinical improvement of patients with peripheral vascular diseases has not been determined. Trental promotes platelet deaggregation. Improvement of red blood cell flexibility and platelet deaggregation contribute to the decrease in blood viscosity. Pharmacokinetics Pentoxifylline is almost completely absorbed after oral administration. The Trental 400 mg sustained release tablet showed an initial peak plasma pentoxifylline concentration 2 to 3 hours post-administration. The drug is extensively metabolized. The active main metabolite 1-(5- hydroxyhexyl)-3,7-dimethyl-xanthine (metabolite I) is measurable in twice the concentration in plasma of that of its parent substance. Biotransformation products are almost exclusively eliminated by the kidneys. Food intake before the administration of Trental delayed the absorption but did not decrease it. In vitro and in vivo Animal Data Pharmacodynamics In dogs, 10mg/kg/i.v pentoxifylline produced a short but significant drop in BP. 5-15 mg/kg/i.v. pentoxifylline produced a dose related increase in heart rate and decrease in peripheral resistance for 30-60 minutes. In dogs, cats, and rats, after 1-3 mg/kg pentoxifylline i.v. the blood pressure, heart rate and respiration remained practically unchanged whereas higher doses of pentoxifylline (14-25 mg/kg/i.v.) caused a transient decrease in blood pressure and an increase in heart rate. In rabbits pentoxifylline (2-10 mg/kg/i.v.) produced a dose related fall in BP. In rabbits, cats and dogs the respiration was slightly stimulated. The blood pressure response in cats and rabbits after epinephrine was slightly inhibited by pentoxifylline. The i.v. administration of pentoxifylline or aminophylline in doses of 3-10 mg/kg to cats resulted in a 20 and 35 % increase on dp/dt respectively. Femoral musculature circulation in cat, measured indirectly by heat-conduction probe, was increased by pentoxifylline (10-50 mg/kg/p.o. and 1-20 mg/kg/i.v.) and papaverine (1 mg/kg/i.v) while aminophylline (1-10 mg/kg/i.v) was without effect. In hepatic circulation in cat, pentoxifylline (2 mg/kg/i.v) was as effective as papaverine (1 mg/kg/i.v.) in increasing blood flow. In carotid artery blood of anaesthetized cat, pentoxifylline (5 mg/kg/i.v.) produced a 5.8 mmHg increase in PO2 whereas papaverine, (1 mg/kg/i.v) produced a 4.0 mmHg increase, aminophylline 3 mg/kg/i.v. produced a 1 mmHg increase in PO2 and 5 mg/kg/i.v. reduce O2 tension 1mmHg. Reserpine pre-treatment did not influence the positive chronotropic effect of pentoxifylline in rats. On isolated rabbit hind limb, pentoxifylline-induced vasodilatation was comparable to acetylcholine-induced vasodilatation at equal doses. In isolated guinea pig heart preparation, pentoxifylline (30-600 μg) produced no significant effect on contractility or heart rate and small increase in coronary flow while aminophylline (30-808 μg) produced a biphasic effect on coronary flow, slight negative inotropism and no rate alteration. The activity of pentoxifylline on coronary flow was not influenced by propanolol (7.5 μg). In isolated guinea pig tracheal chain, the bronchodilator activity of pentoxifylline, was significantly greater than aminophylline. The presence of propanolol 10-6 g/mL did not affect results. Contractions induced in isolated guinea pig seminal vesicle by epinephrine were reduced by pentoxifylline and by aminophylline in the same concentration range. Bronchospasm induced by i.v. acetylcholine in guinea pigs was inhibited by 97%, and that induced by i.v. histamine inhibited by 100%, at pentoxifylline doses of 50 mg/kg/i.v. and 20 mg/kg/i.v. respectively. On rabbit aorta strip preparation both pentoxifylline and aminophylline inhibited the NE-induced contraction. The histamine-induced increase of capillary permeability in rats was not influenced by 10 or 25 mg/kg pentoxifylline i.p. Pentoxifylline given orally (25-100 mg/kg) to rats had no influence on blood sugar while in rabbits given i.v. (10-50 mg/kg) the higher dose pentoxifylline increased blood sugar from 100 to 187 mg% at 1 hour post-dosing. In comparison to aminophylline, the central stimulatory effect of pentoxifylline in rats was significantly milder. Pentoxifylline (40 and 200 mg/kg/p.o.) did not prevent convulsions induced by nicotine in mice. Pentoxifylline does not influence significantly the motility of mice and rats, food consumption of rats, sleeping time after hexobarbital in rats and mice, ptosis, sedation and hypothermia of mice caused by reserpine, catalepsy in rats induced by perphenazine of fighting behaviour in mice. It has no anticonvulsive, anti-inflammatory and local anaesthetic activity and exhibits only a slight analgesic, cholorectic, diuretic and antitussive effect. The results of in vitro studies in which pentoxifylline was added to blood from human volunteers, and in vivo studies in which pentoxifylline was given orally or intravenously to patients with peripheral vascular disease indicate that pentoxifylline can improve impaired erythrocyte flexibility. The possible mechanism involved in this effect are most likely related to intracellular adenosine triphosphate (ATP) inasmuch as ATP depleted cells have reduced flexibility and vice versa. Pentoxifylline raises erythrocytes intracellular ATP concentrations. In another in vitro study using rat erythrocytes, pentoxifylline has been shown to decrease intracellular Ca++ concentrations and increase phosphorylation of the proteins in the erythrocytes membrane by facilitating Mg++ dependent phosphoprotein phosphatase and transglutaminase activity. This results in an increased membrane phosphoprotein concentration, which is believed to increase red blood cell flexibility. In an in vivo rat study designed to test platelet deaggregation properties of drugs, pentoxifylline at doses of 3,6 and 12 mg/kg/i.v. reduced platelet aggregation to “sticky” cancer cells (Walker 256 carcinosarcoma) and inhibited their attachment to endothelium. Monkeys given pentoxifylline 6, 12, 18 and 24 mg/kg/i.v. exhibited dose related reduction in platelet aggregation index. In human pentoxifylline inhibits ADP-stimulated platelet aggregation as measured by the Born method. Epinephrine-induced lipolysis (rat epididymal adipose tissue) was increased by pentoxifylline and aminophylline at 10-3 and 10-4 M in vitro. In vivo, epinephrine-induced glycerine production (same tissue) was significantly inhibited by both compounds (10 mg/kg/i.v.) and FFA was decreased. Pharmacokinetics Beagle dogs were given 3.0 mg/kg/p.o pentoxifylline-14C and radioactivity measured in plasma and body tissues. Mean maximal blood levels (2.1 μg/mL) were reached 1 hour post-dosing. Plasma concentration/time curve displayed a biphasic elimination profile with t1/2 0.8 hours and 30 hours. Over 80% of the radioactivity was found in urine within 24 hours. At maximal blood levels time, highest concentration was found in gallbladder (110.0 μg/g), kidney, liver and bladder (4.8 μg/g): lowest concentrations were found in brain (0.40 μg/g), fat, heart and gonads (1.3 μg/g). Toxicology Acute Toxicity ACUTE TOXICITY (LD50) OF PENTOXIFYLLINE SPECIES ROUTE LD50(MG/KG) Mouse p.o 1385 i.v. 197 i.p 239 Rat (SD) p.o 1772 i.v. 231 Toxicity was characterized by hypersalivation in orally dosed animals, increased or irregular respiration, tonic-clonic convulsions and paresis. Rabbits survived 50 mg i.v; signs and symptoms of toxicity were similar to those seen in rats. Dogs survived 160 mg i.v and 320 mg p.o. They showed aggression and ataxia after oral dosing and aggression, fear, vomiting, diarrhea after i.v dosing. Subacute and Chronic Toxicity Mouse i.v., 14 days: Groups of 8 female 12 week old mice were given daily doses of 0, 12.5, 25, 50 or 100 mg/kg of pentoxifylline. One mouse of the highest dosage group died after 6 days. Death was preceded by dyspnea and clonic convulsions. The other animals of this group showed a decrease in spontaneous activity and had their eyes closed. Mouse, p.o., 78 weeks: Four groups of 20 males and females were given pentoxifylline in diet at 0, 50, 150 or 450 mg/kg/day. Five animals per sex per group were killed after 26 weeks and another 5 at 52 weeks. After 78 weeks the remaining animals were observed for 13 weeks, without exposure to the compound. High dose males showed a greater frequency of bronchiectasis, renal cysts, testicular atrophy, urinary bladder dilatation and bone marrow hyperplasia than controls. High dose females showed a greater frequency of bronchiectasis, fatty degeneration of the liver, fatty degeneration/amyloidosis in the kidneys, splenic hyperplasia, hyperplasia and fibrosis of bone marrow and osteoporosis than controls. There was an increased incidence of benign ovarian and uterine tumours, and angiosarcoma of the liver was observed in 1 animal of each sex in the high dose group. Rat, i.v., 14 days: Groups of 10 females were given pentoxifylline at daily doses of 0, 12.5, 25, 50 or 100 mg/kg. Four of the 10 rats given 100 mg/kg showed depressed spontaneous activity, staggering gait, closed eyelids, salivation and clonic and tonic convulsions and died. There were pulmonary hemorrhages in these 4 rats. Rat, i.v, 30 days: Groups of 10 males and 10 females were given pentoxifylline in doses of 0, 10, 25 or 50 mg/kg/day. There was a slight decrease in cholesterol and esterified cholesterol in the 25 and 50 mg/kg male groups and a slight increase in the mean blood glucose level in the 25 and 50 mg/kg female groups. Perilobular hyaline droplet degeneration of the liver occurred in all groups, but appeared to be more severe in the male rats of the two highest dosage groups. Females on the top dose displayed increased incidence of renal tubule calcification. Rat, p.o., 78 weeks: Groups of 70 males and 70 females were given pentoxifylline in their diet 0, 50, 150 or 450 mg/kg/day. Five animals per sex per group were killed at 52 weeks and another 5 at 78 weeks. After 78 weeks the remaining animals were observed for 26 weeks without additional exposure to pentoxifylline. In the middle-dose group the body weight gain was significantly decreased; at the end of the 6 months follow-up period the body weight were normal. In the high-dosage group the body weight gain was decreased. At the end of the 6 months follow-up period the female weight had returned to normal but the males had not. The mortality rate was significantly increased for the males in the high-dose group. The cause of death was similar in treated and untreated animals, but in the treated animals there was an increase in congestive streaks of the liver, cadiosclerosis and scars in the heart, dilatation of the uterus, and thyroid atrophy (females only). There were more interstitial cell tumours of the testicles in the high dosage group but the difference was not significant. There was a significant increase in fibroadenomas of the mammary gland (females) in the high dose group. Dog, i.v., 30 days: Groups of 3 male and 3 female Beagles were given pentoxifylline in doses of 0, 10, 25 and 63 mg/kg 5days/week for 6 weeks. There was licking of the lips, vomiting, incoordination, uneasiness and dose-related heart rate increase following the injection. Some tubular renal degeneration occurred at 25 and 63 mg/kg. There was also congestion of liver at these doses and congestion of spleen at the highest dose. Dog, p.o., 1 year: Groups of 3 male and 3 female Beagles were given pentoxifylline in doses of 0, 32, 100, 320 or 400 mg/kg/day. There was incoordination, salivation and altered temperament following drug administration. Deaths occurred at doses of 320 and 400 mg/kg due to extensive or focal pulmonary oedema and hemorrhages, and marked congestion in mucosa of the intestinal tract. Acetone was detected in urine at 2 weeks to 26 weeks in some dogs of the 3 highest dose groups. At 52 weeks acetone was no longer detected. Giant cell formation in the testicles was observed in 2 dogs, which died in the 320 mg/kg group. Granuloma in the lymph nodes occurred in 1 dog in the control group, and 2 in the 320 mg/kg group. Reproduction and Teratology Mouse, i.v.: Mice were given 0, 12.5, 25 or 50 mg/kg pentoxifylline from day 15 of gestation through day 21 of lactation. Between days 21 and 23 all the animals were killed. Some of the F1 offspring were reared and mated. The females and F2 offspring were raised to weaning, and then killed. All other F1 offspring were killed at 10 weeks. There was no significant effect on pregnancy and on the fetal development. Rat, p.o.: Groups of 10 males and 20 females were given 0, 57, 170 or 570 mg/kg/day pentoxifylline for 10 weeks before mating and then continuously through gestation and lactation. Fifty percent of the females were killed on the 13th day of gestation and the remaining animals were allowed to raise their young to weaning. The number of resorptions, particularly early resorption, was greater in the high dose group. The number of young reared to weaning was lower for the high dose group. Rat, p.o. and i.v.: Groups of 20 females were given pentoxifylline 0, 57, 100 or 570 mg/kg orally or 0.8, 3.2 or 12.5 mg/kg i.v. from the 6th or 7th day to the 16th day of gestation. Two control groups were used in the i.v. study. One group was given a volume of physiological NaCl similar to the treatment groups and the other group was not treated at all. On the 20th day of pregnancy the fetuses were removed by Caesarean section. There was a significant reduction in the number of fetuses in the highest oral dosage group and the number of resorption sites was increased. There were no fetal abnormalities. The highest i.v. dose caused a slight reduction in number of fetuses and increase in resorption. Rat, p.o.: Groups of 20-24 pregnant animals were given pentoxifylline 0, 57, 170 or 570mg/kg by stomach tube from day 17 of gestation to day 21 postpartum. Between days 21 and 23 all animals were killed. There were no drug effects. Rabbit, i.v. and p.o.: Groups of 10 pregnant females were given pentoxifylline at 0, 26.5, 80 or 265 mg/kg/day orally or 1, 3.2, 0r 10 mg/kg/i.v./day. There were no drug effects. REFERENCES 1. Angelkort B: Influence of pentoxifylline (Trental 400) on microcirculation, poststenotic blood pressure and walking capacity in patients with chronic occlusive arterial disease. IRCS Med Sci 1977; 5: 370. 2. Angelkort B: Platelet function, plasma coagulation and fibrinolysis in chronic arterial occlusive disease. Med Welt 1979; 30: 1239. 3. Angelkort B: Influence of pentoxifylline on erythrocyte deformability in peripheral occlusive arterial disease. Curr Med Res Opin 1979; 6: 255. 4. Bauman JC: Doppler ultrasonic blood pressure measurements in limbs with occlusive arterial disease in normal lower extremities under treatment with pentoxifylline. IRCS Med Sci 1976; 4: 93. 5. Bollinger A, Frei C: Double-blind study of pentoxifylline against placebo in patients with intermittent claudication. Pharmacotherapy 1977; 2: 557- 562. 6. Dettori AG, et al.: Acenocoumarol and pentoxifylline in intermittent claudication. A controlled clinical study. Angiology 1989; 40(4), Part I: 237-248. 7. Ehrly AM: The effect of pentoxifylline on the flow properties of human blood. Curr Med Res Opin 1978; 5: 608-613. 8. Ehrly AM, Saeger-Lorenz K: Increased capillary flow rate of erythrocyte in hyperosmolar human blood by the addition of pentoxifylline. In Microcirculation, Vol. 1. Eds. Graysorl J, Zingg W. Plenum Press, New York and London 1976; 165-166. 9. Gastpar H, Ambrus JL, Ambrus CM, et al: Study of platelet aggregation in-vivo III. Effect of pentoxifylline. J Med 1977; 8: 191. 10. Heidrich H, Schlichting K, Ott M: Change in blood viscosity due to pentoxifylline. IRCS Med Sci 1976; 4: 368. 11. Porter JM, Cutler BS, Lee BY, et al: Pentoxifylline in the treatment of intermittent claudication: a double-blind trial with objective assess ment. Am Heart J 1982; 104(1): 66-72. 12. Schindler H: The clinical use of pentoxifylline. Pharmacotherapy 1977; 2(1): 66-73. 13. Schubotz R: Double-blind trial of pentoxifylline in diabetics with peripheral vascular disorders. Pharmacotherapy 1976; 1: 172-179. 14. Stefanovich V: The biochemical mechanism of action of pentoxifylline. Pharmacotherapy 1978; 2(1): 5-16. 15. Stefanovich V: Effect of pentoxifylline on energy rich phosphates in rat's erythrocytes. Res Comm Chem Path Pharmacol 1975; 10: 747. 16. Stefanovich V: Concerning specificity of the influence of pentoxifylline on various cyclic AmP phosphodiesterases. Res Comm Chem Path Pharmacol 1974; 8: 673. 17. United States Pharmacopeial Convention, Inc. USP DI, 13th edition 1993; 1: 2203. 18. Usvatova LJ, Koschkin VM, Musin II, et al: The haemodynamic and metabolic effects of pentoxifylline and papaverine in peripheral arterial disease. Pharmacotherapy 1978; 2(1): 51-57. 19. Weed RI, LaCelle PL, Merrill EW: Metabolic dependence of red cell deformability. J Clin Invest 1969; 48: 795. 20. Weithmann KV: Pentoxifylline, its influence on interaction between blood vessel wall and platelets. IRCS Med Sci 1980; 8: 293.

CLINICAL PHARMACOLOGY Mode Of Action 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. Pharmacokinetics And Metabolism After oral administration in aqueous solution pentoxifylline is almost completely absorbed. It undergoes a first-pass effect and the various metabolites appear in plasma very soon after dosing. Peak plasma levels of the parent compound and its metabolites are reached within 1 hour. The major metabolites are Metabolite I (1-[5-hydroxyhexyl]-3,7-dimethylxanthine) and Metabolite V (1-[3-carboxypropyl]-3,7- dimethylxanthine), and plasma levels of these metabolites are 5 and 8 times greater, respectively, than pentoxifylline. Following oral administration of aqueous solutions containing 100 to 400 mg of pentoxifylline, the pharmacokinetics of the parent compound and Metabolite I are dose-related and not proportional (nonlinear), with half-life and area under the blood-level time curve (AUC) increasing with dose. The elimination kinetics of Metabolite V are not dose-dependent. The apparent plasma half-life of pentoxifylline varies from 0.4 to 0.8 hours and the apparent plasma half-lives of its metabolites vary from 1 to 1.6 hours. There is no evidence of accumulation or enzyme induction (Cytochrome P450) following multiple oral doses. Excretion is almost totally urinary; the main biotransformation product is Metabolite V. Essentially no parent drug is found in the urine. Despite large variations in plasma levels of parent compound and its metabolites, the urinary recovery of Metabolite V is consistent and shows dose proportionality. Less than 4% of the administered dose is recovered in feces. Food intake shortly before dosing delays absorption of an immediate-release dosage form but does not affect total absorption. The pentoxifylline AUC was increased and elimination rate decreased in an older population (60 to 68 years, n=6) compared to younger individuals (22 to 30 years, n=6) (see PRECAUTIONS, Geriatric Use). After administration of the 400 mg extended-release pentoxifylline tablet, plasma levels of the parent compound and its metabolites reach their maximum within 2 to 4 hours and remain constant over an extended period of time. Coadministration of pentoxifylline extended-release tablets with meals resulted in an increase in mean AUC and Cmax of about 1.1 and 1.3 fold for pentoxifylline, respectively. Cmax for Metabolite I also increased about 1.2 fold. The extended release of pentoxifylline from the tablet eliminates peaks and troughs in plasma levels for improved gastrointestinal tolerance. Patients With Hepatic Impairment In patients with mild to moderate liver impairment AUC and Cmax of pentoxifylline increased 6.5 and 7.5 fold, respectively, after a single 400 mg dose of pentoxifylline extended-release tablet AUC and Cmax of the active Metabolite I also increased 6.9 and 8.2 fold, respectively, in hepatic impaired subjects. Pentoxifylline extended-release tablet has not been studied in patients with severe hepatic failure. Patients With Renal Impairment In patients with mild, moderate, or severe renal impairment the exposure to pentoxifylline and its active Metabolite I are not increased. In contrast, AUC0-tss and Cmax of the active Metabolite V in patients with mild to moderate renal impairment increased 2.4 and 2.1 fold, respectively, with a 400 mg TID regimen of pentoxifylline extended-release tablet. In severe renal impairment AUC0-tss and Cmax of the active Metabolite V increased 12.9 and 10.6 fold, respectively, with a 400 mg pentoxifylline extended-release tablet TID regimen. The increase in exposure to Metabolite V is only slightly smaller in both renal impairment groups if pentoxifylline extended-release tablet is administered BID.

Find Lowest Prices on TRENTAL® (pentoxifylline) Sustainted Release Tablets DESCRIPTION Drug Substance Proper name: pentoxifylline Chemical name: 3,7-Dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione Molecular formula: C13H18N4O3 Molecular mass: 278.3 Structural formula: Pentoxifylline is a white to creamy white, crystalline powder. It is freely soluble in chloroform and methanol, soluble in water, sparingly soluble in ethanol and slightly soluble in ether. It has a melting point of 104°C to 107°C, within a 3°C range.

PENTOXIFYLLINE (pentoxifylline) Extended-Release Tablets, USP 400 mg DESCRIPTION Pentoxifylline extended-release tablets, USP for oral administration contain 400 mg of the active drug and the following inactive ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, magnesium stearate, polyethylene glycol, and titanium dioxide in an extended-release formulation. Pentoxifylline is a tri-substituted xanthine derivative designated chemically as 3,7- Dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione that, unlike theophylline, is a hemorrheologic agent, i.e., an agent that affects blood viscosity. Pentoxifylline is soluble in water and ethanol, and sparingly soluble in toluene. The molecular formula is C13H18N4O3 and its molecular weight is 278.31. The chemical structure is: USP Dissolution Test 9

INDICATIONS Clinical Use Trental® (pentoxifylline) is indicated for the symptomatic treatment of: patients with chronic occlusive peripheral vascular disorders of the extremities; In such patients Trental may give relief of signs and symptoms of impaired blood flow, such as intermittent claudication or trophic ulcers. DOSAGE AND ADMINISTRATION Recommended Dose and Dosage Adjustment The recommended starting dosage of Trental (pentoxifylline) is 400 mg twice daily after meals. The usual dose is 400 mg twice or three times daily. A maximum of 400 mg three times daily should not be exceeded. It may take up to two months to obtain full results. Trental 400 mg sustained release tablets must be swallowed whole. HOW SUPPLIED Storage And Stability Store at room temperature (15 to 30 °C). Protect from light. Protect from moisture and excessive heat. Dosage Forms, Composition And Packaging Composition Trental sustained release tablets 400 mg contain 400 mg medicinal ingredient, pentoxifylline. The qualitative formulation of Trental tablets is: pentoxifylline, benzyl alcohol, FD&C red no.3, hydroxyethyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol 8000, povidone, talc, titanium dioxide. Availability Trental (pentoxifylline) is available as 400 mg, pink, oblong, film-coated, sustained release tablets, packed in Unit Pack boxes of 60 [4x15 clear PVC film and aluminium foil blisterpacked] tablets. One face is debossed with “Trental”, the other face is plain. This leaflet was prepared by sanofi-aventis Canada Inc. Last revised: March 30, 2011

INDICATIONS Pentoxifylline extended-release tablets are indicated for the treatment of patients with intermittent claudication on the basis of chronic occlusive arterial disease of the limbs. Pentoxifylline 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. DOSAGE AND ADMINISTRATION The usual dosage of pentoxifylline in extended-release tablet form is one tablet (400 mg) three times a day with meals. While the effect of pentoxifylline may be seen within 2 to 4 weeks, it is recommended that treatment be continued for at least 8 weeks. Efficacy has been demonstrated in double-blind clinical studies of 6 months duration. 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 pentoxifylline should be discontinued. In patients with severe renal impairment (creatinine clearance below 30 mL/min) reduce dose to 400 mg once a day. Dosing information cannot be provided for patients with hepatic impairment. HOW SUPPLIED Pentoxifylline extended-release tablets, USP are available for oral administration as 400 mg white, oval, unscored, film coated tablets, imprinted “APO 033” on one side and plain on the other side; supplied in bottles of 100 (NDC 60505-0033-6), bottles of 500 (NDC 60505-0033-7), bottles of 1,000 (NDC 60505-0033-9) and bottles of 5,500 (NDC 60505-0033-8). Store at 20° to 25°C (68° to 77°F) [see Controlled Room Temperature]. Dispense in a tight, light-resistant container [see USP]. Manufactured by: Apotex Inc., Toronto, Ontario, Canada M9L 1T9. Manufactured for: Apotex Corp., Weston, Florida, 33326. Revised: May 2016

PATIENT INFORMATION TRENTAL® (Pentoxifylline) Sustained Release Tablets This leaflet is part III of a three-part “Product Monograph” published for Trental® and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about Trental. Contact your doctor or pharmacist if you have any questions about the drug. ABOUT THIS MEDICATION What the medication is used for: Trental has been prescribed to you by your health provider to treat your chronic vascular (blood flow) disorders in your extremities (legs and arms). What it does: Trental belongs to a group of medicines known as vasoactive drugs which improve peripheral blood flow and thus enhances peripheral tissue oxygenation. When it should not be used: Do not use Trental if: You are allergic to it or other xanthine such as caffeine, theophylline and theobromine and to any of the components of its formulation. You have any heart disease You have uncontrolled bleeding or are at risk of such You have peptic (stomach) ulcers What the medicinal ingredient is: Pentoxifylline What the nonmedicinal ingredients are: Benzyl alcohol, FD&C red no.3 (colouring agent), hydoxyethyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol 8000, povidone, talc, titanium dioxide. What dosage forms it comes in: Sustained released tablets of 400 mg Warnings and Precautions BEFORE you use Trental talk to your health provider if: You have liver disease or disorder You have kidney disease or disorder You have coagulation disorder You are pregnant You are a nursing mother You have low or labile blood pressure You have severe cardiac arrhythmias (irregular heart rate) You have diabetes Almost all patients can drive or operate machinery while taking Trental, but you should not perform these tasks, which may require attention, until you know how you tolerate your medicine. INTERACTIONS WITH THIS MEDICATION Sometimes drugs can interact with other drugs, so tell your doctor or pharmacist if you are taking any other medications, including prescription, non-prescription and natural health products. In particular, tell your doctor if you are taking any of the following: Drugs to reduce blood pressure (eg. ACE inhibitors, angiotensin II receptor antagonist) Sympathomimetics (eg amphetamines) Medication for asthma (eg. theophylline) Medication for diabetes Anticoagulants (eg. heparin, warfarin) Erythromycin (an antibiotic) Medication to treat ulcers (eg. cimetidine) PROPER USE OF THIS MEDICATION This drug is specifically prescribed for you. Do not give it to others, even if they have the same symptoms, and you yourself must not use it for any condition other than the one for which it was prescribed. It is important that you take Trental as prescribed by your doctor. Usual dose: Usually your doctor will prescribe Trental tablets at a dose of 400 mg twice or three times daily, which will be individualized based on your condition. A maximum of 400 mg three times daily should not be exceeded. Swallow the tablets whole with a glass of water after meals. You should always respect the prescribed interval between the doses. Never change the dose of Trental you are taking unless your doctor tells you to. Overdose In case of drug overdose, contact a health professional, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms. If you go to the doctor or the hospital, take the Trental container with you. SIDE EFFECTS AND WHAT TO DO ABOUT THEM Along with its beneficial effects, Trental like all other drugs, may sometimes cause undesirable effects. The most frequent ones are: nausea, vomiting, headache, dizziness (light-headedness), abdominal discomfort, bloating, diarrhoea, dyspepsia (heart burns) and flushing, and malaise SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM Symptom / effect Talk with your doctor or pharmacist Stop taking drug and call your doctor or pharmacist Only if severe In all cases Uncommon Allergic reaction or skin reaction (itching, swelling, red spots and blisters). yes Uncommon Chest pain. yes Uncommon Difficulty breathing. yes Uncommon Abnormal bleeding (bleeding around your eyes or blood in your stool). yes This is not a complete list of side effects. For any unexpected effects while taking Trental, contact your doctor or pharmacist. HOW TO STORE IT Store your tablets at room temperature (15° – 30°C). Protect from light. Protect from moisture and excessive heat. There is an expiration date on the label. Do not use the medicine after this date. Return any leftover tablets to the pharmacist, unless the doctor tells you to keep them at home. As with all medicines, keep Trental out of reach of children. REPORTING SUSPECTED SIDE EFFECTS You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways: Report online at: www.healthcanada.gc.ca/medeffect Call toll-free at 1-866-234-2345 Complete a Canada Vigilance Reporting Form and: Fax toll-free to 1-866-678-6789, or Mail to: Canada Vigilance Program Health Canada Postal Locator 0701D Ottawa, ON K1A 0K9 Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect™ Canada Web site at www.healthcanada.gc.ca/medeffect . NOTE: Should you require information related to the management of side effects, contact your health professional. The Canada Vigilance Program does not provide medical advice. MORE INFORMATION This document plus the full product monograph, prepared for health professionals, can be found at www.sanofiaventis.ca or by contacting the sponsor, sanofi-aventis Canada Inc., at: 1-800-265-7927 This leaflet was prepared by sanofi-aventis Canada Inc. Last revised: March 30, 2011

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE Overdosage with pentoxifylline has been reported in pediatric patients and adults. Symptoms appear to be dose related. A report from a poison control center on 44 patients taking overdoses of entericcoated pentoxifylline extended-release tablets noted that symptoms usually occurred 4 to 5 hours after ingestion and lasted about 12 hours. The highest amount ingested was 80 mg/kg; flushing, hypotension, convulsions, somnolence, loss of consciousness, fever, and agitation occurred. All patients recovered. In addition to symptomatic treatment and gastric lavage, special attention must be given to supporting respiration, maintaining systemic blood pressure, and controlling convulsions. Activated charcoal has been used to absorb pentoxifylline in patients who have overdosed. CONTRAINDICATIONS Pentoxifylline 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.

SIDE EFFECTS Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The most frequent adverse event reported with Trental (pentoxifylline) is nausea (14%). Individual signs/symptoms listed in the table below occurred at an incidence between 1 and 3%, except when stated otherwise. Symptoms Body as a whole Malaise Cardiovascular system Flushing Central nervous system Dizziness/light-headedness (9.4%), headache (4.9 %) Gastrointestinal system Nausea (14%), vomiting (3.4%), abdominal discomfort, bloating, diarrhea, dyspepsia Less Common Clinical Trial Adverse Drug Reactions ( < 1%) Body as a whole: Muscle aches/spasm, weight change, backache, bad taste in mouth, leg cramps, fever, weakness, sweating. Cardiovascular: Chest pain, arrhythmia, hypertension, dyspnea, edema, hypotension, angina, tachycardia. Central nervous system: Drowsiness/sleepiness, tremor, agitation anxiety, confusion, insomnia, restlessness. Gastrointestinal: Abdominal burning, abdominal pain, anorexia flatus, constipation, haemorrhage, heartburn, salivation, dry mouth/throat, hepatitis, jaundice, increased liver enzymes. Hemic and lymphatic: Decreased serum fibrinogen, pancytopenia, purpura, thrombocytopenia, leucopenia, anemia, aplastic anemia. Hypersensitivity reactions: Pruritis, rash, urticaria, angioedema. Organs of special sense: Blurred vision, scotoma, lacrimation, epistaxis. Post-Market Adverse Drug Reactions Hepatobiliary disorders: Intrahepatic cholestasis. Immune system disorders: Severe anaphylactic/anaphylactoid reaction with, for example, angioneurotic edema, bronchospasms, sometimes shock. Infections and infestations: Aseptic meningitis. Investigations: Transaminase elevation. Psychiatric: Sleep disturbances. Skin and subcutaneous tissue disorders: Reddening of skin. Vascular disorder: Haemorrhage DRUG INTERACTIONS Drug-Drug Interactions Antacids: In patients with digestive side effects, antacids may be administered with Trental. In comparative bioavailability study, no interference with absorption of Trental by antacids was observed. Antihypertensive agents: Trental (pentoxifylline) may potentiate the action of antihypertensive agents. Patients receiving these agents require blood pressure monitoring and possibly a dose reduction of the antihypertensive agents. Anticoagulants: There have been reports of bleeding and/or prolonged prothrombin time in patients treated with Trental with and without anticoagulants, including vitamin K antagonists, or platelet aggregation inhibitors. Monitoring of anti-coagulant activity in these patients is recommended when pentoxifylline is introduced or the dose is changed. Patients on warfarin should have more frequent monitoring of prothrombin time, while patients with other risk factors complicated by hemorrhage (e.g. recent surgery) should have periodic examinations for signs of bleeding, including hematocrit and haemoglobin. Cimetidine: During concurrent use of cimetidine and pentoxifylline, cimetidine has been shown to significantly increase the steady-state plasma concentration of pentoxifylline, which may enhance the possibility of adverse effects. Erythromycin: No data are available on the possible interaction of Trental and erythromycin. However concurrent administration of erythromycin and theomycin has resulted in significant elevation of serum theophylline levels with toxic reactions. Hypoglycemic agents: The blood-sugar lowering effect of insulin or oral antidiabetic agents may be potentiated. In patients treated with hypoglycemic agents, a moderate adjustment in the dose of these agents may be required when Trental is prescribed. Therefore it is recommended that patients under medication for diabetes mellitus be carefully monitored Sympathomimetics: Combined use with other xanthines or with sympathomimetics may cause excessive CNS stimulation. Theophylline: Although causality has not been established, concurrent use of pentoxifylline with theophylline has resulted in elevated theophylline plasma levels, which may enhance the possibility of adverse effects. Drug-Food Interactions Interactions with food have not been established. Drug-Herb Interactions Interactions with herbal product have not been established. Drug-Laboratory Interactions Interactions with laboratory tests have not been established. Drug-Lifestyle Interactions Interactions with lifestyles have not been established.

SIDE EFFECTS Clinical trials were conducted using either extended-release pentoxifylline tablets for up to 60 weeks or immediate-release pentoxifylline capsules for up to 24 weeks. Dosage ranges in the tablet studies were 400 mg bid to tid and in the capsule studies, 200 to 400 mg tid. The table summarizes the incidence (in percent) of adverse reactions considered drug related, as well as the numbers of patients who received extended-release pentoxifylline tablets, immediate-release pentoxifylline capsules, or the corresponding placebos. The incidence of adverse reactions was higher in the capsule studies (where dose related increases were seen in digestive and nervous system side effects) than in the tablet studies. Studies with the capsule include domestic experience, whereas studies with the extended-release tablets were conducted outside the U.S. The table indicates that in the tablet studies few patients discontinued because of adverse effects. INCIDENCE (%) OF SIDE EFFECTS (Number of Patients at Risk) Extended-Release Tables Immediate-Release Caps ules Commercially Available Used Only For Controlled Clinical Trials Pentoxifylline (321) Placebo (128) Pentoxifylline (177) Placebo (138) Discontinued for Side Effect 3.1 0 9.6 7.2 CARDIOVASCULAR SYSTEM Angina/Chest Pain 0.3 - 1.1 2.2 Arrhythmia/Palpitation - - 1.7 0.7 Flushing - - 2.3 0.7 DIGESTIVE SYSTEM Abdominal Discomfort - - 4.0 1.4 Belching/Flatus/Bloating 0.6 - 9.0 3.6 Diarrhea - - 3.4 2.9 Dyspepsia 2.8 4.7 9.6 2.9 Nausea 2.2 0.8 28.8 8.7 Vomiting 1.2 - 4.5 0.7 NERVOUS SYSTEM Agitation/Nervousness - - 1.7 0.7 Dizziness 1.9 3.1 11.9 4.3 Drowsiness - - 1.1 5.8 Headache 1.2 1.6 6.2 5.8 Insomnia - - 2.3 2.2 Tremor 0.3 0.8 - - Blurred Vision - - 2.3 1.4 Pentoxifylline has been marketed in Europe and elsewhere since 1972. In addition to the above symptoms, the following have been reported spontaneously since marketing or occurred in other clinical trials with an incidence of less than 1%; the causal relationship was uncertain: Cardiovascular - dyspnea, edema, hypotension. Digestive - anorexia, cholecystitis, constipation, dry mouth/thirst. Nervous - anxiety, confusion, depression, seizures, aseptic meningitis. 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. A few rare events have been reported spontaneously worldwide since marketing in 1972. Although they occurred under circumstances in which a causal relationship with pentoxifylline could not be established, they are listed to serve as information for physicians. Cardiovascular - angina, arrhythmia, tachycardia. Digestive - hepatitis, jaundice, cholestasis, increased liver enzymes; and Hemic and Lymphatic - decreased serum fibrinogen, pancytopenia, aplastic anemia, leukemia, purpura, thrombocytopenia. Immune system disorders - anaphylactic reaction, anaphylactoid reaction, anaphylactic shock. DRUG INTERACTIONS Bleeding has been reported in patients treated with pentoxifylline with or without concomitant NSAIDs, anticoagulants, or platelet aggregation inhibitors. Increased prothrombin time has been reported in patients concomitantly treated with pentoxifylline and vitamin K antagonists. Monitoring of anticoagulant activity in these patients is recommended when pentoxifylline is introduced or the dose is changed. Concomitant administration of pentoxifylline and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Monitor theophylline levels when starting pentoxifylline or changing dose. Concomitant administration of strong CYP1A2 inhibitors (including e.g. ciprofloxacin or fluvoxamine) may increase the exposure to pentoxifylline (see ADVERSE REACTIONS). Pentoxifylline has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline plus nifedipine or captopril; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. Postmarketing cases of increased anticoagulant activity have been reported in patients concomitantly treated with pentoxifylline and vitamin K antagonists. Monitoring of anticoagulant activity in these patients is recommended when pentoxifylline is introduced or the dose is changed. Concomitant administration with cimetidine is reported to increase the average steady state plasma concentration of pentoxifylline (~25%) and the Metabolite I (~30%).

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS General At the first signs of an anaphylactic/anaphylactoid reaction, Trental must be discontinued and a physician must be informed. Patients with hepatic impairment should be closely monitored during Trental therapy and may require lower doses. Since Trental (pentoxifylline) is extensively metabolized in the liver, the use of this drug is not recommended in patients with severe hepatic impairment of liver function (Child-Pugh class C, score > 9). Patients with renal impairment (creatinine clearance below 80 mL/min) should be closely monitored during Trental therapy and may require lower doses. Since Trental (pentoxifylline) is eliminated through the kidneys, the use of this drug is not recommended in patients with severe renal impairment (creatinine clearance below 30 mL/min). Cardiovascular Low, labile blood pressure Caution should be exercised when administering Trental (pentoxifylline) to patients with low or labile blood pressure. In such patients any dose increase should be done gradually and careful monitoring is required. Patients with severe cardiac arrhythmias should be closely monitored during Trental therapy. Hematologic The administration of Trental has been associated with bleeding and/or prolonged prothrombin time (see DRUG INTERACTIONS). The risk of bleeding may be increased by combined treatment with anticoagulant agents or use in coagulation disorders. Therefore, in patients with coagulation disorders or being treated with anticoagulant therapy, Trental should be used with caution and only, when in the physician's judgement, the potential benefit outweighs the risk. Careful monitoring is required. Special Populations Pregnant Women Reproduction studies have been performed in rats, mice and rabbits at doses up 23, 2 and 11 times the maximum recommended daily human dose and have revealed no evidence of impaired fertility or harm to the fetus due to pentoxifylline. The drug has been shown to cross the bloodplacenta barrier in mice. There is no adequate experience in pregnant women. Therefore, Trental is not recommended for women who are, or may become, pregnant unless the expected benefits for the mothers outweigh the potential risk to the fetus. Nursing Women Pentoxifylline and its major metabolites are excreted in human milk, following a 400 mg single oral dose of Trental. The patient should be advised to discontinue nursing or to discontinue taking the drug depending on the importance of the drug to the mother. Pediatrics The use of Trental in patients below the age of 18 years is not recommended as safety and effectiveness have not been established in this age group. Geriatrics Trental should be used with caution in elderly patients as peak plasma levels of pentoxifylline and its metabolites are moderately higher in this age group. Elderly patients had a slight increase in the incidence of some adverse effects. Careful dose adjustment is therefore recommended.

WARNINGS No information provided. PRECAUTIONS General At the first sign of anaphylactic/anaphylactoid reaction, pentoxifylline must be discontinued. Patients with chronic occlusive arterial disease of the limbs frequently show other manifestations of arteriosclerotic disease. Pentoxifylline has been used safely for treatment of peripheral arterial disease in patients with concurrent coronary artery and cerebrovascular diseases, but there have been occasional reports of angina, hypotension, and arrhythmia. Controlled trials do not show that pentoxifylline causes such adverse effects more often than placebo, but, as it is a methylxanthine derivative, it is possible some individuals will experience such responses. Patients on warfarin should have more 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. In patients with hepatic or renal impairment, the exposure to pentoxifylline and/or active metabolites is increased. The consequences of the increase in drug exposure are not known (see Pharmacokinetics and Metabolism and DOSAGE AND ADMINISTRATION). Carcinogenesis, Mutagenesis And Impairment Of Fertility Long-term studies of the carcinogenic potential of pentoxifylline were conducted in mice and rats by dietary administration of the drug at doses up to 450 mg/kg (approximately 19 times the maximum recommended human daily dose (MRHD) in both species when based on body weight; 1.5 times the MRHD in the mouse and 3.3 times the MRHD in the rat when based on body surface area). In mice, the drug was administered for 18 months, whereas in rats, the drug was administered for 18 months followed by an additional 6 months without drug exposure. In the rat study, there was a statistically significant increase in benign mammary fibroadenomas in females of the 450 mg/kg group. The relevance of this finding to human use is uncertain. Pentoxifylline was devoid of mutagenic activity in various strains of Salmonella (Ames test) and in cultured mammalian cells (unscheduled DNA synthesis test) when tested in the presence and absence of metabolic activation. It was also negative in the in vivo mouse micronucleus test. Pregnancy Category C. Teratogenicity studies have been performed in rats and rabbits using oral doses up to 576 and 264 mg/kg, respectively. On a weight basis, these doses are 24 and 11 times the maximum recommended human daily dose (MRHD); on a body-surface-area basis, they are 4.2 and 3.5 times the MRHD. No evidence of fetal malformation was observed. Increased resorption was seen in rats of the 576 mg/kg group. There are no adequate and well controlled studies in pregnant women. Pentoxifylline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Pentoxifylline 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. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of pentoxifylline did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The active metabolite V is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.