Trental 400

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

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.

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.

The use of Trental (pentoxifylline) is contraindicated in:

• Patients who are hypersensitive to pentoxifylline or other xanthines such as caffeine, theophylline and theobromine or to any ingredient in the formulation or component of the container (see Dosage Forms, Composition and Packaging).
• Patients with acute myocardial infraction;
• Patients with severe coronary artery disease when, in the physician's judgement, myocardial stimulation might prove harmful;
• Patients with hemorrhage (e.g. extensive retinal bleeding) or at risk of increased bleeding;
• Patients with peptic ulcers or recent history thereof.

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.

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.

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.

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.

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

Overdosage with Trental (pentoxifylline) has been reported in children and adults. Symptoms appear to be dose related and usually occurred 4-5 hours after ingestion and lasted about 12 hours. Initial manifestations of acute overdose with pentoxifylline may be nausea, dizziness, tachycardia, fever, gastrointestinal bleeding – coffee-ground vomiting and areflexia. The highest amount ingested was 80 mg/kg with which flushing, hypotension, convulsions, somnolence, loss of consciousness, fever, and agitation have been observed. All patients recovered.

No specific antidote is known. In addition to symptomatic treatment and gastric lavage, special attention must be given to supporting respiration, maintaining systemic blood pressure, and controlling convulsions with intravenous diazepam. Activated charcoal has been used to absorb pentoxifylline in patients who have overdosed.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

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.