Pr TRENTAL(r) (pentoxifylline film-coated sustained release tablets, 400 mg) Vasoactive agent ATC Code : C04AD03 sanofi-aventis Canada Inc. 2150 St. Elzear Blvd. West Laval, Quebec H7L 4A8 Date of Revision: March 23, 2007 Submission Control No: 110539
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 5 DRUG INTERACTIONS 6 DOSAGE AND ADMINISTRATION 7 OVERDOSAGE 8 ACTION AND CLINICAL PHARMACOLOGY 8 STORAGE AND STABILITY 9 DOSAGE FORMS, COMPOSITION AND PACKAGING 9
PHARMACEUTICAL INFORMATION 10 DETAILED PHARMACOLOGY 10 TOXICOLOGY 13 REFERENCES 17
PrTRENTAL(r) (Pentoxifylline)
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Sustained release tablet 400 mg | For a complete listing see Dosage Forms, Composition and Packaging section. |
Trental(r) (pentoxifylline) is indicated for the symptomatic treatment of: patients with chronic occlusive peripheral vascular disorders of the extremities; In such patients Trental(r) may give relief of signs and symptoms of impaired blood flow, such as intermittent claudication or trophic ulcers.
The use of Trental(r) (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.
General
Patients with hepatic impairment should be closely monitored during Trental(r) therapy and may require lower doses. Since Trental(r) (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(r) therapy and may require lower doses. Since Trental(r) (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(r) (pentoxifylline) to patients with low or labile blood pressure. In such patients any dose increase should be done gradually.
Hematologic
The administration of Trental(r) 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(r) should be used with caution and only when in the physician's judgement the potential benefit outweighs the risk.
Special Populations
Reproduction studies have been performed in rats, mice and rabbits at dose 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 blood- placenta barrier mice. There is no adequate experience in pregnant women. Therefore, Trental(r) 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.
Pentoxifylline and its major metabolites are excreted in human milk, following a 400 mg single oral dose of Trental(r). The patient should be advised to discontinue nursing or to discontinue taking the drug depending on the importance of the drug to the mother.
The use of Trental(r) in patients below the age of 18 years is not recommended as safety and effectiveness have not been established in this age group.
Trental(r) 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.
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(r) (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: Organs of special sense: Post-Market Adverse Drug Reactions
Pruritis, rash, urticaria, angioedema.
Blurred vision, scotoma, lacrimation, epistaxis.
Hepatobiliary disorders:
Intrahepatic cholestasis.
Immune system disorders:
Severe anaphylactic/anaphylactoid reaction with, for example, angioneurotic edema, bronchospasms, sometimes shock.
Infections and infestations: Investigations: Psychiatric:
Aseptic meningitis.
Transaminase elevation.
Sleep disturbances.
Skin and subcutaneous tissue disorders:
Reddening of skin.
Drug-Drug Interactions
Antacids: In patients with digestive side effects, antacids may be administered with Trental(r). In comparative bioavailability study, no interference with absorption of Trental(r) by antacids was observed. Antihypertensive agents: Trental(r) (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(r) with and without anticoagulants or platelet aggregation inhibitors. 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.
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(r) 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(r) is prescribed.
Combined use with other xanthines or with sympathomimetics may cause excessive CNS stimulation.
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.
Recommended Dose and Dosage Adjustment
The recommended starting dosage of Trental(r) (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(r) 400 mg sustained release tablets must be swallowed whole.
Overdosage with Trental(r) (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 give 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.
Mechanism of Action
Trental(r) (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(r) achieves this effect has not been determined, but it is likely that the following factors are involved: Trental(r), as other xanthine derivative, 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(r) 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(r) but the correlation between it and the clinical improvement of patients with peripheral vascular diseases has not been determined. Trental(r) 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(r) 400 mg sustained release tablet showed an initial peak plasma pentoxifylline concentration 2 to 3 hours post-administration. The drug is extensively metabolized. Biotransformation products are almost exclusively eliminated by the kidneys. Food intake before the administration of Trental(r) delayed the absorption but did not decrease it.
Store at room temperature (15 to 30 degC).
Composition
Trental(r) sustained release tablets 400 mg contain 400 mg medicinal ingredient, pentoxifylline. The qualitative formulation of Trental(r) tablets is: pentoxifylline, FD&C red no.3, hydroxyethyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol 8000, povidone, talc, titanium dioxide.
Availability
Trental(r) (pentoxifylline) is available as 400 mg, pink, oblong, film-coated, sustained release tablets, packed in Unit Pack boxes of 60 [6 x 10 clear PVC film and aluminium foil blister- packed] tablets. One face is embossed with "Trental", the other face is plain.