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TRENTAL®
(pentoxifylline)
Extended-Release Tablets, 400 mg
DESCRIPTION
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.
After administration of the 400 mg extended-release TRENTAL 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 TRENTAL 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 about1.2 fold. The extended
release of pentoxifylline from the tablet eliminates peaks and troughs in plasma levels for
improved gastrointestinal tolerance.
TRENTAL has not been studied in patients with severe hepatic failure.
TRENTAL is indicated for the treatment of patients with intermittent claudication on the basis of
chronic occlusive arterial disease of the limbs. TRENTAL 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.
CONTRAINDICATIONS
TRENTAL 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.
PRECAUTIONS
General
Patients with chronic occlusive arterial disease of the limbs frequently show other manifestations
of arteriosclerotic disease. TRENTAL 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 TRENTAL 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).
Drug Interactions
Bleeding has been reported in patients treated with Trental 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.
TRENTAL 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 TRENTAL; periodic systemic blood pressure
monitoring is recommended for patients receiving concomitant antihypertensive therapy. If
indicated, dosage of the antihypertensive agents should be reduced.
Concomitant administration with cimetidine is reported to increase the average steady state
plasma concentration of pentoxifylline (~25%) and the Metabolite I (~30%).
.
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. TRENTAL (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
Geriatric Use
Clinical studies of TRENTAL 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.
ADVERSE REACTIONS
Clinical trials were conducted using either extended-release TRENTAL tablets for up to 60
weeks or immediate-release TRENTAL capsules for up to 24 weeks. Dosage ranges in the tablet
studies were 400 mg bid to tid and in the capsule studies, 200-400 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 TRENTAL tablets, immediate-release TRENTAL
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.
TRENTAL 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.
OVERDOSAGE
Overdosage with TRENTAL 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 enteric-coated pentoxifylline extended-release tablets noted that symptoms usually occurred 4
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.
The usual dosage of TRENTAL in extended-release tablet form is one tablet (400 mg) three
times a day with meals.
While the effect of TRENTAL 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 TRENTAL should be discontinued.
In patients with severe renal impairment (creatinine clearance below 30 mL/min) reduce dose to
400 mg once a day.
HOW SUPPLIED
1-866-9VALIDUS (1-866-982-5438)
info@validuspharma.com