PENTOXIFYLLINE
DESCRIPTION:
TRENTAL (pentoxifylline) tablets for oral administration contain 400 mg of
the active drug.
TRENTAL is a tri-substituted xanthine derivative designated chemically as 1-
(5-oxohexyl)-3, 7-dimethylxanthine that, unlike theophylline, is a
hemorrheologic agent, i.e. and agent that affects blood viscosity.
Pentoxifylline is soluble in water and ethanol, and sparingly soluble in
Toluene
ACTIONS/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 (non-linear), 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 pharmacokinetics and metabolism of TRENTAL have not
been studied in patients with renal and/or hepatic dysfunction, but AUC was
increased and elimination rate decreased in an older population (60-68 years)
compared to younger individuals (22-30 years).
After administration of the 400 mg controlled- 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. The controlled
release of pentoxifylline from the tablet eliminates peaks and troughs in plasma
levels for improved gastrointestinal tolerance.
INDICATIONS AND USAGE:
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.
DRUG INTERACTIONS: Although a causal relationship has not been established,
there have been reports of bleeding and/or prolonged prothrombin time in
patients treated with TRENTAL with and without anticoagulants or platelet
aggregation inhibitors. 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) should have
periodic examinations for bleeding including hematocrit and/or hemoglobin.
Concomitant administration of TRENTAL 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. TRENTAL 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 TRENTAL; periodic
systemic blood pressure monitoring is recommended for patients receiving
concomitant antihypertensive therapy. If indicated, dosage of the
antihypertensive agents should be reduced.
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. Teratogenic 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: Safety and effectiveness in pediatric patients have not been
established.
DRUG INTERACTIONS:
Although a causal relationship has not been established, there have been reports
of bleeding and/or prolonged prothrombin time in patients treated with
TRENTAL with and without anticoagulants or platelet aggregation inhibitors.
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) should have periodic examinations for bleeding
including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL
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. TRENTAL 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 TRENTAL; periodic systemic blood pressure
monitoring is recommended for patients receiving concomitant antihypertensive
therapy. If indicated, dosage of the antihypertensive agents should be reduced.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
Clinical trials were conducted using either controlled-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 controlled-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
controlled-release tablets were conducted outside the U.S. The table indicates
that in the tablet studies few patients discontinued because of adverse effects.
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INCIDENCE (%) OF SIDE EFFECTS
Controlled-Release Immediate-Release
TABLETS CAPSULES
Commercially Used only for
Available Controlled Clinical
Trials
TRENTAL PLACEBO TRENTAL PLACEBO
(NUMBERS OF PATIENTS AT (321) (128) (177) (138)
RISK)
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
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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.
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
anaphylactoid reactions." Digestive--hepatitis, jaundice, increased liver
enzymes; and Hemic and Lymphatic--decreased serum fibrinogen, pancytopenia,
aplastic anemia, leukemia, purpura, thrombocytopenia.
OVERDOSAGE:
Overdosage with TRENTAL has been reported in children and adults. Symptoms
appear to be dose related. A report from a poison control center on 44 patients
taking overdoses of enteric-coated pentoxifylline 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.
DOSAGE AND ADMINISTRATION:
The usual dosage of TRENTAL in controlled- 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 side 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.