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DESCRIPTION:
Persantine(R) (dipyridamole USP) is a platelet inhibitor chemically described as
2,6-bis- (diethanolamino)-4,8-dipiperidino-pyrimido- (5,4-d) pyrimidine.
C24H40N8O4 Mol. Wt. 504.63
Dipyridamole is an odorless yellow crystalline powder, having a bitter taste. It
is soluble in dilute acids, methanol and chloroform, and practically insoluble
in water.
Persantine tablets for oral administration contain:
ACTIVE INGREDIENT: TABLETS 25, 50 And 75 Mg: dipyridamole USP 25, 50 and 75 mg
respectively.
INACTIVE INGREDIENTS: TABLETS 25, 50 And 75 Mg: acacia, carnauba wax,
cornstarch, FD&C blue No. 1 aluminum lake, D&C yellow No. 10 aluminum lake, D&C
red No. 30 aluminum lake, lactose, magnesium stearate, polyethylene glycol,
povidone, shellac, sodium benzoate, sucrose, talc, titanium dioxide, white wax.
ACTIONS/CLINICAL PHARMACOLOGY:
It is believed that platelet reactivity and interaction with prosthetic cardiac
valve surfaces, resulting in abnormally shortened platelet survival time, is a
significant factor in thromboembolic complications occurring in connection with
prosthetic heart valve replacement.
Persantine(R) (dipyridamole USP) has been found to lengthen abnormally shortened
platelet survival time in a dose-dependent manner.
In three randomized controlled clinical trials involving 854 patients who had
undergone surgical placement of a prosthetic heart valve, Persantine, in
combination with warfarin, decreased the incidence of postoperative
thromboembolic events by 62% to 91% compared to warfarin treatment alone. The
incidence of thromboembolic events in patients receiving the combination of
Persantine and warfarin ranged from 1.2% to 1.8%. In three additional studies
involving 392 patients taking Persantine and coumarin-like anticoagulants, the
incidence of thromboembolic events ranged from 2.3% to 6.9%.
In these trials, the coumarin anticoagulant was begun between 24 hours and 4
days postoperatively, and the Persantine was begun between 24 hours and 10 days
postoperatively. The length of follow-up in these trials varied from 1 to 2
years.
Persantine does not influence prothrombin time or activity measurements when
administered with warfarin.
MECHANISM OF ACTION: Persantine is a platelet adhesion inhibitor, although the
mechanism of action has not been fully elucidated. The mechanism may relate to
inhibition of red blood cell uptake of adenosine, itself an inhibitor of
platelet reactivity, phosphodiesterase inhibition leading to increased cyclic-
3', 5'-adenosine monophosphate within platelets, and inhibition of thromboxane
A2 formation, which is a potent stimulator of platelet activation.
HEMODYNAMICS: In dogs intraduodenal doses of Persantine of 0.5 to 4.0 mg/kg
produced dose- related decreases in systemic and coronary vascular resistance
leading to decreases in systemic blood pressure and increases in coronary blood
flow. Onset of action was in about 24 minutes and effects persisted for about 3
hours.
Similar effects were observed following IV Persantine in doses ranging from
0.025 to 2.0 mg/kg.
In man the same qualitative hemodynamic effects have been observed. However,
acute intravenous administration of Persantine may worsen regional myocardial
perfusion distal to partial occlusion of coronary arteries.
PHARMACOKINETICS AND METABOLISM: Following an oral dose of Persantine, the
average time to peak concentration is about 75 minutes. The decline in plasma
concentration following a dose of Persantine fits a two-compartment model. The
alpha half-life (the initial decline following peak concentration) is
approximately 40 minutes. The beta half-life (the terminal decline in plasma
concentration) is approximately 10 hours. Persantine is highly bound to plasma
proteins. It is metabolized in the liver where it is conjugated as a glucuronide
and excreted with the bile.
INDICATIONS AND USAGE:
Persantine(R) (dipyridamole USP) is indicated as an adjunct to coumarin
anticoagulants in the prevention of postoperative thromboembolic complications
of cardiac valve replacement.
CONTRAINDICATIONS:
None known.
PRECAUTIONS:
GENERAL: Persantine(R) (dipyridamole USP) should be used with caution in
patients with hypotension since it can produce peripheral vasodilation.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: In a 111 week oral study
in mice and in a 128-142 week oral study in rats, Persantine produced no
significant carcinogenic effects at doses of 8, 25 and 75 mg/kg (1, 3.1 and 9.4
times the maximum recommended daily human dose). Mutagenicity testing with
Persantine was negative. Reproduction studies with Persantine revealed no
evidence of impaired fertility in rats at dosages up to 60 times the maximum
recommended human dose. A significant reduction in number of corpora lutea with
consequent reduction in implantations and live fetuses was, however, observed at
155 times the maximum recommended human dose.
TERATOGENIC EFFECTS: PREGNANCY CATEGORY B Reproduction studies have been
performed in mice at doses up to 125 mg/kg (15.6 times the maximum recommended
daily human dose), rats at doses up to 1000 mg/kg (125 times the maximum
recommended daily dose) and rabbits at doses up to 40 mg/kg (5 times the maximum
recommended daily human dose) and have revealed no evidence of harm to the fetus
due to Persantine. There are, however, no adequate and well-controlled studies
in pregnant women. Because animal reproduction studies are not always predictive
of human response, this drug should be used during pregnancy only if clearly
needed.
NURSING MOTHERS: As dipyridamole is excreted in human milk, caution should be
exercised when Persantine is administered to a nursing woman.
PEDIATRIC USE: Safety and effectiveness in the pediatric population below the
age of 12 years have not been established.
ADVERSE REACTIONS:
Adverse reactions at therapeutic doses are usually minimal and transient. On
long-term use of Persantine(R) (dipyridamole USP) initial side effects usually
disappear. The following reactions were reported in two heart valve replacement
trials comparing Persantine and warfarin therapy to either warfarin alone or
warfarin and placebo:
PERSANTINE/ PLACEBO/
WARFARIN WARFARIN
(N = 147) (N = 170)
Dizziness 13.6% 8.2%
Abdominal
distress 6.1% 3.5%
Headache 2.3% 0.0
Rash 2.3% 1.1%
Other reactions from uncontrolled studies include diarrhea, vomiting, flushing
and pruritus. In addition, angina pectoris has been reported rarely and there
have been rare reports of liver dysfunction. On those uncommon occasions when
adverse reactions have been persistent or intolerable, they have ceased on
withdrawal of the medication.
When Persantine was administered concomitantly with warfarin, bleeding was no
greater in frequency or severity than that observed when warfarin was
administered alone.
OVERDOSAGE:
Hypotension, if it occurs, is likely to be of short duration, but a vasopressor
drug may be used if necessary. The oral LD50 in mice is 2,150mg/kg. Single oral
doses of 6,000 mg/kg in rats and 350 mg/kg in dogs were lethal. Symptoms of
acute toxicity included ataxia, decreased locomotion and diarrhea in rodents and
emesis, ataxia and depression in dogs. Since Persantine(R) (dipyridamole USP) is
highly protein bound, dialysis is not likely to be of benefit.
DOSAGE AND ADMINISTRATION:
Adjunctive Use In Prophylaxis Of Thromboembolism After Cardiac Valve Replacement
The recommended dose is 75-100 mg four times daily as an adjunct to the usual
warfarin therapy. Please note that aspirin is not to be administered
concomitantly with coumarin anticoagulants.
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