Persantine

Xanthine derivatives (e.g., found in coffee, tea) may weaken the effect of Persantine and therefore should be avoided 24 hours before myocardial imaging with Persantine.

The recommended oral dose is 100 mg q.i.d., one hour before meals. The maximum daily dose is 600 mg. A lower dose of 100 mg of Persantine (dipyridamole) daily together with 1 g ASA daily, prolongs platelet survival to the same extent.

The dose of intravenous Persantine used as an adjunct to myocardial perfusion imaging should be adjusted according to the weight of the patient.

Immediately prior to infusion, Persantine i.v. should be diluted at least 1:2 with Dextrose Injection, USP 5%. The recommended dose is 0.142 mg/kg/min., infused over 4 minutes.

A total dose of greater than 60 mg is not recommended for use in any patient. The imaging agent should be injected within 5 minutes following the 4 minute infusion of Persantine. Do not mix i.v. Persantine with other drugs in the same syringe or infusion container. Infusion of undiluted Persantine may cause local irritation.

As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

dyspepsia, dry mouth, abdominal pain, flatulence, vomiting, eructation, dysphagia, tenesmus, increased appetite.

hypoaesthesia, hypertonia, nervousness/anxiety, tremor, abnormal coordination, somnolence, dysphonia, migraine, vertigo.

Adverse reactions at therapeutic doses are usually minimal and transient. Occasionally diarrhoea, vomiting, headache, dizziness, nausea, flushing, syncope or weakness, myalgia, and skin rash have occurred during initiation of therapy. Mild occasional gastric distress can be avoided by administration of the tablets with a glass of milk. Gastric irritation, emesis and abdominal cramping may occur at high dosage levels. Rare cases of what appears to be an aggravation of angina pectoris have been reported, usually at the initiation of therapy.

On those uncommon occasions when adverse reactions have been persistent or intolerable to the patient, withdrawal of the medication has been followed promptly by cessation of the undesirable symptoms.

When Persantine (dipyridamole) is used in combination with ASA, the only side effect clearly attributable to Persantine is headache. This symptom shows an increase of 5.5% in the combination treated group over that occurring in a group of patients treated with ASA alone. Other adverse reactions which occur during combination therapy are similar to those mentioned above, together with the well documented side effects of ASA therapy, notably gastric distress and gastrointestinal bleeding.

At the higher doses of Persantine there may be an increase in the incidence of adverse reactions.

In very rare cases, increased bleeding during or after surgery has been reported.

Serious adverse events (fatal and non-fatal myocardial infarction, severe ventricular arrhythmias, and serious CNS abnormalities) associated with the intravenous administration of Persantine for myocardial imaging are described in Warnings and Precautions.

As a result of its vasodilator properties, Persantine may cause hypotension, hot flushes, and tachycardia. Worsening of symptoms of coronary heart disease has been observed.

Hypersensitivity reactions such as rash, urticaria, severe bronchospasm and angio-oedema have been reported.

Dipyridamole has been shown to be incorporated into gallstones (see Warnings and Precautions).

Isolated cases of thrombocytopenia have been reported in conjunction with treatment with Persantine.

myalgia, back pain, injection site reaction unspecified, diaphoresis, asthenia, malaise, arthralgia, injection site pain, rigor, earache, tinnitus, vision abnormalities unspecified, dysgeusia, thirst, depersonalization, eye pain, renal pain, perineal pain, breast pain, intermittent claudication, leg cramping.

pharyngitis, bronchospasm, hyperventilation, rhinitis, coughing, pleural pain.

electrocardiographic abnormalities unspecified, arrhythmia unspecified, palpitation, ventricular tachycardia, bradycardia, myocardial infarction, AV block, syncope, orthostatic hypotension, atrial fibrillation, supraventricular tachycardia, ventricular arrhythmia unspecified, heart block unspecified, cardiomyopathy, and edema.

Persantine (dipyridamole) ampoules can be used to:

• Induce pharmacologic vasodilation for myocardial perfusion imaging.

Persantine (dipyridamole) tablets are indicated for:

• The prevention of post-operative thromboembolic complications associated with prosthetic heart valve.

No cases of overdose in humans have been reported in this indication. Signs and symptoms as described under Side Effects are expected to occur. Aminophylline, as described in Warnings and Precautions may be administered. Due to its wide distribution to tissue and its predominantly hepatic elimination, dipyridamole is not likely to be accessible to enhanced removal procedures.

Symptomatic therapy is recommended. A gastric decontamination procedure should be considered. Administration of xanthine derivatives (e.g. aminophylline) may reverse the haemodynamic effects of dipyridamole overdose. Due to its wide distribution to tissues and its predominantly hepatic elimination, dipyridamole is not likely to be accessible to enhanced removal procedures.

Each coral-red, round, sugar-coated tablet, imprinted with the Ingelheim tower on one side contains: dipyridamole 50 mg. Nonmedicinal ingredients: acacia, calcium hydrogen phosphate, carnauba wax, colloidal silica, FD&C Yellow No. 6, magnesium stearate, maize starch, polyethylene glycol, red iron oxide, sucrose, talc, titanium dioxide and white wax. Bottles of 100.

Each mL contains: dipyridamole 5 mg. Nonmedicinal ingredients: hydrochloric acid, polyethylene glycol, tartaric acid and sterile water for injection (SWFI). Ampuls of 10 mL, packages of 5.

Each reddish-orange, round, sugar-coated tablet, imprinted with the Ingelheim tower on one side contains: dipyridamole 75 mg. Nonmedicinal ingredients: acacia, calcium hydrogen phosphate, carnauba wax, colloidal silica, FD&C Yellow No. 6, magnesium stearate, maize starch, methyl and propyl parabens, polyethylene glycol, sucrose, talc, titanium dioxide and white wax. Bottles of 100.

A small number of cases have been reported in which unconjugated dipyridamole was shown to be incorporated into gallstones to a variable extent (up to 70% by dry weight of stone). These patients were all elderly, had evidence of ascending cholangitis and had been treated with oral dipyridamole for a number of years. There is no evidence that dipyridamole was the initiating factor in causing gallstones to form in these patients. It is possible that bacterial deglucuronidation of conjugated dipyridamole in bile may be the mechanism responsible for the presence of dipyridamole in gallstones.

Rare serious adverse reactions associated with the administration of intravenous Persantine for myocardial imaging have been reported. These have included fatal and non-fatal myocardial infarction, ventricular fibrillation, symptomatic ventricular tachycardia, stroke and transient cerebral ischemia.

Patients with a history or presence of bronchial hyperreactivity may be at risk of developing bronchospasm during the use of intravenous Persantine as an adjunct to myocardial perfusion imaging. Although the actual overall incidence of this occurrence is small (~0.2%), the clinical information to be gained through the use of intravenous Persantine should be weighed against the potential risk to the patient.

Reproductive studies have been performed in mice, rats, and rabbits at doses of up to 125 mg/kg and have not revealed evidence of impaired embryonic development attributable to dipyridamole. However, there have not been adequate, well controlled studies in pregnant women and the drug should be used during pregnancy only if the expected benefits outweigh the potential risks.

The safety and effectiveness of Persantine have not been established in the pediatric population.

Dipyridamole is excreted in human milk. Caution should therefore be used when this drug is administered to nursing mothers.

Since excessive doses of dipyridamole (intravenous or oral) or intravenous doses given too rapidly can produce peripheral vasodilation, Persantine should be used with caution in patients with hypotension, coronary artery disease, including rapidly worsening angina, left ventricular outflow obstruction, (including subvalvular aortic stenosis), or hemodynamic instability. In rare cases, such patients may be at risk for developing myocardial ischemia and infarction.

Clinical experience suggests that patients being treated with oral dipyridamole who also require pharmacological stress testing with intravenous dipyridamole, should discontinue drugs containing oral dipyridamole for twenty-four hours prior to stress testing. Failure to do so may impair the sensitivity of the test.

An intravenous bolus of Persantine (40-50 mg over 4 minutes) can result in chest pain in patients with coronary artery disease. Rarely, hypotension or ventricular arrhythmias occur with a rapid, i.v. bolus. The infusion rate should be monitored to minimize this risk. The symptoms can generally be reversed with an intravenous injection of 50-250 mg of aminophylline over several minutes.

Intravenous Persantine (dipyridamole) as an adjunct to myocardial perfusion imaging should be used with caution in patients with unstable angina; as such patients may be at risk for severe myocardial infarction.

As with exercise induced stress, the use of intravenous Persantine as an adjunct to myocardial perfusion imaging may occasionally precipitate cardiac arrhythmias in patients with severe heart disease. Scanning should therefore be performed with constant monitoring of the patient's ECG. Parenteral aminophylline should be readily available and should be administered as a slow intravenous injection of 50-250 mg in the event of occurrences such as chest pain, bronchospasm, severe nausea/vomiting, hypotension, severe headache.

In the case of severe hypotension, the patient should be placed in a supine position with the head tilted down if necessary, before administration of parenteral aminophylline. If 250 mg of aminophylline does not relieve chest pain symptoms within a few minutes, sublingual nitroglycerin may be administered. If chest pain continues despite use of aminophylline and nitroglycerin, the possibility of myocardial infarction should be considered. If the clinical condition of a patient with an adverse event permits a one minute delay in the administration of parenteral aminophylline, thallium-201 may be injected and allowed to circulate for one minute before the injection of aminophylline. This will allow initial thallium perfusion imaging to be performed before reversal of the pharmacologic effects of Persantine on the coronary circulation.

Following intravenous administration, the distribution half-life in man is about 25 minutes and after oral administration about 3 hours. When plasma levels of drug are followed for up to 60 hours after i.v. or oral administration of 20 to 50 mg, plasma levels decline tri-exponentially with half-lives of 5 minutes (i.v. only), 53 minutes and about 10-12 hours. The volume of distribution is about 140 L with about 92-99% binding to plasma proteins, primarily alpha1-acid glycoprotein.

Dipyridamole is readily absorbed from the gastrointestinal tract, reaching peak plasma levels in man 1-3 hours following oral administration. Peak plasma levels are dose-dependent and range from about 0.5 µg/mL after a 25 mg dose to 1.6 µg/mL after a 75 mg dose. Blood levels are quite variable, possibly depending on food intake and gastrointestinal peristalsis. Ingestion on an empty stomach may result in higher blood levels.

Persantine (dipyridamole) normalizes increased platelet adhesiveness and tendency to aggregate (Hellem's Method). Persantine has been found to lengthen abnormally shortened platelet survival time in a dose-dependent manner; 400 mg/day or 100 mg/day plus 1 g ASA.

It is believed that platelet reactivity and interaction with prosthetic cardiac valve surfaces, resulting in abnormal shortened platelet survival time is a significant factor in connection with prosthetic heart valve replacement.

In a controlled clinical trial involving patients who had undergone surgical placement of prosthetic heart valves (mitral and/or aortic valve replacement), Persantine, in combination with anticoagulants, significantly decreased the incidence of post-operative thromboembolic events, without increasing hemorrhagic complications. The incidence of thromboembolic events in patients receiving dipyridamole in a dose of 400 mg/day in combination with anticoagulants was 1.3% compared to 14.3% to the control group treated with anticoagulant alone.

In vitro dipyridamole potentiates the aggregation-inhibiting effects of adenosine and prostaglandin E₁, inhibits platelet uptake of adenosine, serotonin and glucose, and increases platelet cyclic AMP levels. At higher concentrations dipyridamole inhibits platelet aggregation induced by ADP or collagen.

Myocardial blood flow increases in a dose-dependent fashion after i.v. or oral dipyridamole, with flows 170% or more above normal. Maximal increases are achieved at about 2.0 µg/mL with 0.8 µg/mL being the threshold serum level. Single oral doses of 150 mg dipyridamole produce the maximal response. At normal therapeutic doses, no significant alterations of peripheral blood flow, systemic blood pressure, or heart rate have been observed.

Persantine is a coronary vasodilator in man. The mechanism of vasodilation has not been fully elucidated, but may result from inhibition of uptake of adenosine, an important mediator of coronary vasodilation. The vasodilatory effects of Persantine are abolished by administration of the adenosine receptor antagonist theophylline.

How Persantine-induced vasodilation leads to abnormalities in thallium distribution (when administered intravenously for myocardial perfusion imaging) and ventricular function is also uncertain, but presumably represents a “steal” phenomenon. In this situation, relatively intact vessels dilate, and sustain enhanced flow, leaving reduced pressure and flow across areas of hemodynamically important coronary vascular constriction.