DIPYRIDAMOLE: 1,481 Adverse Event Reports & Safety Profile

DESCRIPTION Dipyridamole USP is a platelet inhibitor chemically described as 2,2',2'',2'''-[(4,8­ Dipiperidinopyrimido[5,4- d ]pyrimidine-2,6-diyl)dinitrilo]-tetraethanol. It has the following structural formula: 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. Dipyridamole tablets for oral administration contain: Active Ingredient TABLETS 25 mg, 50 mg, and 75 mg : dipyridamole USP 25 mg, 50 mg and 75 mg, respectively.

Inactive

Ingredients TABLETS 25 mg, 50 mg, and 75 mg : Carnauba wax, D&C yellow no. 10, FD&C yellow no. 6, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, methylparaben, microcrystalline cellulose, polyethylene glycol, potassium sorbate, povidone, propylene glycol, propylparaben, silicon dioxide, sodium citrate, sodium starch glycolate, stearic acid, talc, titanium dioxide, and xanthan gum.

Indications and Usage Dipyridamole Injection is indicated as an alternative to exercise in thallium myocardial perfusion imaging for the evaluation of coronary artery disease in patients who cannot exercise adequately. In a study of about 1100 patients who underwent coronary arteriography and Dipyridamole Injection assisted thallium imaging, the results of both tests were interpreted blindly and the sensitivity and specificity of the dipyridamole thallium study in predicting the angiographic outcome were calculated. The sensitivity of the dipyridamole test (true positive dipyridamole divided by the total number of patients with positive angiography) was about 85%. The specificity (true negative divided by the number of patients with negative angiograms) was about 50%. In a subset of patients who had exercise thallium imaging as well as dipyridamole thallium imaging, sensitivity and specificity of the two tests were almost identical.

Dosage and Administration The dose of intravenous Dipyridamole Injection as an adjunct to thallium myocardial perfusion imaging should be adjusted according to the weight of the patient. The recommended dose is 0.142 mg/kg/min (0.57 mg/kg total) infused over 4 minutes. Although the maximum tolerated dose has not been determined, clinical experience suggests that a total dose beyond 60 mg is not needed for any patient. Prior to intravenous administration, Dipyridamole Injection should be diluted in at least a 1:2 ratio with sodium chloride injection 0.45%, sodium chloride injection 0.9% or dextrose injection 5% for a total volume of approximately 20 to 50 mL. Infusion of undiluted dipyridamole may cause local irritation. Thallium-201 should be injected within 5 minutes following the 4-minute infusion of dipyridamole. Do not mix Dipyridamole Injection with other drugs in the same syringe or infusion container. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

CONTRAINDICATIONS Hypersensitivity to dipyridamole and any of the other components.

ADVERSE REACTIONS Adverse reaction information concerning intravenous Dipyridamole Injection is derived from a study of 3911 patients in which intravenous dipyridamole was used as an adjunct to thallium myocardial perfusion imaging and from spontaneous reports of adverse reactions and the published literature. Serious adverse events (cardiac death, fatal and non-fatal myocardial infarction, ventricular fibrillation, asystole, sinus node arrest, symptomatic ventricular tachycardia, stroke, transient cerebral ischemia, seizures, anaphylactoid reaction and bronchospasm) are described above (see WARNINGS ). In a study of 3911 patients, the most frequent adverse reactions were: chest pain/angina pectoris (19.7%), electrocardiographic changes (most commonly ST-T changes) (15.9%), headache (12.2%) and dizziness (11.8%). Adverse reactions occurring in greater than 1% of the patients in the study are shown in the following table: Incidence (%) of Drug-Related Adverse Events Chest pain/angina pectoris

19.7 Headache

12.2 Dizziness

11.8 Electrocardiographic Abnormalities/ST-T changes

7.5 Electrocardiographic Abnormalities/Extrasystoles

5.2 Hypotension

4.6 Nausea

4.6 Flushing

3.4 Electrocardiographic Abnormalities/Tachycardia

3.2 Dyspnea

2.6 Pain Unspecified

2.6 Blood Pressure Lability

1.6 Hypertension

1.5 Paresthesia

1.3 Fatigue

1.2 Less common adverse reactions occurring in 1% or less of the patients within the study included: Cardiovascular System Electrocardiographic abnormalities unspecified (0.8%), arrhythmia unspecified (0.6%), palpitation (0.3%), ventricular tachycardia (0.2%-see WARNINGS ), bradycardia (0.2%), myocardial infarction (0.1%–see WARNINGS ), AV block (0.1%), syncope (0.1%), orthostatic hypotension (0.1%), atrial fibrillation (0.1%), supraventricular tachycardia (0.1%), ventricular arrhythmia unspecified (0.03%–see WARNINGS ), heart block unspecified (0.03%), cardiomyopathy (0.03%), edema (0.03%). Central and Peripheral Nervous System Hypothesia (0.5%), hypertonia (0.3%), nervousness/anxiety (0.2%), tremor (0.1%), abnormal coordination (0.03%), somnolence (0.03%), dysphonia (0.03%), migraine (0.03%), vertigo (0.03%).

Gastrointestinal System

Dyspepsia (1%), dry mouth (0.8%), abdominal pain (0.7%), flatulence (0.6%), vomiting (0.4%), eructation (0.1%), dysphagia (0.03%), tenesmus (0.03%), appetite increase (0.03%).

Respiratory System

Pharyngitis (0.3%), bronchospasm (0.2%–see WARNINGS ), hyperventilation (0.1%), rhinitis (0.1%), coughing (0.03%), pleural pain (0.03%).

Other

Myalgia (0.9%), back pain (0.6%), injection site reaction unspecified (0.4%), diaphoresis (0.4%), asthenia (0.3%), malaise (0.3%), arthralgia (0.3%), injection site pain (0.1%), rigor (0.1%), earache (0.1%), tinnitus (0.1%), vision abnormalities unspecified (0.1%), dysgeusia (0.1%), thirst (0.03%), depersonalization (0.03%), eye pain (0.03%), renal pain (0.03%), perineal pain (0.03%), breast pain (0.03%), intermittent claudication (0.03%), leg cramping (0.03%). In additional postmarketing experience, there have been rare reports of allergic reaction including urticaria, pruritus, dermatitis and rash.

WARNINGS Serious adverse reactions associated with the administration of intravenous Dipyridamole Injection have included cardiac death, fatal and non-fatal myocardial infarction, ventricular fibrillation, symptomatic ventricular tachycardia, stroke, transient cerebral ischemia, seizures, anaphylactoid reaction and bronchospasm. There have been reported cases of asystole, sinus node arrest, sinus node depression and conduction block. Patients with abnormalities of cardiac impulse formation/conduction or severe coronary artery disease may be at increased risk for these events. In a study of 3911 patients given intravenous dipyridamole as an adjunct to thallium myocardial perfusion imaging, two types of serious adverse events were reported: 1) four cases of myocardial infarction (0.1%), two fatal (0.05%) and two non-fatal (0.05%) and 2) six cases of severe bronchospasm (0.2%). Although the incidence of these serious adverse events was small (0.3%, 10 of 3911), the potential clinical information to be gained through use of intravenous dipyridamole thallium imaging (see INDICATIONS AND USAGE noting the rate of false positive and false negative results) must be weighed against the risk to the patient. Patients with a history of unstable angina may be at a greater risk for severe myocardial ischemia. Patients with a history of asthma may be at a greater risk for bronchospasm during Dipyridamole Injection use. When thallium myocardial perfusion imaging is performed with intravenous dipyridamole, parenteral aminophylline should be readily available for relieving adverse events such as bronchospasm or chest pain. Vital signs should be monitored during, and for 10-15 minutes following, the intravenous infusion of dipyridamole and an electrocardiographic tracing should be obtained using at least one chest lead. Should severe chest pain or bronchospasm occur, parenteral aminophylline may be administered by slow intravenous injection (50-100 mg over 30-60 seconds) in doses ranging from 50 to 250 mg. 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 dipyridamole on the coronary circulation.

PRECAUTIONS General Coronary Artery Disease Dipyridamole has a vasodilatory effect and should be used with caution in patients with severe coronary artery disease (e.g., unstable angina or recently sustained myocardial infarction). Chest pain may be aggravated in patients with underlying coronary artery disease who are receiving dipyridamole.

Hepatic Insufficiency

Elevations of hepatic enzymes and hepatic failure have been reported in association with dipyridamole administration.

Hypotension

Dipyridamole should be used with caution in patients with hypotension since it can produce peripheral vasodilation.

Stress

Testing with Intravenous Dipyridamole and Other Adenosinergic Agents Clinical experience suggests that patients being treated with dipyridamole tablets who also require pharmacological stress testing with intravenous dipyridamole or other adenosinergic agents (e.g. adenosine, regadenoson) should interrupt dipyridamole tablets for 48 hours prior to stress testing. Intake of dipyridamole tablets within 48 hours prior to stress testing with intravenous dipyridamole or other adenosinergic agents may increase the risk for cardiovascular side effects of these agents and may impair the sensitivity of the test.

Laboratory Tests

Dipyridamole has been associated with elevated hepatic enzymes.

Drug

Interactions No pharmacokinetic drug-drug interaction studies were conducted with dipyridamole tablets. The following information was obtained from the literature. Adenosinergic agents (e.g., adenosine, regadenoson) Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary. Dipyridamole also increases the cardiovascular effects of regadenoson, an adenosine A 2A -receptor agonist. The potential risk of cardiovascular side effects with intravenous adenosinergic agents may be increased during the testing period when dipyridamole is not held 48 hours prior to stress testing.

Cholinesterase Inhibitors

Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis. Carcinogenesis, Mutagenesis, Impairment of Fertility In studies in which dipyridamole was administered in the feed to mice (up to 111 weeks in males and females) and rats (up to 128 weeks in males and up to 142 weeks in females), there was no evidence of drug-related carcinogenesis. The highest dose administered in these studies (75 mg/kg/day) was, on a mg/m 2 basis, about equivalent to the maximum recommended daily human oral dose (MRHD) in mice and about twice the MRHD in rats. Mutagenicity tests of dipyridamole with bacterial and mammalian cell systems were negative. There was no evidence of impaired fertility when dipyridamole was administered to male and female rats at oral doses up to 500 mg/kg/day (about 12 times the MRHD on a mg/m 2 basis). A significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was, however, observed at 1250 mg/kg (more than 30 times the MRHD on a mg/m 2 basis).

Pregnancy Teratogenic

Effects: PREGNANCY CATEGORY B Reproduction studies have been performed in mice, rabbits and rats at oral dipyridamole doses of up to 125 mg/kg, 40 mg/kg and 1000 mg/kg, respectively (about 1 1/2 , 2 and 25 times the maximum recommended daily human oral dose, respectively, on a mg/m 2 basis) and have revealed no evidence of harm to the fetus due to dipyridamole. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, dipyridamole tablets should be used during pregnancy only if clearly needed.

Nursing

Mothers As dipyridamole is excreted in human milk , caution should be exercised when dipyridamole tablets are administered to a nursing woman.

Pediatric Use

Safety and effectiveness in the pediatric population below the age of 12 years have not been established.

Drug Interactions No pharmacokinetic drug-drug interaction studies were conducted with dipyridamole tablets. The following information was obtained from the literature. Adenosinergic agents (e.g., adenosine, regadenoson): Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary. Dipyridamole also increases the cardiovascular effects of regadenoson, an adenosine A 2A -receptor agonist. The potential risk of cardiovascular side effects with intravenous adenosinergic agents may be increased during the testing period when dipyridamole is not held 48 hours prior to stress testing.

Cholinesterase

Inhibitors: Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis.