Dipyridamole 5 mg/mL Injection — NDC 0641-2569-44 (Billing 00641-2569-44)

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, bronchospasm, severe hypotension, anaphylaxis with laryngospasm, and angioedema. 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.

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, angioedema, 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: Table 1 Drug-Related Adverse Reactions (%) Occurring in Greater than 1% of Patients 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

1.2Less common adverse reactions occurring in 1% or less of the patients within the study included: Cardiovascular System Electrocardiographic abnormalities (0.8%), arrhythmia (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 (0.03%–see WARNINGS ), heart block (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.

Drug Interactions Oral maintenance theophylline and other xanthine derivatives such as caffeine may abolish the coronary vasodilatation induced by intravenous Dipyridamole Injection administration. This could lead to a false negative thallium imaging result (see CLINICAL PHARMACOLOGY – Mechanism of Action ). Myasthenia gravis patients receiving therapy with cholinesterase inhibitors may experience worsening of their disease in the presence of dipyridamole.

PRECAUTIONS See WARNINGS . Drug Interactions Oral maintenance theophylline and other xanthine derivatives such as caffeine may abolish the coronary vasodilatation induced by intravenous Dipyridamole Injection administration. This could lead to a false negative thallium imaging result (see CLINICAL PHARMACOLOGY – Mechanism of Action ).

Myasthenia gravis patients receiving therapy with cholinesterase inhibitors may experience worsening of their disease in the presence of dipyridamole. Carcinogenesis, Mutagenesis, Impairment of Fertility In studies in which dipyridamole was administered in the feed to mice (up to 128 weeks in males and up to 142 weeks in females) and rats (up to 111 weeks in males and 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 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 1½, 2 and 25 times the maximum recommended daily human oral dose, respectively, on a mg/m2 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 injection should be used during pregnancy only if clearly needed.

Nursing Mothers As dipyridamole is excreted in human milk, caution should be exercised when dipyridamole injection is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established.