SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 5 DRUG INTERACTIONS 8 DOSAGE AND ADMINISTRATION 9 OVERDOSAGE 9 ACTION AND CLINICAL PHARMACOLOGY 10 STORAGE AND STABILITY 11 SPECIAL HANDLING INSTRUCTIONS 11 DOSAGE FORMS, COMPOSITION AND PACKAGING 11

PART II: SCIENTIFIC INFORMATION 13

PHARMACEUTICAL INFORMATION 13 CLINICAL TRIALS 14 DETAILED PHARMACOLOGY 14 TOXICOLOGY 16 REFERENCES 18

PART III: CONSUMER INFORMATION. 22

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. Intravenous administration of DIPYRIDAMOLE FOR INJECTION is not recommended in states of shock or collapse.

WARNINGS AND PRECAUTIONS

Rare serious adverse reactions associated with the administration of intravenous dipyridamole 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.

Since excessive doses of dipyridamole (intravenous or oral) or intravenous doses given too rapidly can produce peripheral vasodilation, dipyridamole 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 DIPYRIDAMOLE FOR INJECTION (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 DIPYRIDAMOLE FOR INJECTION 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 dipyridamole 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 DIPYRIDAMOLE FOR INJECTION on the coronary circulation.

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.

Patients with a history or presence of bronchial hyperreactivity may be at risk of developing bronchospasm during the use of intravenous DIPYRIDAMOLE FOR INJECTION 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 DIPYRIDAMOLE FOR INJECTION should be weighed against the potential risk to the patient.

Pregnant Women

: 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.

Nursing Women:

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

Pediatrics

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

ADVERSE REACTIONS

PARENTERAL ADMINISTRATION (i.v. infusion)

Adverse Drug Reaction Overview

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

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

When intravenous dipyridamole was used as an adjunct to myocardial perfusion imaging in a study of 3911 patients, the following events occurred in greater than 1% of the patients:

Event Description	Incidence (%) of Occurrence In 3911 Patients
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 Clinical Trial Adverse Drug Reactions (<1%)

Cardiovascular

: 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.

Central and Peripheral Nervous System

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

RespiratoryGastrointestinal

: Pharyngitis, bronchospasm, hyperventilation, rhinitis, coughing, pleural pain.

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

Other

: 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.

Post-Market Adverse Drug Reactions

When using dipyridamole as an adjunct to myocardial imaging, the following adverse events have been reported: cardiac death, cardiac arrest, myocardial infraction (rarely fatal), arrhythmias (e.g. sinus node arrest), tachycardia, fibrillation, and cerebrovascular events (e.g. stroke, TIA, seizures). Dipyridamole may cause severe hypotension and hot flushes. Diarrhea has been observed. Hypersensitivity reactions such as rash, urticaria, angio-oedema, laryngospasm, severe bronchospasm and very rarely anaphylactoid reactions have been reported. ORAL ADMINISTRATION 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 dipyridamole is used in combination with ASA, the only side effect clearly attributable to dipyridamole 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 dipyridamole there may be an increase in the incidence of adverse reactions. In very rare cases, increased bleeding during or after surgery has been reported.

Post-Market Adverse Drug Reactions

As a result of its vasodilator properties, dipyridamole 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). Isolated cases of thrombocytopenia have been reported in conjunction with treatment with dipyridamole.

DRUG INTERACTIONS

Table 1- Established or Potential Drug-Drug Interactions

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

DOSAGE AND ADMINISTRATION

Thromboembolic Disease

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 NOVO-DIPIRADOL (dipyridamole) daily together with 1 g ASA daily, prolongs platelet survival to the same extent. PARENTERAL ADMINISTRATION

Myocardial Perfusion Imaging Recommended Dose and Dosage Adjustment

The dose of intravenous DIPYRIDAMOLE FOR INJECTION used as an adjunct to myocardial perfusion imaging should be adjusted according to the weight of the patient. Immediately prior to infusion, DIPYRIDAMOLE FOR INJECTION 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 DIPYRIDAMOLE FOR INJECTION. Do not mix DIPYRIDAMOLE FOR INJECTION with other drugs in the same syringe or infusion container. Infusion of undiluted DIPYRIDAMOLE FOR INJECTION 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.

OVERDOSAGE

Hypotension, if it occurs, is likely to be of short duration but vasopressor substances may be used if necessary. Symptoms such as feeling warm, flushes, sweating, accelerated pulse, restlessness, feeling of weakness and dizziness, and anginal complaints may occur. A drop in blood pressure and tachycardia might be observed. ORAL ADMINISTRATION 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 PARENTERAL ADMINISTRATION (I.V. INFUSION) 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.

ACTION AND CLINICAL PHARMACOLOGY

Dipyridamole normalizes increased platelet adhesiveness and tendency to aggregate (Hellem's Method)4,5. Dipyridamole has been found to lengthen abnormally shortened platelet survival time in a dose-dependent manner; 400 mg/day or 100 mg/day plus 1 gram ASA.15, 16,17, 35, 36 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), dipyridamole, 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.37

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.1,4,29,30,33 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 ug/mL with 0.8 ug/mL being the threshold serum level. Single oral doses of 150 mg dipyridamole produce the maximal response20,21. At normal therapeutic doses, no significant alterations of peripheral blood flow, systemic blood pressure, or heart rate have been observed.

Dipyridamole 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 dipyridamole are abolished by administration of the adenosine receptor antagonist theophylline. How dipyridamole -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.

Absorption: Dipyridamole is readily absorbed from the gastrointestinal tract, reaching peak plasma levels in man 1-3 hours following oral administration.22,26,29,41 Peak plasma levels are dose-dependent and range from about 0.5 ug/mL after a 25 mg dose to 1.6 ug/mL after a 75 mg dose. 6,29,32,41 Blood levels are quite variable, possibly depending on food intake and gastrointestinal peristalsis. Ingestion on an empty stomach may result in higher blood levels.22,32 Distribution: Following intravenous administration, the distribution half-life in man is about 25 minutes41 and after oral administration about 3 hours.26,29,30 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.22,32 The volume of distribution is about 140 litres with about 92-99% binding to plasma proteins, primarily alphal-acid glycoprotein.22,32

STORAGE AND STABILITY

Store bottles between 15deg - 30degC. Unit dose should be stored between 15deg- 25degC and protected from high humidity. DIPYRIDAINOLE FOR INJECTION vials should be stored between 15degto 25degC. Avoid freezing. Protect from light. Single dose vials. Discard unused portion.

SPECIAL HANDLING INSTRUCTIONS

DOSAGE FORMS, COMPOSITION AND PACKAGING

NOVO-DIPIRADOL (dipyridamole) is available as 25 mg orange, round, sugar-coated tablets in bottles of 100 and 500 and unit dose strips of 100 tablets. Each tablet contains 25 mg of dipyridamole. NOVO-DIPIRADOL is available as 50 mg brown, round, sugar-coated tablets in bottles of 100 and 500 and unit dose strips of 100 tablets. Each tablet contains 50 mg of dipyridamole. NOVO-DIPIRADOL is available as 75 mg deep orange, round, sugar-coated tablets in bottles of 100 and 500 and unit dose strips of 100 tablets. Each tablet contains 75 mg of dipyridamole. NOVO-DIPIRADOL is available as 100 mg white, round, sugar coated tablets in bottles of 100 and 500 and unit dose strips of 100 tablets. Each tablet contains 100 mg of dipyridamole.

10 mL, single dose vials, containing 5 mg/mL dipyridamole. Dipyridamole For Injection is supplied as 1 vial per box and 5 vials per box.

NOVO-DIPIRADOL tablets contain: 25 mg SC tablets: magnesium stearate, microcrystalline cellulose, pregelatinized starch, silica, sodium lauryl sulfate, sodium starch glycolate, starch. The sugar coating contains: acacia, acetylated monoglycerides, colloidal silicon dioxide, ethylcellulose, hydroxypropyl methylcellulose, sucrose, talc, FD & C Yellow No. 6 and titanium dioxide. 50 mg SC tablets: magnesium stearate, microcrystalline cellulose, pregelatinized starch, silica, sodium lauryl sulfate, sodium starch glycolate, starch. The sugar coating contains: acacia, acetylated monoglycerides, colloidal silicon dioxide, ethylcellulose, hydroxypropyl methylcellulose, sucrose, talc, FD & C Yellow No. 6 A1 Lake, FD & C Red No. 40 A1 Lake and FD & C Blue No. 2 A1 Lake. 75 mg SC tablets: magnesium stearate, microcrystalline cellulose, pregelatinized starch, silica, sodium lauryl sulfate, sodium starch glycolate, starch. The sugar coating contains: acacia, acetylated monoglycerides, colloidal silicon dioxide, ethylcellulose, hydroxypropyl methylcellulose, sucrose, talc, FD & C Yellow No. 6 A1 Lake and titanium dioxide. 100 mg SC tablets: magnesium stearate, microcrystalline cellulose, pregelatinized starch, silica, sodium lauryl sulfate, sodium starch glycolate, starch. The sugar coating contains: acacia, acetylated monoglycerides, colloidal silicon dioxide, ethylcellulose, hydroxypropyl methylcellulose, sucrose, talc, FD & C Blue No. 2 and titanium dioxide. Non-medicinal ingredients contained in DIPYRIDAMOLE FOR INJECTION vials include tartaric acid, polyethylene glycol 600, hydrochloric acid, water for injection and sodium hydroxide, if necessary to adjust the pH.

Route of Administration	Dose Form/Strength	Clinically Relevant Nonmedicinal Ingredients
oral	tablet 25, 50, 75 and 100 mg	Magnesium stearate, microcrystalline cellulose, pregelatinized starch, silica, sodium lauryl sulfate, sodium starch glycolate, starch. The sugar coating contains: acacia, acetylated monoglycerides, colloidal silicon dioxide, ethylcellulose, hydroxypropyl methylcellulose, sucrose, talc, titanium dioxide and: 25 mg: FD & C Yellow No. 6 50 mg: FD & C Yellow No. 6 A1 Lake, FD & C Red No. 40 A1 Lake and FD & C Blue No. 2 A1 Lake 75 mg: FD & C Yellow No. 6 A1 Lake 100 mg: FD & C Blue No. 2
i.v. (intravenous)	10 mL vials, 5 mg/mL	Tartaric acid, polyethylene glycol 600, hydrochloric acid, water for injection and sodium hydroxide, if necessary to adjust the pH.

Dipyridamole	Effect	Clinical comment
Dipyridamole - Adenosine	Dipyridamole increases plasma levels and cardiovascular effects of adenosine.	Adjustment of adenosine dosage should be considered
Dipyridamole For Injection - Theophylline, aminophylline	The use of oral maintenance xanthines (eg., theophylline, aminophylline) may abolish the coronary vasodilation produced by intravenous dipyridamole administration.	This could lead to false negative imaging results.
Dipyridamole For Injection - Oral dipyridamole	In patients already receiving oral dipyridamole, clinical experience suggests that the sensitivity of the intravenous dipyridamole testing may be impaired	Oral dipyridamole treatment should be discontinued for 24-hours prior to testing.
Dipyridamole - Anticoagulants, thrombolytics	the combined use of such agents may result in an increased risk of hemorrhage	Caution is necessary when dipyridamole is used concurrently with anticoagulants or thrombolytics.
Dipyridamole - ASA	the addition of dipyridamole to acetylsalicylic acid does not increase the incidence of bleeding events.
Dipyridamole - Warfarin	When dipyridamole was administered concomitantly with warfarin, bleeding was no greater in frequency or severity than that observed when warfarin was administered alone.
Dipyridamole - Blood pressure lowering drugs	Dipyridamole may increase the hypotensive effect of blood pressure lowering drugs
Dipyridamole - Cholinesterase inhibitors	Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors	In patients with myasthenia gravis, readjustment of therapy may be necessary during treatment with dipyridamole.

PART I: HEALTH PROFESSIONAL INFORMATION 3