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CLINICAL PHARMACOLOGYIn a study of 10 patients with angiographically normal or minimally stenosed (less than 25% luminal diameter narrowing) coronary vessels, IV Persantine® (dipyridamole USP) in a dose of 0.56 mg/kg infused over 4 minutes resulted in an average fivefold increase in coronary blood flow velocity compared to resting coronary flow velocity (range 3.8 to 7 times resting velocity). The mean time to peak flow velocity was 6.5 minutes from the start of the 4-minute infusion (range 2.5 to 8.7 minutes). Cardiovascular responses to the intravenous administration of Persantine® when given to patients in the supine position include a mild but significant increase in heart rate of approximately 20% and mild but significant decreases in both systolic and diastolic blood pressure of approximately 2-8%, with vital signs returning to baseline values in approximately 30 minutes. Mechanism of Action 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 and ventricular function is also uncertain but presumably represents a "steal" phenomenon in which relatively intact vessels dilate, and sustain enhanced flow, leaving reduced pressure and flow across areas of hemodynamically important coronary vascular constriction. Pharmacokinetics and Metabolism Plasma dipyridamole concentrations decline in a triexponential fashion following intravenous infusion of Persantine®, with half-lives averaging 3-12 minutes, 33-62 minutes, and 11.6-15 hours. Two minutes following a 0.568 mg/kg dose of IV Persantine® administered as a 4-minute infusion, the mean dipyridamole serum concentration is 4.6±1.3 mcg/mL. The average plasma protein binding of dipyridamole is approximately 99%, primarily to a1 -glycoprotein. Dipyridamole is metabolized in the liver to the glucuronic acid conjugate and excreted with the bile. The average total body clearance is 2.3-3.5 mL/min/kg, with an apparent volume of distribution at steady state of 1-2.5 L/kg and a central apparent volume of 3-5 liters.

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 (dipyridamole USP) tablets have 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 (dipyridamole) tablets, 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 (dipyridamole) tablets and warfarin ranged from 1.2 to 1.8%. In three additional studies involving 392 patients taking Persantine (dipyridamole) tablets 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 (dipyridamole) tablets were begun between 24 hours and 10 days postoperatively. The length of follow-up in these trials varied from 1 to 2 years. Persantine (dipyridamole) tablets do not influence prothrombin time or activity measurements when administered with warfarin. Mechanism of Action Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes in vitro and in vivo; the inhibition occurs in a dose-dependent manner at therapeutic concentrations (0.5-1.9 µg/mL). This inhibition results in an increase in local concentrations of adenosine which acts on the platelet A2-receptor thereby stimulating platelet adenylate cyclase and increasing platelet cyclic-3',5'-adenosine monophosphate (cAMP) levels. Via this mechanism, platelet aggregation is inhibited in response to various stimuli such as platelet activating factor (PAF), collagen and adenosine diphosphate (ADP). Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. While the inhibition of cAMP-PDE is weak, therapeutic levels of dipyridamole inhibit cyclic-3',5'-guanosine monophosphate-PDE (cGMP-PDE), thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, now identified as nitric oxide). Hemodynamics In dogs intraduodenal doses of dipyridamole 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 (dipyridamole) 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 (dipyridamole) may worsen regional myocardial perfusion distal to partial occlusion of coronary arteries. Pharmacokinetics and Metabolism Following an oral dose of Persantine (dipyridamole) tablets, the average time to peak concentration is about 75 minutes. The decline in plasma concentration following a dose of Persantine (dipyridamole) tablets 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. Dipyridamole is highly bound to plasma proteins. It is metabolized in the liver where it is conjugated as a glucuronide and excreted with the bile.

IV PERSANTINE® (dipyridamole USP) Prescribing Information DESCRIPTIONPersantine® (dipyridamole USP) for intravenous injection is a coronary vasodilator described as 2,6-Bis(diethanolamino)-4,8-dipiperidinopy-rimido [5,4-d]-pyrimidine. Dipyridamole in solution is an odorless, pale yellow liquid which can be diluted in normal saline and dextrose and water for intravenous administration. IV Persantine® as a sterile solution for intravenous administration contains: Active Ingredient VIAL10 mL: dipyridamole USP 50 mg. Inactive Ingredients VIAL10 mL: polyethylene glycol 600 500 mg, tartaric acid 20 mg. pH is adjusted to 2.7 ±0.5 with hydrochloric acid.

Find Lowest Prices on Persantine® (dipyridamole USP) 25 mg, 50 mg, and 75 mg Tablets DESCRIPTION Persantine (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. Persantine (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: acacia, carnauba wax, corn starch, edible white ink, lactose monohydrate, magnesium stearate, D&C yellow #10 aluminum lake, D&C red #30, helendon aluminum pink lake, sodium benzoate, methylparaben, propylparaben, polyethylene glycol, povidone, sucrose, talc, titanium dioxide, and white wax.

INDICATIONSIV Persantine® (dipyridamole USP) 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 IV Persantine® assisted thallium imaging, the results of both tests were interpreted blindly and the sensitivity and specificity of the Persantine® thallium study in predicting the angiographic outcome were calculated. The sensitivity of the Persantine® test (true positive Persantine® 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 Persantine® thallium imaging, sensitivity and specificity of the two tests was almost identical. DOSAGE AND ADMINISTRATION The dose of intravenous Persantine® (dipyridamole USP) 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/minute (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, IV Persantine® should be diluted in at least a 1:2 ratio with 0.45% sodium chloride injection, 0.9% sodium chloride injection, or 5% dextrose injection for a total volume of approximately 20 to 50 mL. Infusion of undiluted Persantine® may cause local irritation. Thallium-201 should be injected within 5 minutes following the 4-minute infusion of Persantine®. Do not mix IV Persantine® with other drugs in the same syringe or infusion container. Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. HOW SUPPLIEDIV Persantine® (dipyridamole USP) for intravenous injection is available in boxes of five, ten and twenty vials. Each 10 mL vial contains 50 mg of dipyridamole, NDC number 11994-005-05, 11994-005-10, 11994-005-20. Store at 25°C (77°F); excursions permitted to 15-30°C (59°-86°F). [see USP Controlled Room Temperature]. Protect from direct light. Avoid freezing. Bristol-Myers Squibb Medical Imaging, Inc. 513113-1201 Rev 7 Jan 2002

INDICATIONS Persantine (dipyridamole USP) tablets are indicated as an adjunct to coumarin anticoagulants in the prevention of postoperative thromboembolic complications of cardiac valve replacement. 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. HOW SUPPLIED PERSANTINE (dipyridamole USP) tablets are available as round, orange, sugar-coated tablets of 25 mg, 50 mg and 75 mg coded BI/17, BI/18 and BI/19, respectively. They are available in bottles of 100 tablets as indicated below: 25 mg Tablets...........................(NDC 0597-0017-01) 50 mg Tablets...........................(NDC 0597-0018-01) 75 mg Tablets...........................(NDC 0597-0019-01) STORE AT 25°C (77°F); EXCURSIONS PERMITTED TO 15-30°C (59°-86°F) [SEE USP CONTROLLED ROOM TEMPERATURE]. KEEP OUT OF REACH OF CHILDREN. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877, USA. Licensed from: Boehringer Ingelheim International GmbH, Manufactured by: Boehringer Ingelheim Promeco, S.A. de C.V. Mexico City, Mexico. Revised 01/21/05. FDA Rev date: 8/1/2005

PATIENT INFORMATIONNo specific information available. However, see Warnings and Precautions

PATIENT INFORMATION No information provided. Please refer to the PRECAUTIONS section.

OVERDOSENo cases of overdosage in humans have been reported. It is unlikely that overdosage will occur because of the nature of use (i.e., single intravenous administration in controlled settings). Signs and symptoms as described under ADVERSE REACTIONS are expected to occur and could be even more severe in single cases. Symptomatic therapy is recommended. Should severe chest pain or brochospasm occur, parenteral aminophylline may be administered by slow intravenous injection (50-100 mg over 30 to 60 seconds) in doses ranging from 50 to 250 mg. See WARNINGS. CONTRAINDICATIONS Hypersensitivity to dipyridamole or any of the other components of the drug.

OVERDOSE In case of real or suspected overdose, seek medical attention or contact a Poison Control Center immediately. Careful medical management is essential. Based upon the known hemodynamic effects of dipyridamole, symptoms such as warm feeling, flushes, sweating, restlessness, feeling of weakness and dizziness may occur. A drop in blood pressure and tachycardia might also be observed. Symptomatic treatment is recommended, possibly including a vasopressor drug. Gastric lavage should be considered. Administration of xanthine derivatives (e.g., aminophylline) may reverse the hemodynamic effects of dipyridamole overdose. Since dipyridamole is highly protein bound, dialysis is not likely to be of benefit. CONTRAINDICATIONS Hypersensitivity to dipyridamole and any of the other components.

SIDE EFFECTSAdverse reaction information concerning intravenous Persantine® (dipyridamole USP) is derived from a study of 3911 patients in which intravenous Persantine® 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 the 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 occuring in greater than 1% of the patients in the study are shown in Table 1: Table 1 Drug-Related Adverse Reactions (%) Occurring in Greater than 1% of Patients Incidence (%) of Drug-Related Adverse Reaction Adverse Reactions 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 (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 (1.0%), dry mouth (0.8%), abdominal pain (0.7%), flatulence (0.6%), vomiting (0.4%), eructation (0.1%), dysphagia (0.03%), tenesmus (0.03%), appetite increased (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 diarrhea, allergic reaction including urticaria, pruritus, dermatitis and rash. Mesenteric ischemia and mesenteric infarction have also been observed in association with intravenous Persantine® (dipyridamole USP) administration. DRUG INTERACTIONS Oral maintenance theophylline and other xanthine derivatives such as caffeine may abolish the coronary vasodilatation induced by intravenous Persantine® (dipyridamole USP) administration. This could lead to a false negative thallium imaging result (see Mechanism of Action). Xanthine derivatives should be avoided 24 hours before myocardial imaging with IV Persantine. Dipyridamole has been reported to increase the plasma levels and cardiovasular effects of adenosine. Adjustment of adenosine dosage may be necessary. 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 a 111 week oral study in mice and in a 128-142 week oral study in rats, dipyridamole USP produced no significant carcinogenic effects at doses up to 75 mg/kg (0.8 times and 1.5 times the maximum recommended daily human oral dose on a mg/m2 basis in mice and rats, respectively). Mutagenicity testing with dipyridamole was negative. Reproduction studies with dipyridamole revealed no evidence of impaired fertility in rats at dosages up to 500 mg/kg, or 10 times the maximum recommended human oral dose on a mg/m2 basis. A significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was, however, observed at 1250 mg/kg (25 times the maximum recommended human oral dose on a mg/m2 basis). Pregnancy Teratogenic Effects PREGNANCY CATEGORY B Reproduction studies have been performed in mice at doses up to 125 mg/kg, rats at doses up to 1000 mg/kg and rabbits at doses up to 40 mg/kg (1.3, 20, and 1.6 times the maximum recommended daily human oral dose on a mg/m2 basis, respectively) 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 responses, 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 IV Persantine® (dipyridamole USP) ia administered to a nursing woman. Pediatric Use Safety and effectiveness in the pediatric population have not been established.

SIDE EFFECTS Adverse reactions at therapeutic doses are usually minimal and transient. On long-term use of Persantine (dipyridamole USP) tablets initial side effects usually disappear. The following reactions in Table 1 were reported in two heart valve replacement trials comparing Persantine (dipyridamole) E tablets and warfarin therapy to either warfarin alone or warfarin and placebo: Table 1: Adverse Reactions Reported in 2 Heart Valve Replacement Trials Adverse Reaction PERSANTINE Tablets / Warfarin Placebo/ Warfarin Number of patients 147 170 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 (dipyridamole) tablets were administered concomitantly with warfarin, bleeding was no greater in frequency or severity than that observed when warfarin was administered alone. In rare cases, increased bleeding during or after surgery has been observed. In post-marketing reporting experience, there have been rare reports of hypersensitivity reactions (such as rash, urticaria, severe bronchospasm, and angioedema), larynx edema, fatigue, malaise, myalgia, arthritis, nausea, dyspepsia, paresthesia, hepatitis, thrombocytopenia, alopecia, cholelithiasis, hypotension, palpitation, and tachycardia. DRUG INTERACTIONS No pharmacokinetic drug-drug interaction studies were conducted with Persantine (dipyridamole USP) Tablets. The following information was obtained from the literature. Adenosine: Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary. Cholinesterase Inhibitors: Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis.

WARNINGSSerious adverse reactions associated with the administration of intravenous Persantine® (dipyridamole USP) 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 Persantine® 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 Persantine® 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 IV Persantine® use. When thallium myocardial perfusion imaging is performed with intravenous Persantine®, 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 Persantine® 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 amino-phylline 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. PRECAUTIONSSee WARNINGS

WARNINGS No information provided. 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. Laboratory Tests Dipyridamole has been associated with elevated hepatic enzymes. 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/m2 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/m2 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/m2 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 ½, 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, Persantine (dipyridamole) should be used during pregnancy only if clearly needed. Nursing Mothers As dipyridamole is excreted in human milk, caution should be exercised when Persantine (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.