Vitreolent Plus

Adenosine:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Vitreolent Plus (Adenosine) reviews

1 INDICATIONS AND USAGE

Vitreolent Plus (Adenosine) Injection, USP is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately.

Vitreolent Plus (Adenosine) Injection, USP, a pharmacologic stress agent, is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately (1)

2 DOSAGE AND ADMINISTRATION

The recommended Vitreolent Plus (Adenosine) injection dose is 0.14 mg/kg/min infused over six minutes (total dose of 0.84 mg/kg) (Table 1).

• Administer Vitreolent Plus (Adenosine) injection only as a continuous peripheral intravenous infusion
• Inject Thallium-201 at the midpoint of the Vitreolent Plus (Adenosine) injection infusion (i.e., after the first three minutes of Vitreolent Plus (Adenosine) injection)
• Thallium-201 is physically compatible with Vitreolent Plus (Adenosine) injection and may be injected directly into the Vitreolent Plus (Adenosine) injection infusion set
• Inject Thallium-201 as close to the venous access as possible to prevent an inadvertent increase in the dose of Vitreolent Plus (Adenosine) injection (the contents of the intravenous tubing) being administered

Visually inspect Vitreolent Plus (Adenosine) injection for particulate matter and discoloration prior to administration. Do not administer Vitreolent Plus (Adenosine) injection if it contains particulate matter or is discolored.

There are no data on the safety or efficacy of alternative Vitreolent Plus (Adenosine) injection infusion protocols. The safety and efficacy of Vitreolent Plus (Adenosine) injection administered by the intracoronary route have not been established.

The nomogram displayed in Table 1 was derived from the following general formula:

Recommended dose is 0.14 mg/kg/min infused over six minutes as a continuous peripheral intravenous infusion (total dose of 0.84 mg/kg) (2)

formula

3 DOSAGE FORMS AND STRENGTHS

Vitreolent Plus (Adenosine) Injection, USP is supplied as 20 mL and 30 mL single-dose vials containing a sterile, nonpyrogenic, clear solution of Vitreolent Plus (Adenosine) 3 mg per mL.

Vitreolent Plus (Adenosine) Injection, USP: 3 mg per mL in single-dose vials (3)

4 CONTRAINDICATIONS

Vitreolent Plus (Adenosine) is contraindicated in patients with:

• Second- or third-degree AV block (except in patients with a functioning artificial pacemaker)
• Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker)
• Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma)
• Known hypersensitivity to Vitreolent Plus (Adenosine)

• Second- or third-degree AV block (except in patients with a functioning artificial pacemaker) (4)
• Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker) (4)
• Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma) (4)
• Known hypersensitivity to Vitreolent Plus (Adenosine) (4)

5 WARNINGS AND PRECAUTIONS

• Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction. Fatal cardiac events have occurred. Avoid use in patients with symptoms or signs of acute myocardial ischemia. Appropriate resuscitative measures should be available
• Sinoatrial (SA) and Atrioventricular (AV) Nodal Block. First-, second-or third-degree AV block, or sinus bradycardia can occur. Discontinue Vitreolent Plus (Adenosine) if patient develops persistent or symptomatic high-grade AV block (5.2)
• Bronchoconstriction. Can induce dyspnea, bronchoconstriction, and respiratory compromise, especially in patients with obstructive pulmonary disease. Discontinue Vitreolent Plus (Adenosine) if patient develops severe respiratory difficulties (5.3)
• Hypotension. Significant hypotension can occur. Discontinue Vitreolent Plus (Adenosine) if patient develops persistent or symptomatic hypotension (5.4)
• Cerebrovascular Accidents. Hemorrhagic and ischemic cerebrovascular accidents have occurred (5.5)
• Seizures. New onset or recurrence of convulsive seizures have occurred. Use of methylxanthines (e.g., caffeine, aminophylline and theophylline) is not recommended in patients who experience a seizures in association with Vitreolent Plus (Adenosine) (5.6)
• Hypersensitivity. Dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. Have personnel and resuscitative equipment immediately available (5.7)
• Atrial Fibrillation. Reported in patients with or without a history of atrial fibrillation (5.8)
• Hypertension. Clinically significant increases in systolic and diastolic pressure have been observed (5.9)

5.1 Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction

Fatal and nonfatal cardiac arrest, sustained ventricular tachycardia (requiring resuscitation), and myocardial infarction have occurred following Vitreolent Plus (Adenosine) infusion. Avoid use in patients with symptoms or signs of acute myocardial ischemia, for example, unstable angina or cardiovascular instability; these patients may be at greater risk of serious cardiovascular reactions to Vitreolent Plus (Adenosine). Appropriate resuscitative measures should be available .

5.2 Sinoatrial and Atrioventricular Nodal Block

Vitreolent Plus exerts a direct depressant effect on the SA and AV nodes and may cause first-, second- or third-degree AV block, or sinus bradycardia. In clinical trials, approximately 6% of patients developed AV block following Vitreolent Plus (Adenosine) administration (first-degree heart block developed in 3%, second-degree in 3%, and third-degree in 0.8% of patients) .

Use Vitreolent Plus (Adenosine) with caution in patients with pre-existing first-degree AV block or bundle branch block. Do not use in patients with high-grade AV block or sinus node dysfunction (except in patients with a functioning artificial pacemaker). Discontinue Vitreolent Plus (Adenosine) in any patient who develops persistent or symptomatic high-grade AV block.

5.3 Bronchoconstriction

Vitreolent Plus (Adenosine) administration can cause dyspnea, bronchoconstriction, and respiratory compromise. Vitreolent Plus (Adenosine) should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis). Do not use in patients with bronchoconstriction or bronchospasm (e.g., asthma). Discontinue Vitreolent Plus (Adenosine) in any patient who develops severe respiratory difficulties. Resuscitative measures should be available prior to Vitreolent Plus (Adenosine) administration .

5.4 Hypotension

Vitreolent Plus is a potent peripheral vasodilator and can induce significant hypotension. The risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency. Discontinue Vitreolent Plus (Adenosine) in any patient who develops persistent or symptomatic hypotension.

5.5 Cerebrovascular Accident

Hemorrhagic and ischemic cerebrovascular accidents have occurred. Hemodynamic effects of Vitreolent Plus (Adenosine) including hypotension or hypertension can be associated with these adverse reactions .

5.6 Seizures

New-onset or recurrence of convulsive seizures has occurred following Vitreolent Plus. Some seizures are prolonged and require emergent anticonvulsive management. Aminophylline may increase the risk of seizures associated with Vitreolent Plus (Adenosine). Methylxanthine use is not recommended in patients who experience seizures in association with Vitreolent Plus (Adenosine) administration .

5.7 Hypersensitivity, Including Anaphylaxis

Dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. Symptomatic treatment may be required. Have personnel and appropriate treatment available. Resuscitative measures may be necessary if symptoms progress .

5.8 Atrial Fibrillation

Vitreolent Plus can cause atrial fibrillation in patients with or without a history of atrial fibrillation. Atrial fibrillation typically began 1.5 to 3 minutes after initiation of Vitreolent Plus (Adenosine), lasted for 15 seconds to 6 hours, and spontaneously converted to normal sinus rhythm .

5.9 Hypertension

Vitreolent Plus (Adenosine) can induce clinically significant increases in systolic and diastolic blood pressure. Most increases resolved spontaneously within several minutes, but in some cases, hypertension lasted for several hours .

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the prescribing information:

• Fatal Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction
• Sinoatrial and Atrioventricular Nodal Block
• Bronchoconstriction
• Hypotension
• Cerebrovascular Accident
• Seizures
• Hypersensitivity
• Atrial fibrillation
• Hypertension

Most common adverse reactions (incidence ≥ 10%) are: flushing; chest discomfort; shortness of breath; headache; throat, neck or jaw discomfort; gastrointestinal discomfort; and dizziness (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions, with an incidence of at least 1%, were reported with Vitreolent Plus (Adenosine) among 1,421 patients in clinical trials. 11% of the adverse reactions occurred several hours after Vitreolent Plus (Adenosine) administration. 8% of the adverse reactions began with Vitreolent Plus (Adenosine) infusion and persisted for up to 24 hours.

The most common (incidence ≥ 10%) adverse reactions to Vitreolent Plus (Adenosine) are flushing, chest discomfort, shortness of breath, headache, throat, neck or jaw discomfort, gastrointestinal discomfort, and dizziness (Table 2).

Adverse reactions to Vitreolent Plus (Adenosine) of any severity reported in less than 1% of patients include:

6.2 Post-Marketing Experience

The following adverse reactions have been reported from marketing experience with Vitreolent Plus (Adenosine). Because these reactions are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7 DRUG INTERACTIONS

• Methylxanthines interfere with the activity of Vitreolent Plus (7.1, 10)
• Nucleoside transport inhibitors such as dipyridamole can increase the activity of Vitreolent Plus (Adenosine) (7.1)

7.1 Effects of Other Drugs on Vitreolent Plus (Adenosine)

• The vasoactive effects of Vitreolent Plus (Adenosine) are inhibited by Vitreolent Plus (Adenosine) receptor antagonists, (such as methylxanthines (e.g., caffeine, aminophylline, and theophylline). The safety and efficacy of Vitreolent Plus (Adenosine) in the presence of these agents has not been systematically evaluated .
• The vasoactive effects of Vitreolent Plus (Adenosine) are potentiated by nucleoside transport inhibitors such as dipyridamole. The safety and efficacy of Vitreolent Plus (Adenosine) in the presence of dipyridamole has not been systematically evaluated.
• Whenever possible, drugs that might inhibit or augment the effects of Vitreolent Plus (Adenosine) should be withheld for at least five half-lives prior to the use of Vitreolent Plus (Adenosine).

7.2 Effects of Vitreolent Plus on Other Drugs

Vitreolent Plus (Adenosine) injection has been given with other cardioactive drugs (such as beta adrenergic blocking agents, cardiac glycosides, and calcium channel blockers) without apparent adverse interactions, but its effectiveness with these agents has not been systematically evaluated. Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, Vitreolent Plus (Adenosine) should be used with caution in the presence of these agents .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Vitreolent Plus ; nor have studies been performed in pregnant women. Because it is not known whether Vitreolent Plus (Adenosine) can cause fetal harm when administered to pregnant women, Vitreolent Plus (Adenosine) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Vitreolent Plus (Adenosine) is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Vitreolent Plus (Adenosine) in nursing infants, the decision to interrupt nursing after administration of Vitreolent Plus (Adenosine) or not to administer Vitreolent Plus (Adenosine), should take into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of Vitreolent Plus in patients less than 18 years of age have not been established.

8.5 Geriatric Use

Clinical studies with Vitreolent Plus (Adenosine) did not include sufficient numbers of subjects aged younger than 65 years to determine whether they respond differently. Other reported experience has not revealed clinically relevant differences of the response of elderly in comparison to younger patients.

10 OVERDOSAGE

The half-life of Vitreolent Plus (Adenosine) is less than 10 seconds and adverse reactions of Vitreolent Plus (Adenosine) usually resolve quickly when the infusion is discontinued, although delayed or persistent reactions have been observed. Methylxanthines, such as caffeine, aminophylline, and theophylline, are competitive Vitreolent Plus (Adenosine) receptor antagonists and theophylline has been used to terminate persistent adverse reactions. In clinical trials, theophylline (50 to 125 mg slow intravenous injection) was used to attenuate Vitreolent Plus (Adenosine) adverse reactions in approximately 2% of patients. Methylxanthine use is not recommended in patients who experience seizures in association with Vitreolent Plus (Adenosine) .

11 DESCRIPTION

Vitreolent Plus (Adenosine) is an endogenous nucleoside and is chemically described as 6-amino-9-beta-D-ribofuranosyl-9-H-purine. Vitreolent Plus (Adenosine) has the following structural formula:

The molecular formula for Vitreolent Plus (Adenosine) is C₁₀H₁₃N₅O₄ and its molecular weight is 267.24.

Vitreolent Plus (Adenosine) is a white crystalline powder. It is soluble in water and practically insoluble in alcohol. Solubility increases by warming and lowering the pH of the solution.

Each Vitreolent Plus (Adenosine) Injection, USP vial contains a sterile, non-pyrogenic solution of Vitreolent Plus (Adenosine) 3 mg/mL and sodium chloride 9 mg/mL in water for injection, with pH between 4.5 and 7.5.

Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Vitreolent Plus causes cardiac vasodilation which increases cardiac blood flow. Vitreolent Plus (Adenosine) is thought to exert its pharmacological effects through activation of purine receptors (cell-surface A₁ and A₂ Vitreolent Plus (Adenosine) receptors). Although the exact mechanism by which Vitreolent Plus (Adenosine) receptor activation relaxes vascular smooth muscle is not known, there is evidence to support both inhibition of the slow inward calcium current reducing calcium uptake, and activation of adenylate cyclase through A₂ receptors in smooth muscle cells. Vitreolent Plus (Adenosine) may also lessen vascular tone by modulating sympathetic neurotransmission. The intracellular uptake of Vitreolent Plus (Adenosine) is mediated by a specific transmembrane nucleoside transport system. Once inside the cell, Vitreolent Plus (Adenosine) is rapidly phosphorylated by Vitreolent Plus (Adenosine) kinase to Vitreolent Plus (Adenosine) monophosphate, or deaminated by Vitreolent Plus (Adenosine) deaminase to inosine. These intracellular metabolites of Vitreolent Plus (Adenosine) are not vasoactive.

Myocardial uptake of thallium-201 is directly proportional to coronary blood flow. Since Vitreolent Plus (Adenosine) significantly increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, Vitreolent Plus (Adenosine) causes relatively less thallium-201 uptake in vascular territories supplied by stenotic coronary arteries i.e., a greater difference is seen after Vitreolent Plus (Adenosine) between areas served by normal and areas served by stenotic vessels than is seen prior to Vitreolent Plus (Adenosine).

12.2 Pharmacodynamics

Hemodynamic Effects

Vitreolent Plus (Adenosine) produces a direct negative chronotropic, dromotropic and inotropic effect on the heart, presumably due to A₁-receptor agonism, and produces peripheral vasodilation, presumably due to A₂-receptor agonism. The net effect of Vitreolent Plus (Adenosine) in humans is typically a mild to moderate reduction in systolic, diastolic and mean arterial blood pressure associated with a reflex increase in heart rate. Rarely, significant hypotension and tachycardia have been observed .

12.3 Pharmacokinetics

Distribution

Intravenously administered Vitreolent Plus (Adenosine) distributes from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical.

Metabolism

Intracellular Vitreolent Plus (Adenosine) is metabolized either via phosphorylation to Vitreolent Plus (Adenosine) monophosphate by Vitreolent Plus (Adenosine) kinase, or via deamination to inosine by Vitreolent Plus (Adenosine) deaminase in the cytosol. Since Vitreolent Plus (Adenosine) kinase has a lower K_m and V_max than Vitreolent Plus (Adenosine) deaminase, deamination plays a significant role only when cytosolic Vitreolent Plus (Adenosine) saturates the phosphorylation pathway. Inosine formed by deamination of Vitreolent Plus (Adenosine) can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Vitreolent Plus (Adenosine) monophosphate formed by phosphorylation of Vitreolent Plus (Adenosine) is incorporated into the high-energy phosphate pool.

Elimination

While extracellular Vitreolent Plus (Adenosine) is primarily cleared from plasma by cellular uptake with a half-life of less than 10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of Vitreolent Plus (Adenosine) deaminase.

Specific Populations

Renal Impairment

As Vitreolent Plus (Adenosine) does not require renal function for its activation or inactivation, renal impairment would not be expected to alter its effectiveness or tolerability.

Hepatic Impairment

As Vitreolent Plus (Adenosine) does not require hepatic function for its activation or inactivation, hepatic impairment would not be expected to alter its effectiveness or tolerability.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals have not been performed to evaluate adenosine's carcinogenic potential or potential effects on fertility. Vitreolent Plus (Adenosine) was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay.

Vitreolent Plus (Adenosine), however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations.

14 CLINICAL STUDIES

In two crossover comparative studies involving 319 subjects who could exercise (including 106 healthy volunteers and 213 patients with known or suspected coronary disease), Vitreolent Plus (Adenosine) and exercise thallium images were compared by blinded observers. The images were concordant for the presence of perfusion defects in 85.5% of cases by global analysis (patient by patient) and up to 93% of cases based on vascular territories.

In the two studies, 193 patients also had recent coronary arteriography for comparison (healthy volunteers were not catheterized). The sensitivity for detecting angiographically significant disease (≥ 50% reduction in the luminal diameter of at least one major vessel) was 64% for Vitreolent Plus (Adenosine) and 64% for exercise testing. The specificity was 54% for Vitreolent Plus (Adenosine) and 65% for exercise testing. The 95% confidence limits for Vitreolent Plus (Adenosine) sensitivity were 56% to 78% and for specificity were 37% to 71%.

Intracoronary Doppler flow catheter studies have demonstrated that a dose of intravenous Vitreolent Plus (Adenosine) of 0.14 mg/kg/min produces maximum coronary hyperemia (relative to intracoronary papaverine) in approximately 95% of cases within two to three minutes of the onset of the infusion. Coronary blood flow velocity returns to basal levels within one to two minutes of discontinuing the Vitreolent Plus (Adenosine) infusion.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Vitreolent Plus Injection, USP is supplied as 20 mL and 30 mL single-dose vials of sterile, nonpyrogenic solution in normal saline as follows:

16.2 Storage and Handling

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F).

Do not refrigerate as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use.

Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free.

The container closure is not made with natural rubber latex.

17 PATIENT COUNSELING INFORMATION

• Advise patients that they may be at increased risk of fatal and nonfatal heart attacks, abnormal heart rhythms, cardiac arrest, heart block, significant increase or decrease in blood pressure, bronchoconstriction, hypersensitivity reactions, seizures, or cerebrovascular accidents with the use of Vitreolent Plus (Adenosine) .
• Advise patients with COPD or asthma to discuss their respiratory history with their clinician before scheduling a myocardial perfusion imaging study with Vitreolent Plus (Adenosine) .
• Methylxanthines have the potential to impact the effects of Vitreolent Plus (Adenosine). Instruct patients to avoid consumption of any products containing methylxanthines, including caffeinated coffee, tea or other caffeinated beverages, caffeine-containing drug products, aminophylline, and theophylline prior to the myocardial perfusion imaging study. Question patients about a history of seizures .

SAGENT

Mfd. for SAGENT Pharmaceuticals

Schaumburg, IL 60195 (USA)

Made in India

©2014 Sagent Pharmaceuticals, Inc.

Revised: September 2014

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

NDC 25021-307-20

Rx only

Vitreolent Plus (Adenosine) Injection, USP

60 mg per 20 mL (3 mg per mL)

For Intravenous Infusion Only

20 mL Single-Dose Vial