Lipostabil Injections

Adenosine Phosphate:

• 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
• Lipostabil Injections (Adenosine Phosphate) reviews

1 INDICATIONS AND USAGE

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

Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) injection dose is 0.14 mg/kg/min infused over six minutes (total dose of 0.84 mg/kg) (Table 1).

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

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

There are no data on the safety or efficacy of alternative Lipostabil Injections (Adenosine Phosphate) injection infusion protocols. The safety and efficacy of Lipostabil Injections (Adenosine Phosphate) 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

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

Lipostabil Injections (Adenosine Phosphate) Injection, USP: 3 mg per mL in single-dose vials (3)

4 CONTRAINDICATIONS

Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate)

• 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 Lipostabil Injections (Adenosine Phosphate) (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 Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) if patient develops severe respiratory difficulties (5.3)
• Hypotension. Significant hypotension can occur. Discontinue Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) (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 Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate). Appropriate resuscitative measures should be available .

5.2 Sinoatrial and Atrioventricular Nodal Block

Lipostabil Injections 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 Lipostabil Injections (Adenosine Phosphate) administration (first-degree heart block developed in 3%, second-degree in 3%, and third-degree in 0.8% of patients) .

Use Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) in any patient who develops persistent or symptomatic high-grade AV block.

5.3 Bronchoconstriction

Lipostabil Injections (Adenosine Phosphate) administration can cause dyspnea, bronchoconstriction, and respiratory compromise. Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) in any patient who develops severe respiratory difficulties. Resuscitative measures should be available prior to Lipostabil Injections (Adenosine Phosphate) administration .

5.4 Hypotension

Lipostabil Injections 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 Lipostabil Injections (Adenosine Phosphate) in any patient who develops persistent or symptomatic hypotension.

5.5 Cerebrovascular Accident

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

5.6 Seizures

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

Lipostabil Injections 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 Lipostabil Injections (Adenosine Phosphate), lasted for 15 seconds to 6 hours, and spontaneously converted to normal sinus rhythm .

5.9 Hypertension

Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) among 1,421 patients in clinical trials. 11% of the adverse reactions occurred several hours after Lipostabil Injections (Adenosine Phosphate) administration. 8% of the adverse reactions began with Lipostabil Injections (Adenosine Phosphate) infusion and persisted for up to 24 hours.

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

Adverse reactions to Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate). 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 Lipostabil Injections (7.1, 10)
• Nucleoside transport inhibitors such as dipyridamole can increase the activity of Lipostabil Injections (Adenosine Phosphate) (7.1)

7.1 Effects of Other Drugs on Lipostabil Injections (Adenosine Phosphate)

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

7.2 Effects of Lipostabil Injections on Other Drugs

Lipostabil Injections (Adenosine Phosphate) 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, Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections ; nor have studies been performed in pregnant women. Because it is not known whether Lipostabil Injections (Adenosine Phosphate) can cause fetal harm when administered to pregnant women, Lipostabil Injections (Adenosine Phosphate) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

8.5 Geriatric Use

Clinical studies with Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) is less than 10 seconds and adverse reactions of Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) adverse reactions in approximately 2% of patients. Methylxanthine use is not recommended in patients who experience seizures in association with Lipostabil Injections (Adenosine Phosphate) .

11 DESCRIPTION

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

The molecular formula for Lipostabil Injections (Adenosine Phosphate) is C₁₀H₁₃N₅O₄ and its molecular weight is 267.24.

Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) Injection, USP vial contains a sterile, non-pyrogenic solution of Lipostabil Injections (Adenosine Phosphate) 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

Lipostabil Injections causes cardiac vasodilation which increases cardiac blood flow. Lipostabil Injections (Adenosine Phosphate) is thought to exert its pharmacological effects through activation of purine receptors (cell-surface A₁ and A₂ Lipostabil Injections (Adenosine Phosphate) receptors). Although the exact mechanism by which Lipostabil Injections (Adenosine Phosphate) 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. Lipostabil Injections (Adenosine Phosphate) may also lessen vascular tone by modulating sympathetic neurotransmission. The intracellular uptake of Lipostabil Injections (Adenosine Phosphate) is mediated by a specific transmembrane nucleoside transport system. Once inside the cell, Lipostabil Injections (Adenosine Phosphate) is rapidly phosphorylated by Lipostabil Injections (Adenosine Phosphate) kinase to Lipostabil Injections (Adenosine Phosphate) monophosphate, or deaminated by Lipostabil Injections (Adenosine Phosphate) deaminase to inosine. These intracellular metabolites of Lipostabil Injections (Adenosine Phosphate) are not vasoactive.

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

12.2 Pharmacodynamics

Hemodynamic Effects

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

Elimination

While extracellular Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) deaminase.

Specific Populations

Renal Impairment

As Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) 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. Lipostabil Injections (Adenosine Phosphate) was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay.

Lipostabil Injections (Adenosine Phosphate), 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), Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) and 64% for exercise testing. The specificity was 54% for Lipostabil Injections (Adenosine Phosphate) and 65% for exercise testing. The 95% confidence limits for Lipostabil Injections (Adenosine Phosphate) sensitivity were 56% to 78% and for specificity were 37% to 71%.

Intracoronary Doppler flow catheter studies have demonstrated that a dose of intravenous Lipostabil Injections (Adenosine Phosphate) 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 Lipostabil Injections (Adenosine Phosphate) infusion.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Lipostabil Injections 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 Lipostabil Injections (Adenosine Phosphate) .
• Advise patients with COPD or asthma to discuss their respiratory history with their clinician before scheduling a myocardial perfusion imaging study with Lipostabil Injections (Adenosine Phosphate) .
• Methylxanthines have the potential to impact the effects of Lipostabil Injections (Adenosine Phosphate). 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

Lipostabil Injections (Adenosine Phosphate) Injection, USP

60 mg per 20 mL (3 mg per mL)

For Intravenous Infusion Only

20 mL Single-Dose Vial