Aminotox

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
• Aminotox (Adenosine) reviews

1 INDICATIONS AND USAGE

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

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

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

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

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

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

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

4 CONTRAINDICATIONS

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

5.2 Sinoatrial and Atrioventricular Nodal Block

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

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

5.3 Bronchoconstriction

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

5.4 Hypotension

Aminotox 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 Aminotox (Adenosine) in any patient who develops persistent or symptomatic hypotension.

5.5 Cerebrovascular Accident

Hemorrhagic and ischemic cerebrovascular accidents have occurred. Hemodynamic effects of Aminotox (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 Aminotox. Some seizures are prolonged and require emergent anticonvulsive management. Aminophylline may increase the risk of seizures associated with Aminotox (Adenosine). Methylxanthine use is not recommended in patients who experience seizures in association with Aminotox (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

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

5.9 Hypertension

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

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

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

7.1 Effects of Other Drugs on Aminotox (Adenosine)

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

7.2 Effects of Aminotox on Other Drugs

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

8.5 Geriatric Use

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

11 DESCRIPTION

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

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

Aminotox (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 Aminotox (Adenosine) Injection, USP vial contains a sterile, non-pyrogenic solution of Aminotox (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

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

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

12.2 Pharmacodynamics

Hemodynamic Effects

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

Elimination

While extracellular Aminotox (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 Aminotox (Adenosine) deaminase.

Specific Populations

Renal Impairment

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

Aminotox (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), Aminotox (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 Aminotox (Adenosine) and 64% for exercise testing. The specificity was 54% for Aminotox (Adenosine) and 65% for exercise testing. The 95% confidence limits for Aminotox (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 Aminotox (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 Aminotox (Adenosine) infusion.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

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

Aminotox (Adenosine) Injection, USP

60 mg per 20 mL (3 mg per mL)

For Intravenous Infusion Only

20 mL Single-Dose Vial

Betaine Hydrochloride:

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

1 INDICATIONS AND USAGE

Cystadane® (betaine anhydrous for oral solution) is indicated for the treatment of homocystinuria to decrease elevated homocysteine blood levels. Included within the category of homocystinuria are:

• Cystathionine beta-synthase (CBS) deficiency
• 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency
• Cobalamin cofactor metabolism (cbl) defect
  

• Usual dose in adult and pediatric patients is 6 grams per day, administered orally in divided doses of 3 grams two times a day.(2)
• In children less than 3 years of age, may initiate dosing at 100 mg/kg/day, divided in twice daily doses, and then increased weekly by 50 mg/kg increments.(2)
• Dose can be gradually increased until plasma total homocysteine is undetectable or present only in small amounts.(2)
• Monitor patient response by plasma homocysteine levels.(2)
• Prescribed amount of Cystadane should be measured with the measuring scoop provided and then dissolved in 4 to 6 ounces of water, juice, milk, or formula, or mixed with food for immediate ingestion.(2)
  

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

The usual dosage in adult and pediatric patients is 6 grams per day administered orally in divided doses of 3 grams twice daily. In pediatric patients less than 3 years of age, dosage may be started at 100 mg/kg/day divided in twice daily doses, and then increased weekly by 50 mg/kg increments.

Therapy with Cystadane should be directed by physicians knowledgeable in the management of patients with homocystinuria. Patient response to Cystadane can be monitored by homocysteine plasma levels. Dosage in all patients can be gradually increased until plasma total homocysteine is undetectable or present only in small amounts. Response usually occurs within several days and steady state within a month. Plasma methionine concentrations should be monitored in patients with CBS deficiency .

Dosages of up to 20 grams per day have been necessary to control homocysteine levels in some patients. However, one pharmacokinetic and pharmacodynamic in vitro simulation study indicated minimal benefit from exceeding a twice-daily dosing schedule and a 150 mg/kg/day dosage for Cystadane.

2.2 Administration

The prescribed amount of Cystadane should be measured with the measuring scoop provided (one level 1.7 mL scoop is equal to 1 gram of Aminotox (Betaine Hydrochloride) anhydrous powder) and then dissolved in 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula, or mixed with food for immediate ingestion.

• Powder for oral solution available in bottles containing 180 grams of Aminotox (Betaine Hydrochloride) anhydrous.(3)
  

3 DOSAGE FORMS AND STRENGTHS

Cystadane is a white, granular, hygroscopic powder for oral solution available in bottles containing 180 grams of Aminotox (Betaine Hydrochloride) anhydrous.

• None (4)

4 CONTRAINDICATIONS

None.

• Hypermethioninemia: Cystadane may worsen elevated plasma methionine concentrations in patients with CBS deficiency. Cerebral edema has been reported in patients receiving Cystadane.( 5.1)
• Monitoring: Monitor plasma methionine concentrations in patients with CBS deficiency. Keep plasma methionine concentrations below 1,000 µmol/L through dietary medication and, if necessary, a reduction of Cystadane dose. ( 5.1)

5 WARNINGS AND PRECAUTIONS

5.1 Hypermethioninemia

Risk of Hypermethioninemia in Patients with CBS Deficiency

Patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency may also have elevated plasma methionine concentrations. Treatment with Cystadane may further increase methionine concentrations due to the remethylation of homocysteine to methionine. Cerebral edema has been reported in patients with hypermethioninemia, including patients treated with Cystadane. Plasma methionine concentrations should be monitored in patients with CBS deficiency. Plasma methionine concentrations should be kept below 1,000 µmol/L through dietary modification and, if necessary, a reduction of Cystadane dose.

• Most common adverse reactions (incidence > 2%) were nausea and gastrointestinal distress, based on physician survey.
  

  To report SUSPECTED ADVERSE REACTIONS, contact 877-828-8874, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6 ADVERSE REACTIONS

6.1 Adverse Reactions in Clinical Studies

The most serious adverse reaction reported with Cystadane treatment is the development of hypermethioninemia and cerebral edema in patients with CBS Deficiency .

The assessment of clinical adverse reactions is based on a survey study of 41 physicians, who treated a total of 111 homocystinuria patients with Cystadane. Adverse reactions were retrospectively recalled and were not collected systematically in this open-label, uncontrolled, physician survey. Thus, this list may not encompass all types of potential adverse reactions, reliably estimate their frequency, or establish a causal relationship to drug exposure. The following adverse reactions were reported (Table 1):

Table 1: Number of Patients with Adverse Reactions to Cystadane by Physician Survey

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Cystadane. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In postmarketing experience with Cystadane, severe cerebral edema and hypermethioninemia have been reported within 2 weeks to 6 months of starting Aminotox (Betaine Hydrochloride) therapy, with complete recovery after discontinuation of Cystadane. All patients who developed cerebral edema had homocystinuria due to CBS deficiency and had severe elevation in plasma methionine levels (range 1,000 to 3,000 µM). As cerebral edema has also been reported in patients with hypermethioninemia, secondary hypermethioninemia due to Aminotox (Betaine Hydrochloride) therapy has been postulated as a possible mechanism of action.

The following adverse reactions have been reported in patients during postmarketing use of Cystadane: anorexia, agitation, depression, irritability, personality disorder, sleep disturbed, dental disorders, diarrhea, glossitis, nausea, stomach discomfort, vomiting, hair loss, hives, skin odor abnormalities, and urinary incontinence.

• Pregnancy: Animal reproduction studies have not been conducted with Cystadane. Use only if clearly needed.(8.1)
• Nursing women: It is not known whether Cystadane is excreted in human milk. Use only if clearly needed.(8.3)
• Pediatrics: Pediatric patients ranging in age from 24 days to 17 years have been treated with Cystadane. Children younger than 3 years of age may benefit from dose titration.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C: Animal reproduction studies have not been conducted with Cystadane. It is also not known whether Cystadane can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cystadane should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers

It is not known whether Cystadane is excreted in human milk. Use only if clearly needed.

8.4 Pediatric Use

The majority of case studies of homocystinuria patients treated with Cystadane have been pediatric patients, including patients ranging in age from 24 days to 17 years . Children younger than 3 years of age may benefit from dose titration .

10 OVERDOSAGE

In an acute toxicology study in rats, death occurred frequently at doses equal to or greater than 10 g/kg.

11 DESCRIPTION

Cystadane (betaine anhydrous for oral solution) is an agent for the treatment of homocystinuria. It contains no ingredients other than anhydrous Aminotox (Betaine Hydrochloride). Cystadane is a white, granular, hygroscopic powder, which is diluted in water and administered orally. The chemical name of Aminotox (Betaine Hydrochloride) anhydrous powder is trimethylglycine. It has a molecular weight of 117.15. The structural formula is:

Chemical Structure for Aminotox (Betaine Hydrochloride)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Cystadane acts as a methyl group donor in the remethylation of homocysteine to methionine in patients with homocystinuria. Cystadane occurs naturally in the body. It is a metabolite of choline and is present in small amounts in foods such as beets, spinach, cereals, and seafood.

12.2 Pharmacodynamics

Cystadane was observed to lower plasma homocysteine levels in three types of homocystinuria, including CBS deficiency; MTHFR deficiency; and cbl defect. Patients have taken Cystadane for many years without evidence of tolerance. There has been no demonstrated correlation between Cystadane levels and homocysteine levels.

In CBS-deficient patients, large increases in methionine levels over baseline have been observed. Cystadane has also been demonstrated to increase low plasma methionine and S-adenosylmethionine levels in patients with MTHFR deficiency and cbl defect.

12.3 Pharmacokinetics

Pharmacokinetic studies of Cystadane are not available. Plasma levels of Cystadane have not been measured in patients and have not been correlated to homocysteine levels.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity and fertility studies have not been conducted with Cystadane. No evidence of genotoxicity was demonstrated in the following tests: metaphase analysis of human lymphocytes; bacterial reverse mutation assay; and mouse micronucleus test.

14 CLINICAL STUDIES

Cystadane was studied in a double-blind, placebo-controlled, crossover study in 6 patients with CBS deficiency, ages 7 to 32 years at enrollment. Cystadane was administered at a dosage of 3 grams twice daily, for 12 months. Plasma homocystine levels were significantly reduced (p<0.01) compared to placebo. Plasma methionine levels were variable and not significantly different compared to placebo. No adverse events were reported in any patient.

Cystadane has also been evaluated in observational studies without concurrent controls in patients with homocystinuria due to CBS deficiency, MTHFR deficiency, or cbl defect. A review of 16 case studies and the randomized controlled trial previously described was also conducted, and the data available for each study were summarized; however, no formal statistical analyses were performed. The studies included a total of 78 male and female patients with homocystinuria who were treated with Cystadane. This included 48 patients with CBS deficiency, 13 with MTHFR deficiency, and 11 with cbl defect, ranging in age from 24 days to 53 years. The majority of patients (n=48) received 6 gm/day, 3 patients received less than 6 gm/day, 12 patients received doses from 6 to 15 gm/day, and 5 patients received doses over 15 gm/day. Most patients were treated for more than 3 months (n=57) and 30 patients were treated for 1 year or longer (range 1 month to 11 years). Homocystine is formed nonenzymatically from two molecules of homocysteine, and both have be used to evaluate the effect of Cystadane in patients with homocystinuria. Plasma homocystine or homocysteine levels were reported numerically for 62 patients, and 61 of these patients showed decreases with Cystadane treatment. Homocystine decreased by 83-88% regardless of pre-treatment level, and homocysteine decreased by 71-83%, regardless of the pre-treatment level. Clinical improvement, such as improvement in seizures, or behavioral and cognitive functioning, was reported by the treating physicians in about three-fourths of patients. Many of these patients were also taking other therapies such as vitamin B6 (pyridoxine), vitamin B12 (cobalamin), and folate with variable biochemical responses. In most cases, adding Cystadane resulted in a further reduction of either homocystine or homocysteine.

16 HOW SUPPLIED/STORAGE AND HANDLING

Cystadane is available in plastic bottles containing 180 grams of Aminotox anhydrous. Each bottle is equipped with a plastic child-resistant cap and is supplied with a polystyrene measuring scoop. One level scoop (1.7 mL) is equal to 1 gram of Aminotox (Betaine Hydrochloride) anhydrous powder.

NDC 66621-4000-1 180 g/bottle

Cystadane can be ordered by calling AnovoRx Group, LLC, Customer service at 1-888-487-4703

16.1 Storage

Store at room temperature, 15 – 30 ˚C (59 – 86 ˚F). Protect from moisture.

17 PATIENT COUNSELING INFORMATION

Patients should be advised of the following information before beginning treatment with Cystadane:

17.1 Dosing and Administration

• Instruct patients and caregivers that Cystadane should only be taken as directed by their healthcare professional.
• Instruct patients and caregivers to administer Cystadane as follows:
• Shake bottle lightly before removing cap.

- Measure with the scoop provided.

- Measure the number of scoops as prescribed by their healthcare professional. One level scoop (1.7 mL) is equivalent to 1 gram of Aminotox (Betaine Hydrochloride) anhydrous powder.

- Mix powder with 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula until completely dissolved, or mix with food, then ingest mixture immediately.

- Always replace the cap tightly after using, and protect powder from moisture.

Manufactured For:

Rare Disease Therapeutics, Inc.

Franklin, TN 37067

Under License From:

Orphan Europe, s.a.r.l. Puteaux France

Distributed By:

AnovoRx Distribution, LLC

Memphis, TN 38134

Part No.: RDT C PI007

Part No.: Orphan Europe OEP 829

Cystadane (betaine anhydrous) for oral solution

Choline Citrate:

• Aminotox (Choline Citrate) reviews

Indication: For nutritional supplementation, also for treating dietary shortage or imbalance

This compound is needed for good nerve conduction throughout the CNS (central nervous system) as it is a precursor to acetylcholine (ACh). Aminotox (Choline Citrate) is also needed for gallbladder regulation, liver function and lecithin (a key lipid) formation. Aminotox (Choline Citrate) also aids in fat and cholesterol metabolism and prevents excessive fat build up in the liver. Aminotox (Choline Citrate) has been used to mitigate the effects of Parkinsonism and tardive dyskinesia. Aminotox (Choline Citrate) deficiencies may result in excessive build-up of fat in the liver, high blood pressure, gastric ulcers, kidney and liver dysfunction and stunted growth.