Aminocore 5-S Plus

Arginine:

• Aminocore 5-S Plus (Arginine) reviews

Nutritive Wound - Skin Cream

For Minor Cuts and Wounds

- Eases Discomfort

- Soothing Cream

CONTAINS:

Aminocore 5-S Plus (Arginine) Aminobenzoate 2.5% Patent # 5734080

In a cream base with Safflower Oil, Apricot Kernel Oil, Mixed Tocopherols, Glycerin, Coconut Oil, Borage Oil, Tea Tree Oil, Camphor, Thymine, Lecithin, Grapefruit Extract, Lemon Oil and Aloe Vera.

DIRECTIONS:

Apply topically as needed to superficial wounds and abrasions.

INDICATIONS FOR USE:

FelineAid can be used on minor cuts, abrasions and irritations as well as superficial wounds and skin lesions on cats.

CAUTIONS:

Avoid contact with eyes. If contact occurs, flush with copious amounts of water. If condition persists or worsens discontinue use.

Shake Well

Store at room temperature.

For Veterinary Use Only

Asparaginase:

• 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
• Aminocore 5-S Plus (Asparaginase) reviews

1 INDICATIONS AND USAGE

Aminocore 5-S Plus (Asparaginase) (asparaginase Erwinia chrysanthemi) is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. coli-derived Aminocore 5-S Plus (Asparaginase).

Aminocore 5-S Plus (Asparaginase) (asparaginase Erwinia chrysanthemi) is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. coli-derived asparaginase. (1)

2 DOSAGE AND ADMINISTRATION

• To substitute for a dose of pegaspargase: The recommended dose for each planned dose of pegaspargase is 25,000 International Units/m² administered intramuscularly or intravenously 3 times a week for 6 doses. (2.1)
• To substitute for a dose of native E. coli Aminocore 5-S Plus (Asparaginase): The recommended dose is 25,000 International Units/m² administered intramuscularly or intravenously for each scheduled dose of native E. coli Aminocore 5-S Plus (Asparaginase). (2.1)

2.1 Recommended Dose

To substitute for a dose of pegaspargase:

The recommended dose for each planned dose of pegaspargase is 25,000 International Units/m² administered intramuscularly or intravenously three times a week (Monday/Wednesday/Friday) for six doses.

To substitute for a dose of native E. coli Aminocore 5-S Plus (Asparaginase):

The recommended dose is 25,000 International Units/m² administered intramuscularly or intravenously for each scheduled dose of native E. coli Aminocore 5-S Plus (Asparaginase) within a treatment.

When administering Aminocore 5-S Plus (Asparaginase) intravenously, consider monitoring nadir (pre-dose) serum Aminocore 5-S Plus (Asparaginase) activity (NSAA) levels and switching to intramuscular administration if desired NSAA levels are not achieved [see Clinical Pharmacology (12.3)].

2.2 Preparation and Handling Instructions

1. Visually inspect the Aminocore 5-S Plus powder for foreign particulate matter and discoloration prior to reconstitution. Discard vial if present.

2. Reconstitute the contents of each vial by slowly injecting 1 or 2 mL of preservative free sterile sodium chloride (0.9%) injection (USP) against the inner vial wall.

3. Do not forcefully inject solution for reconstitution directly onto or into the powder. When reconstituted with 1 mL the resultant concentration is 10,000 International Units per mL. When reconstituted with 2 mL the resultant concentration is 5,000 International Units per mL.

4. Dissolve contents by gentle mixing or swirling. Do not shake or invert vial.

5. When reconstituted, Aminocore 5-S Plus (Asparaginase) should be a clear, colorless solution. Inspect the solution after reconstitution and discard if any visible particles or protein aggregates are present.

6. Calculate the dose needed and the volume needed to obtain the calculated dose.

7. Withdraw the volume containing the calculated dose from the vial into a polypropylene syringe within 15 minutes of reconstitution. For intravenous use, slowly inject the reconstituted Aminocore 5-S Plus (Asparaginase) into an IV infusion bag containing 100 mL of normal saline acclimatized to room temperature. Do not shake or squeeze the IV bag.

8. If partial vial is used, do not save or reuse the unused drug for later administration. Discard unused portions.

9. Do not freeze or refrigerate reconstituted solution and administer within 4 hours or discard [see How Supplied/Storage and Handling (16)].

2.3 Administration Instructions

Aminocore 5-S Plus (Asparaginase) solution can be administered by intramuscular injection or by intravenous infusion.

• For intramuscular use, limit the volume of reconstituted Aminocore 5-S Plus (Asparaginase) at a single injection site to 2 mL; if reconstituted dose to be administered is greater than 2 mL, use multiple injection sites.
• For intravenous use, infuse Aminocore 5-S Plus (Asparaginase) in 100 mL of normal saline over 1 to 2 hours. Do not infuse other intravenous drugs through the same intravenous line while infusing Aminocore 5-S Plus (Asparaginase).

3 DOSAGE FORMS AND STRENGTHS

Lyophilized powder 10,000 International Units per vial

- 10,000 International Units lyophilized powder per vial.

4 CONTRAINDICATIONS

• History of serious hypersensitivity reactions to Aminocore 5-S Plus (Asparaginase), including anaphylaxis
• History of serious pancreatitis with prior L-asparaginase therapy
• History of serious thrombosis with prior L-asparaginase therapy
• History of serious hemorrhagic events with prior L-asparaginase therapy

• History of serious hypersensitivity reactions to Aminocore 5-S Plus (Asparaginase), including anaphylaxis (4)
• History of serious pancreatitis with prior L-asparaginase therapy (4)
• History of serious thrombosis with prior L-asparaginase therapy (4)
• History of serious hemorrhagic events with prior L-asparaginase therapy (4)

5 WARNINGS AND PRECAUTIONS

• If the following occur, discontinue Aminocore 5-S Plus :
  

  Serious hypersensitivity reactions, including anaphylaxis (5.1)
  

  Severe or hemorrhagic pancreatitis (5.2)

• Glucose intolerance can occur and, in some cases, may be irreversible. Perform appropriate monitoring and treat hyperglycemia with insulin, as necessary (5.3)
• Thrombosis, hemorrhage: discontinue Aminocore 5-S Plus (Asparaginase) until resolved (5.4)

5.1 Hypersensitivity Reactions

Grade 3 and 4 hypersensitivity reactions after the use of Aminocore 5-S Plus (Asparaginase) have occurred in 5% of patients in clinical trials [see Adverse Reactions (6.1)].

Administer this product in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. If a serious hypersensitivity reaction occurs, discontinue Aminocore 5-S Plus (Asparaginase) and initiate appropriate therapy.

5.2 Pancreatitis

Pancreatitis has been reported in 4% of patients in clinical trials [see Adverse Reactions ].

Evaluate patients with symptoms compatible with pancreatitis to establish a diagnosis. Discontinue Aminocore 5-S Plus (Asparaginase) for severe or hemorrhagic pancreatitis manifested by abdominal pain > 72 hours and amylase elevation ≥ 2.0 x ULN. Severe pancreatitis is a contraindication to additional Aminocore 5-S Plus (Asparaginase) administration. In the case of mild pancreatitis, hold Aminocore 5-S Plus (Asparaginase) until the signs and symptoms subside and amylase levels return to normal. After resolution, treatment with Aminocore 5-S Plus (Asparaginase) may be resumed.

5.3 Glucose Intolerance

Glucose intolerance has been reported in 5% of patients receiving Aminocore 5-S Plus (Asparaginase) in clinical trials [see Adverse Reactions (6.1)]. In some cases glucose intolerance may be irreversible. Monitor glucose levels in patients at baseline and periodically during treatment. Administer insulin therapy as necessary in patients with hyperglycemia.

5.4 Thrombosis and Hemorrhage

Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism have been reported with both E. coli and Erwinia-derived L-asparaginase therapy. The following coagulation proteins were decreased in the majority of patients after a 2-week course of Aminocore 5-S Plus (Asparaginase) by intramuscular administration: fibrinogen, protein C activity, protein S activity, and anti-thrombin III. Discontinue Aminocore 5-S Plus (Asparaginase) for a thrombotic or hemorrhagic event until symptoms resolve; after resolution, treatment with Aminocore 5-S Plus (Asparaginase) may be resumed.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Hypersensitivity reactions [see Warnings and Precautions ]
• Pancreatitis [see Warnings and Precautions (5.2)]
• Glucose intolerance [see Warnings and Precautions (5.3)]
• Thrombosis and hemorrhage [see Warnings and Precautions (5.4)]

The most common adverse reactions (incidence 1% or greater) with Aminocore 5-S Plus (Asparaginase) treatment are systemic hypersensitivity, hyperglycemia, transaminases abnormal, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, and diarrhea.

Most common adverse reactions (incidence 1% or greater) are: systemic hypersensitivity, hyperglycemia, transaminases abnormal, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, and diarrhea.

To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Studies

Because clinical trials are conducted under controlled, but widely varying conditions, adverse reaction rates observed in clinical trials of Aminocore 5-S Plus (Asparaginase) cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.

The data presented below are based on information collected from Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial (intramuscular administration), the Aminocore 5-S Plus (Asparaginase) Master Treatment Protocol (EMTP), an expanded access program (both intramuscular, intravenous, and other or unknown administration), and Study 2, a single-arm, multi-center, open-label, pharmacokinetic (PK) study trial of intravenous administration of Aminocore 5-S Plus (Asparaginase).

Study 1 enrolled 58 patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions. Patients received 6 doses of Aminocore 5-S Plus (Asparaginase) 25,000 International Units/m² intramuscularly on a Monday, Wednesday, and Friday schedule as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol. The Study 1 population included patients with a median age of 11 years (2 to 18 years); 59% were male, 78% were White, 10% were Black/African American, 5% were Asian, and 7% were other or unknown. A total of 35% were Hispanic or Latino. In Study 1, the number of Aminocore 5-S Plus (Asparaginase) courses ranged from 1 to 9. In this study, 76% (44 of 58) completed all planned therapy. Fourteen (24%) patients stopped therapy prior to completion; seven due to allergic reactions, five due to physician or patient choice, one due to disease progression, and one due to discontinuation during frontline protocol. All other chemotherapy was continued according to the patient’s prescribed treatment regimen [see Clinical Studies ( 14 )].

Study 2 enrolled 30 patients [29 were being treated for ALL and one for lymphoblastic lymphoma (LBL)] following allergy to native E. coli Aminocore 5-S Plus (Asparaginase) or pegaspargase. Patients received Aminocore 5-S Plus (Asparaginase) 25,000 International Unit/m²/dose, administered by intravenous infusion on a Monday, Wednesday, and Friday schedule (6 doses) as a replacement for doses remaining on their original treatment plan. The Study 2 population included patients with a median age of 7 years (1 to 17 years); 63% were male, 27% were Hispanic or Latino, 83% were White, 3% were Black/African American, 7% were Asian, and 7% were other (American Indian, Alaska Native or Indian) [see Clinical Studies (14)].

The EMTP trial enrolled 1368 patients with ALL or lymphoblastic lymphoma who received Aminocore 5-S Plus (Asparaginase) after developing systemic hypersensitivity to an E. coli-derived Aminocore 5-S Plus (Asparaginase). Of these 1368 patients, safety data were received for 940 patients with a median age of 9 years (0 to 76 years), 63% were male, 91% with leukemia, 3% with lymphoma, and 6% with unknown disease information. Patients received Aminocore 5-S Plus (Asparaginase) according to several schedules, and treatment center specifications with doses that ranged from 20,000 to 25,000 International Units/m². The route of administration was intramuscular n=852, intravenous n=29, other or unknown n=59. In the EMTP trial, the planned number of doses of Aminocore 5-S Plus (Asparaginase) ranged from 3 to 48 doses. Seventy-eight percent of patients (693 of 893) were able to receive all planned doses to complete their prescribed treatment regimen.

In Study 1 and Study 2, safety information was prospectively and systematically collected. In Study 1, all Grades of adverse events were reported for the following adverse events of special interest: allergy, pancreatitis, coagulopathy (hemorrhage, thrombosis or infarct), hyperbilirubinemia, hyperglycemia, hyperlipidemia, ketoacidosis, and CNS events (hemorrhage, thrombosis or infarction, and cerebral venous thrombosis) and only Grade 3 and 4 events were reported for other adverse events. In Study 2 all adverse events of all Grades were prospectively collected. In the EMTP trial, safety data were derived from case report forms that collected adverse event information. The forms specifically requested information on occurrence of allergic reactions, thrombotic events, hemorrhagic events, hepatobiliary disorders, pancreatic disorders, and hyperglycemia.

The incidence of non-hematologic, non-infectious, adverse events (all Grades) in Study 1, Study 2, and the EMTP trial is provided in Table 1.

The incidence of Grade 3 or greater non-hematologic, non-infectious adverse reactions occurring with Aminocore 5-S Plus (Asparaginase) in Study 1, Study 2 and EMTP trial is provided in Table 2.

Table 1 Table 2

6.2 Immunogenicity

As with most therapeutic proteins, patients may develop anti-drug antibodies (ADA) to Aminocore 5-S Plus (Asparaginase).

In a study with Aminocore 5-S Plus (Asparaginase) treatment by intramuscular administration (Study 1), 6 of 56 (11%) patients treated with Aminocore 5-S Plus (Asparaginase) developed antibodies to Aminocore 5-S Plus (Asparaginase). Of these 6 ADA positive patients, one experienced a hypersensitivity reaction during Study 1 (2%, 1 of 56). None of these 6 patients had neutralizing antibodies.

In a study with Aminocore 5-S Plus (Asparaginase) treatment by intravenous administration (Study 2), 4 of 30 (13.3%) patients treated with Aminocore 5-S Plus (Asparaginase) developed anti-ERWINAZE antibodies. Of these 4 patients who developed anti-ERWINAZE antibodies, 3 experienced hypersensitivity reactions (10%, 3 of 30) during the study. None of these 4 patients had neutralizing antibodies.

The presence of ADA to Aminocore 5-S Plus (Asparaginase) is associated with a higher risk of hypersensitivity reactions in patients who received Aminocore 5-S Plus (Asparaginase) through intravenous infusion compared to intramuscular administration of Aminocore 5-S Plus (Asparaginase).

Immunogenicity assay are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Aminocore 5-S Plus (Asparaginase) with the incidence of antibodies to other products may be misleading.

7 DRUG INTERACTIONS

No formal drug interaction studies between Aminocore 5-S Plus (Asparaginase) and other drugs have been performed.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies of Aminocore 5-S Plus in pregnant women. In embryofetal development studies in rats and rabbits, Aminocore 5-S Plus (Asparaginase) Erwinia chrysanthemi produced embryofetal toxicities and fetal abnormalities. Aminocore 5-S Plus (Asparaginase) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data

In embryofetal development studies, Aminocore 5-S Plus (Asparaginase) Erwinia chrysanthemi was administered intramuscularly every other day during the period of organogenesis to pregnant rats (at 500, 1000, or 2000 IU/kg) and rabbits (at 10, 25, and 40 IU/kg). In rats given 2000 IU/kg (approximately 50% of the recommended human dose, adjusted for body surface area), maternal toxicity of decreased body weight gain was observed, as well as a fetal finding of increased incidence of partially undescended thymic tissue.

In rabbits, maternal toxicity consisting of decreased body weight was observed at 40 IU/kg (approximately 2% of the recommended human dose, adjusted for body surface area). Increased post-implantation loss, a decrease in the number of live fetuses, and gross abnormalities (e.g., absent kidney, absent accessory lung lobe, additional subclavian artery, and delayed ossification) were observed at doses of ≥10 IU/kg (approximately 0.5% of the recommended human dose, adjusted for body surface area).

8.3 Nursing Mothers

It is not known whether Aminocore 5-S Plus (Asparaginase) is secreted in human milk. Because many drugs are secreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Aminocore 5-S Plus (Asparaginase), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

[see Clinical Studies ].

8.5 Geriatric Use

The safety and efficacy of Aminocore 5-S Plus (Asparaginase) has not been studied in geriatric patients.

10 OVERDOSAGE

There are no known cases of overdose with Aminocore 5-S Plus (Asparaginase).

11 DESCRIPTION

Aminocore 5-S Plus (Asparaginase) (asparaginase Erwinia chrysanthemi) contains an asparagine specific enzyme derived from Erwinia chrysanthemi. L-asparaginase is a tetrameric enzyme consisting of four identical subunits, each having a molecular weight of about 35 kDa. The activity of Aminocore 5-S Plus (Asparaginase) is expressed in terms of International Units.

Aminocore 5-S Plus (Asparaginase) is supplied as a sterile, lyophilized, white powder in vials. Each vial contains 10,000 International Units of Aminocore 5-S Plus (Asparaginase) Erwinia chrysanthemi, and the following inactive ingredients: glucose monohydrate (5.0 mg), sodium chloride (0.5 mg).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Aminocore 5-S Plus Erwinia chrysanthemi catalyzes the deamidation of asparagine to aspartic acid and ammonia, resulting in a reduction in circulating levels of asparagine. The mechanism of action of Aminocore 5-S Plus (Asparaginase) is thought to be based on the inability of leukemic cells to synthesize asparagine due to lack of asparagine synthetase activity, resulting in cytotoxicity specific for leukemic cells that depend on an exogenous source of amino acid asparagine for their protein metabolism and survival.

12.3 Pharmacokinetics

Based on a population PK model, the mean (%CV) half-life of intravenous Aminocore 5-S Plus (Asparaginase) was 7.51 (23.9%) hours in contrast to a mean (%CV) half-life of 15.6 (20%) hours reported for intramuscular Aminocore 5-S Plus (Asparaginase). These differences in PK between intravenous and intramuscular Aminocore 5-S Plus (Asparaginase) are reflected in the proportion of patients with 2-day and 3-day nadir serum Aminocore 5-S Plus (Asparaginase) activity (NSAA) levels of Aminocore 5-S Plus (Asparaginase) Erwinia chrysanthemi ≥ 0.1 or 0.4 IU/mL [see Clinical Studies (14)].

Following administration of Aminocore 5-S Plus (Asparaginase) 25,000 International Units/m² intramuscularly to 48 ALL patients aged ≥ 2 years to ≤ 18 years in Study 1 on a Monday, Wednesday, and Friday schedule for 6 doses, 100% of patients who completed Course 1 achieved NSAA levels ≥ 0.1 International Units/mL at either 48 hours (n=35) or 72 hours (n=13) post dose 3. Eighty percent (28/35) of those evaluated at 48 hours and 38% (5/13) evaluated at 72 hours had nadir serum Aminocore 5-S Plus (Asparaginase) activity levels ≥ 0.4 International Units/mL [see Clinical Studies (14)].

Following intravenous administration of Aminocore 5-S Plus (Asparaginase) 25,000 International Units/m² to 24 evaluable patients (aged ≥ 1 year to ≤ 17 years) in Study 2 on a Monday, Wednesday, and Friday schedule, 83% (20/24) and 43% (9/21) of patients who completed Course 1 achieved NSAA levels ≥ 0.1 International Units/mL at 48 hours post-dose 5 and 72 hours post dose 6, respectively. Twenty-nine percent (7/24) of those evaluated at 48 hours and no patients (0/21) evaluated at 72 hours had nadir serum Aminocore 5-S Plus (Asparaginase) activity levels ≥ 0.4 International Units/mL [see Clinical Studies (14)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term carcinogenicity studies in animals have been performed with Aminocore 5-S Plus (Asparaginase) Erwinia chrysanthemi. No studies that assess the mutagenic potential of Aminocore 5-S Plus (Asparaginase) Erwinia chrysanthemi have been conducted.

In a fertility and early embryonic development study in rats, Aminocore 5-S Plus (Asparaginase) Erwinia chrysanthemi had no effect on male or female fertility when administered intramuscularly at doses of up to 2000 IU/kg (approximately 50% of the recommended human dose, when adjusted for total body surface area) every other day for a total of 35 doses. Findings in males included decreased sperm count at doses of more than 500 IU/kg (approximately 12% of the recommended human dose).

14 CLINICAL STUDIES

The safety and efficacy of Aminocore 5-S Plus (Asparaginase) was established in Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial. Additional safety data were obtained in the Aminocore 5-S Plus (Asparaginase) Master Treatment Protocol (EMTP), an expanded access program [see Adverse Reactions (6)]. Study 1 enrolled patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions. The main outcome measure was determination of the proportion of patients who achieved a serum trough Aminocore 5-S Plus (Asparaginase) level greater than or equal to 0.1 International Units/mL. Serum trough Aminocore 5-S Plus (Asparaginase) activity ≥ 0.1 International Units/mL has been demonstrated to correlate with asparagine depletion (asparagine < 0.4 mcg/mL or 3 µM) and to serum levels that predict clinical efficacy. Patients received Aminocore 5-S Plus (Asparaginase) 25,000 International Units/m² intramuscularly for two weeks (total 6 doses) as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol.

Fifty-eight patients were enrolled in Study 1, of these 48 were evaluable for the main outcome measure based on availability of pharmacokinetic samples in Course 1. The median age was 11 years (2 to 18 years); 59% were male, 78% were White, 10% were Black/African American, 5% were Asian, and 7% were other or unknown. A total of 35% were Hispanic or Latino.

Study 1 met its main outcome measure of demonstrating that greater than 50% of the patients achieved the pre-specified trough Aminocore 5-S Plus (Asparaginase) activity level of ≥ 0.1 International Units/mL at 48 or 72 hours following the third dose. Results for the main outcome measure and for an exploratory analysis using a higher cut-off (trough serum Aminocore 5-S Plus (Asparaginase) activity levels ≥ 0.4 International Units/mL are presented in Table 3 [see Clinical Pharmacology (12.3)].

The safety and efficacy of intravenous administration were determined in Study 2 by characterizing the PK of a 25,000 International Units/m² Aminocore 5-S Plus (Asparaginase) dose given 3 days per week on a Monday, Wednesday, and Friday schedule for up to 30 weeks. This open-label, single-arm, multicenter PK study enrolled 30 patients. The main outcome measure was determination of the proportion of patients with 2-day NSAA levels (48-hour levels taken after the fifth dose) ≥ 0.1 International Unit/mL in the first 2 weeks of Aminocore 5-S Plus (Asparaginase) treatment.

Of the thirty patients enrolled, 24 were evaluable for the main outcome measure based on the pharmacokinetic samples in Course 1. The median age was 7 years (1-17 years), 63% were male, 27% were Hispanic or Latino, 83% were White, 3% were Black/African American, 7% were Asian, and 7% were other (American Indian, Alaska Native, or Indian).

In Study 2, serum Aminocore 5-S Plus (Asparaginase) activity of Aminocore 5-S Plus (Asparaginase) Erwinia chrysanthemi was determined in 24 evaluable patients (aged ≥ 1 year to ≤17 years) following intravenous administration of Aminocore 5-S Plus (Asparaginase) 25,000 International Units/m². Five minutes after the 60-minute infusion in Course 1, the mean Aminocore 5-S Plus (Asparaginase) activity level was 12.65 ± 3.16 International Unit/mL post-dose 1 and 12.11 ± 3.11 International Unit/mL post dose 4. The main study objective was met with an Aminocore 5-S Plus (Asparaginase) activity level of ≥ 0.1 International Units/mL 48 hours after the fifth dose observed in 83% of patients. The 72-hour post dose 6 Aminocore 5-S Plus (Asparaginase) activity level of ≥ 0.1 International Unit/mL was the secondary endpoint, with 43% of patients achieving this endpoint. Results are presented in Table 3 [see Clinical Pharmacology (12.3)].

Table 3

16 HOW SUPPLIED/STORAGE AND HANDLING

Aminocore 5-S Plus (Asparaginase) is a sterile, white lyophilized powder supplied in a clear 3 mL glass vial. Each carton of Aminocore 5-S Plus (Asparaginase) (NDC 57902-249-05) contains 5 vials. Each single vial (NDC 57902-249-01) contains 10,000 International Units Aminocore 5-S Plus (Asparaginase) Erwinia chrysanthemi.

Store unused or unopened vials and cartons at 36°F to 46°F (2°C to 8°C). Protect from light. Do not use Aminocore 5-S Plus (Asparaginase) after the expiration date on the vial.

17 PATIENT COUNSELING INFORMATION

• Instruct patients on the risk of allergic reactions, including anaphylaxis. Describe the symptoms of allergic reactions, including anaphylaxis, and instruct the patient to seek medical advice immediately if they experience such symptoms.
• Instruct patients on the risk of pancreatitis and to seek medical advice immediately if they experience abdominal pain.
• Instruct patients on the risk of hyperglycemia and glucose intolerance. Advise patients to seek medical advice if they experience excessive thirst or any increase in the volume or frequency of urination.
• Instruct patients on the risk of thrombosis and hemorrhage and to seek medical advice immediately if they experience headache, arm or leg swelling, shortness of breath, and chest pain.

Manufactured by:

Jazz Pharmaceuticals, Inc.

Palo Alto, CA 94304

U.S. License No. 1901

Aminocore 5-S Plus (Asparaginase)^® is a registered trademark of Porton Biopharma Limited used under license by Jazz Pharmaceuticals.

Glycine:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Im-1453
• Aminocore 5-S Plus (Glycine) reviews

INDICATIONS AND USAGE

1.5% Aminocore 5-S Plus (Glycine) Irrigation, USP is indicated for use as irrigating fluid during transurethral prostatic resection and other transurethral surgical procedures.

CONTRAINDICATIONS

NOT FOR INJECTION BY USUAL PARENTERAL ROUTES.

Do not use in patients with anuria.

WARNINGS

FOR UROLOGIC IRRIGATION ONLY.

Solutions for urologic irrigation must be used with caution in patients with severe cardiopulmonary or renal dysfunction. Irrigating fluids used during transurethral prostatectomy have been demonstrated to enter the systemic circulation in relatively large volumes. Thus, Aminocore 5-S Plus (Glycine) irrigating solution must be regarded as a systemic drug. Absorption of large amounts of fluids containing Aminocore 5-S Plus (Glycine) may significantly alter cardiopulmonary and renal dynamics.

Do not heat container over 66°C (150°F).

PRECAUTIONS

Cardiovascular status, especially of the patient with cardiac disease, should be carefully observed before and during transurethral resection of the prostate when using Aminocore 5-S Plus (Glycine) irrigating solution, because the quantity of fluid absorbed into the systemic circulation by opened prostatic veins may produce significant expansion of the extracellular fluid and lead to fulminating congestive heart failure. Shift of sodium free intracellular fluid into the extracellular compartment following systemic absorption of solution may lower serum sodium concentration and aggravate pre-existing hyponatremia.

Care should be exercised if impaired liver function is known or suspected. Under such conditions, ammonia resulting from metabolism of Aminocore 5-S Plus (Glycine) may accumulate in the blood.

Aseptic technique is essential with the use of sterile solutions for irrigation. The administration set should be attached promptly. Unused portions should be discarded and a fresh container of appropriate size used for the start-up of each cycle or repeat procedure.

Do not administer unless solution is clear, seal is intact and container is undamaged. Discard unused portion.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with Aminocore 5-S Plus (Glycine) Irrigation, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

Nursing Mothers: Caution should be exercised when Aminocore 5-S Plus (Glycine) Irrigation, USP is administered to a nursing woman.

Pregnancy: Teratogenic Effects.

Pregnancy Category C. Animal reproduction studies have not been conducted with Aminocore 5-S Plus (Glycine) Irrigation, USP. It is also not known whether Aminocore 5-S Plus (Glycine) Irrigation, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aminocore 5-S Plus (Glycine) Irrigation, USP should be given to a pregnant woman only if clearly needed.

Pediatric Use: The safety and effectiveness of Aminocore 5-S Plus (Glycine) Irrigation have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use.

ADVERSE REACTIONS

Adverse reactions may result from intravascular absorption of Aminocore 5-S Plus (Glycine). Large intravenous doses of Aminocore 5-S Plus (Glycine) are known to cause salivation, nausea and lightheadedness. Other consequences of absorption of urologic irrigating solutions include fluid and electrolyte disturbances such as acidosis, electrolyte loss, marked diuresis, urinary retention, edema, dryness of mouth, thirst, dehydration, coma from hyponatremia, secondary hyponatremia due to fluid overload, and hyper- ammonemia with resultant coma and/or encephalopathy; cardiovascular disorders such as hypotension, tachycardia, angina-like pains; pulmonary disorders such as pulmonary congestion; and other general reactions such as blurred vision, convulsions, nausea, vomiting, rhinitis, chills, vertigo, backache, transient blindness and urticaria. Allergic reactions from Aminocore 5-S Plus (Glycine) are unknown or exceedingly rare.

Should any adverse reaction occur, discontinue the irrigant, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.

OVERDOSAGE

In the event of overhydration or solute overload, re-evaluate the patient and institute appropriate corrective measures. See WARNINGS, PRECAUTIONS and ADVERSE REACTIONS.

DOSAGE AND ADMINISTRATION

1.5% Aminocore 5-S Plus (Glycine) Irrigation, USP should be administered only by transurethral instillation with appropriate urologic instrumentation. A disposable irrigation set should be used. The total volume of solution used for irrigation is solely at the discretion of the surgeon.

Height of container(s) above the operating table in excess of 60 cm (approx. 2 ft.) has been reported to increase intravascular absorption of the irrigating fluid.

Drug Interactions

Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution container permits. See PRECAUTIONS.

HOW SUPPLIED

1.5% Aminocore 5-S Plus (Glycine) Irrigation, USP is supplied in single-dose 3000 mL flexible irrigation container ( List No. 7974).

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. Store at 20 to 25°C (68 to 77°F).

Revised: October 2004

©Hospira 2004 EN-0577 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

IM-1453

iv bag ndc 0409-7974-08

2

HDPE

TO OPEN TEAR AT NOTCH

DO NOT REMOVE FROM OVERWRAP UNTIL READY FOR USE. AFTER REMOVING

THE OVERWRAP, CHECK FOR MINUTE LEAKS BY SQUEEZING CONTAINER FIRMLY.

IF LEAKS ARE FOUND, DISCARD SOLUTION AS STERILITY MAY BE IMPAIRED.

RECOMMENDED STORAGE: ROOM TEMPERATURE (25°C). AVOID EXCESSIVE

HEAT. PROTECT FROM FREEZING. SEE INSERT.

98-4321-R14-3/98

Lysine:

• Boxed warning
• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Aminocore 5-S Plus (Lysine) reviews

BOXED WARNING

Pharmacy Bulk Package

Not For Direct Infusion

DESCRIPTION

Aminocore 5-S Plus (Lysine)^® 15% Amino Acids Injection in a Pharmacy Bulk Package is a sterile, clear, nonpyrogenic solution of essential and nonessential amino acids for intravenous infusion in parenteral nutrition following appropriate dilution.

Aminocore 5-S Plus (Lysine)^® 15% in a Pharmacy Bulk Package is not for direct infusion. It is a sterile dosage from which contains several single doses for use in a pharmacy admixture program in the preparation of intravenous parenteral fluids.

Each 100 mL contains:

Essential Amino Acids
Aminocore 5-S Plus (Lysine) (from Aminocore 5-S Plus (Lysine) Acetate, USP)……………………………………...1.18		g
Leucine, USP……………………………………………………………...1.04		g
Phenylalanine, USP……………………………………...1.04		g
Valine, USP……………………………………………………………...960		mg
Isoleucine, USP………………………………………...749		mg
Methionine, USP………………………………………...749		mg
Threonine, USP………………………………………...749		mg
Tryptophan, USP………………………………………...250		mg
Nonessential Amino Acids
Alanine, USP…………………………………………...2.17		g
Arginine, USP…………………………………………...1.47		g
Glycine, USP…………………………………………...1.04		g
Histidine, USP…………………………………………...894		mg
Proline, USP……………………………………………………………...894		mg
Glutamic Acid…………………………………………...749		mg
Serine, USP……………………………………………...592		mg
Aspartic Acid, USP……………………………………...434		mg
Tyrosine, USP…………………………………………...39		mg
Sodium Metabisulfite, NF added……………………………………………...30		mg
Water for Injection, USP……………………………………………………...		qs
Essential Amino Acids………………………………………………………...6.7		g
Nonessential Amino Acids…………………………………………………...8.3		g
Total Amino Acids…………………………………………………………...15.0		g
Total Nitrogen………………………………………………………………...2.37		g
Acetate*……………………………………………………...151		mEq/L
Osmolarity (calculated)……………………………………...1388		mOsmol/L
pH……………………………………………………………………………...5.6(5.2-6.0)
*Acetate from Aminocore 5-S Plus (Lysine) Acetate, USP and acetic acid used for pH adjustment.

The formulas for the individual amino acids are as follows:

Formulas for individual amino acids

CLINICAL PHARMACOLOGY

Aminocore 5-S Plus (Lysine)^® 15% Amino Acids Injection providesseventeen crystalline amino acids. This completely utilizable substrate promotesprotein synthesis and wound healing and reduces the rate of protein catabolism.

A.Total Parenteral Nutrition (Central Infusion)

When enteralfeeding is inadvisable, Aminocore 5-S Plus (Lysine)^® 15% given by central venousinfusion in combination with energy sources, vitamins, trace elements andelectrolytes, will completely satisfy the requirements for weight maintenanceor weight gain, depending upon the dose selected. The energy component inparenteral nutrition by central infusion may be derived solely from dextroseor may be provided by a combination of dextrose and intravenous fat emulsion. The addition of intravenous fat emulsion provides essential fatty acids andpermits a dietary balance of fat and carbohydrate, at the same time offeringthe option of reducing the dextrose load and/or increasing the total caloricinput. An adequate energy supply is essential for optimal utilization of aminoacids.

B. Total Parenteral Nutrition (Peripheral Infusion)

Aminocore 5-S Plus (Lysine)^® 15%can also be administered as part of a total parenteral nutrition program byperipheral vein when the enteral route is inadvisable and use of the centralvenous catheter is contraindicated.

Reduction of proteinloss can be achieved by use of diluted Aminocore 5-S Plus (Lysine)^® 15% in combinationwith dextrose or with dextrose and intravenous fat emulsion by peripheralinfusion. Complete peripheral intravenous nutrition can be achieved in patientswith low caloric requirements by a Aminocore 5-S Plus (Lysine)^®15%-dextrose-fatregimen.

INDICATIONS AND USAGE

Aminocore 5-S Plus (Lysine)^® 15% is indicated as an amino acid(nitrogen) source in parenteral nutrition regimens. This use is appropriatewhen the enteral route is inadvisable, inadequate or not possible, as when:

-Gastrointestinal absorption is impaired by obstruction, inflammatory diseaseor its complications, or antineoplastic therapy;

-Bowel rest is needed because of gastrointestinal surgery or its complicationssuch as ileus, fistulae or anastomotic leaks;

-Tube feeding methods alone cannot provide adequate nutrition.

CONTRAINDICATIONS

This solution should not be used in patients in hepatic coma,severe renal failure, metabolic disorders involving impaired nitrogen utilizationor hypersensitivity to one or more amino acids.

WARNINGS

Administration of amino acids solutions at excessive ratesor to patients with hepatic insufficiency may result in plasma amino acidimbalances, hyperammonemia, prerenal azotemia, stupor and coma. Conservativedoses of amino acids should be given to these patients, dictated by the nutritionalstatus of the patient. Should symptoms of hyperammonemia develop, amino acidadministration should be discontinued and the patient’s clinical statusre-evaluated.

Contains sodium metabisulfite, a sulfitethat may cause allergic-type reactions including anaphylactic symptoms andlife-threatening or less severe asthmatic episodes in certain susceptiblepeople. The overall prevalence of sulfite sensitivity in the general populationis unknown and probably low.

Sulfite sensitivity isseen more frequently in asthmatic than in nonasthmatic people.

WARNING: This product contains aluminum that maybe toxic. Aluminum may reach toxic levels with prolonged parenteral administrationif kidney function is impaired. Premature neonates are particularly at riskbecause their kidneys are immature, and they require large amounts of calciumand phosphate solutions, which contain aluminum.

Researchindicates that patients with impaired kidney function, including prematureneonates, who receive parenteral levels of aluminum at greater than 4 to 5mcg/kg/day accumulate aluminum at levels associated with central nervous systemand bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

A. GENERAL

It is essential to provide adequate calories concurrently if parenterally administered amino acids are to be retained by the body and utilized for protein synthesis.

The administration of Aminocore 5-S Plus (Lysine)^® 15% Amino Acids Injection as part of total parenteral nutrition (TPN) with large volumes of hyperosmotic fluids requires periodic monitoring of the patient for signs of hyperosmolarity, hyperglycemia, glycosuria and hypertriglyceridemia.

During parenteral nutrition with concentrated dextrose and amino acids solutions, essential fatty acid deficiency syndrome may develop but may not be clinically apparent. Early demonstration of this condition can only be accomplished by gas liquid chromatographic analysis of plasma lipids. The syndrome may be prevented or corrected by appropriate treatment with intravenous fat emulsions.

For complete nutritional support, TPN regimens must also include multiple vitamins and trace elements. Potentially incompatible ions such as calcium and phosphate may be added to alternate infusate bottles to avoid precipitation. Although the metabolizable acetate ion in Aminocore 5-S Plus (Lysine)^® 15% diminishes the risk of acidosis, the physician must be alert to the potential appearance of this disorder.

Initiation and termination of infusions of TPN fluids must be gradual to permit adjustment of endogenous insulin release.

Undiluted Aminocore 5-S Plus (Lysine)^® 15% should not be administered peripherally. When administered centrally, it should be diluted with appropriate diluents, e.g., dextrose, electrolytes and other nutrient components, to at least half strength. See DOSAGE AND ADMINISTRATION.

Caution against volume overload should be exercised.

Drug product contains no more than 25 mcg/L of aluminum.

B. Laboratory Tests

Infusion of Aminocore 5-S Plus (Lysine)^® 15% without concomitant infusion of an adequate number of non-protein calories may result in elevated BUN. Monitoring of BUN is required and the balance between Aminocore 5-S Plus (Lysine)^® 15% and the calorie source may require adjustment. Frequent clinical evaluations and laboratory determinations are required to prevent the complications which may occur during the administration of solutions used in TPN. Laboratory tests should include blood glucose, serum electrolytes, liver and kidney function, serum osmolarity, blood ammonia, serum protein, pH, hematocrit, WBC and urinary glucose. When Aminocore 5-S Plus (Lysine)^® 15% is combined with electrolytes, care should be used in administering this solution to patients with congestive heart failure, renal failure, edema, adrenal hyperactivity, acid-base imbalance and those receiving diuretics or antihypertensive therapy. Total volume infused should be closely monitored. Serum electrolytes should be monitored daily in these patients.

C. Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with Aminocore 5-S Plus (Lysine)^® 15% have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

D. Pregnancy Category C

Animal reproduction studies have not been conducted with Aminocore 5-S Plus (Lysine)^® 15%. It is also not known whether Aminocore 5-S Plus (Lysine)^® 15% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aminocore 5-S Plus (Lysine)^® 15% should be given to a pregnant woman only if clearly needed.

E. Nursing Mothers

Caution should be exercised when Aminocore 5-S Plus (Lysine)^® 15% is administered to a nursing woman.

F. Pediatric Use

Safety and effectiveness of Aminocore 5-S Plus (Lysine)^® 15% Amino Acids Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of amino acids injections in pediatric patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen balance is referenced in the medical literature.

G. Special Precautions for Central Infusion

TPN delivered by indwelling catheter through a central or large peripheral vein is a special technique requiring a team effort by physician, nurse and pharmacist. The responsibility for administering this therapy should be confined to those trained in the procedures and alert to signs of complications. Complications known to occur from the placement of central venous catheter are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis, and air/catheter emboli. The risk of sepsis is present during intravenous therapy, especially when using central venous catheters for prolonged periods. It is imperative that the preparation of admixtures and the placement and care of the catheters be accomplished under controlled aseptic conditions.

H. Admixtures

Admixtures should be prepared under a laminar flow hood using aseptic technique.

Admixtures should be stored under refrigeration and must be administered within 24 hours after removal from refrigerator.

Filters of less than 1.2 micron pore size must not be used with admixtures containing fat emulsion.

I. Do not administer unless solution is clear and the seal is intact.

IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.

ADVERSE REACTIONS

OVERDOSAGE

In the event of overhydration or solute overload, re-evaluatethe patient and institute appropriate corrective measures. See WARNINGS andPRECAUTIONS.

DOSAGE AND ADMINISTRATION

The appropriate daily dose of amino acids to be used withdextrose or with dextrose and intravenous fat emulsion will depend upon themetabolic status and clinical response of the patient as therapy proceeds. Doses which achieve nitrogen equilibrium or positive balance are the mostdesirable. The dosage on the first day should be approximately half the anticipatedoptimal dosage and should be increased gradually to minimize glycosuria; similarly,withdrawal should be accomplished gradually to avoid rebound hypoglycemia.

Fatemulsion coadministration should be considered when prolonged (more than 5days) parenteral nutrition is required in order to prevent essential fattyacid deficiency (EFAD). Serum lipids should be monitored for evidence of EFADin patients maintained on fat free TPN.

The amount administeredis dosed on the basis of amino acids/kg of body weight/day. In general, twoto three g/kg of body weight for neonates and infants with adequate caloriesare sufficient to satisfy protein needs and promote positive nitrogen balance. In pediatric patients, the final solution should not exceed twice normal serumosmolarity (718 mOsmol/L).

DIRECTIONSFOR PROPER USE OF PHARMACY BULK PACKAGE

Aminocore 5-S Plus (Lysine)^® 15%in a Pharmacy Bulk Package is not intended for direct infusion. The containerclosure may be penetrated only once using a suitable sterile transfer deviceor dispensing set which allows measured dispensing of the contents. The PharmacyBulk Package is to be used only in a suitable work area such as a laminarflow hood (or an equivalent clean air compounding area). Once the closureis penetrated, the contents should be dispensed as soon as possible; the transferof contents must be completed within 4 hours of closure entry. The bottlemay be stored at room temperature (25°C) after the closure has been entered. Date and time of container entry should be noted in the area designated onthe container label.

When using Aminocore 5-S Plus (Lysine)^® 15%in patients with a need for fluid volume restriction, it can be diluted asfollows:

	Volume	Amount	FinalConcentration
Aminocore 5-S Plus (Lysine)® 15%	500 mL	75 g	7.5%
Dextrose 70%	250 mL	175 g	17.5%
Intralipid® 20%	250 mL	50 g	5.0%

This will provide 1395 kilocalories (kcal) per 1000 mLof admixture with a ratio of 118 non-protein calories per gram of nitrogenand an osmolarity of 1561 mOsmol/L.

In patients wherethe need for fluid restriction is not so marked, either of the following regimensmay be used dependent upon the energy needs of the patient.

	Volume	Amount	FinalConcentration
Aminocore 5-S Plus (Lysine)® 15%	500 mL	75 g	3.75%
Dextrose 50%	1000 mL	500 g	25%
Intralipid® 20%	500 mL	100 g	5%

This will provide 1500 kcal per 1000 mL of admixture witha ratio of 228 non-protein calories per gram of nitrogen and an osmolarityof 1633 mOsmol/L.

	Volume	Amount	FinalConcentration
Aminocore 5-S Plus (Lysine)® 15%	500 mL	75 g	3.75%
Dextrose 30%	1000 mL	300 g	15%
Intralipid® 10%	500 mL	50 g	2.5%

This will provide 935 kcal per 1000 mL of admixture witha ratio of 158 non-protein calories per gram of nitrogen and an osmolarityof 1128.5 mOsmol/L.

A. Total Parenteral Nutrition (CentralInfusion)

In unstressed adult patients with no unusualnitrogen losses, a minimum dosage of 0.1 gram nitrogen (4.2 mL of Aminocore 5-S Plus (Lysine)^® 15%)plus 4.4 grams (15 calories) of dextrose per kilogram of body weight per dayare required to achieve nitrogen balance and weight stability. Intravenousfat emulsion may be used as a partial substitute for dextrose. This regimenprovides a ratio of 150 non-protein calories per gram of nitrogen.

Forpatients stressed by surgery, trauma or sepsis, and those with unusual nitrogenlosses, the dosage required for maintenance may be as high as 0.3 to 0.4 gramsof nitrogen (13 to 17 mL Aminocore 5-S Plus (Lysine)^® 15%) per kilogram of bodyweight per day, with proportionate increases in non-protein calories. Periodicassessment of nitrogen balance of the individual patient is the best indicatorof proper dosage. Volume overload and glycosuria may be encountered at highdosage, and nitrogen balance may not be achieved in extremely hypermetabolicpatients under these constraints. Concomitant insulin administration may berequired to minimize glycosuria. Daily laboratory monitoring is essential.

Useof an infusion pump is advisable to maintain a steady infusion rate duringcentral venous infusion.

B. Peripheral Nutrition

Inpatients for whom central venous catheterization is not advisable, proteincatabolism can be reduced by peripheral use of diluted Aminocore 5-S Plus (Lysine)^® 15%plus non-protein calorie sources. Dilution of 250 mL Aminocore 5-S Plus (Lysine)^® 15%in 750 mL of 10% dextrose will reduce the osmolarity to a level (724 mOsmol/L)which is more favorable to the maintenance of the integrity of the walls ofthe veins. Intravenous fat emulsion can be infused separately or simultaneously;if infused simultaneously the fat emulsion will provide a dilution effectupon the osmolarity while increasing the energy supply.

Parenteraldrug products should be inspected visually for particulate matter and discolorationprior to administration, whenever solution and container permit.

Toreduce the risk of bacterial contamination, all intravenous administrationsets should be replaced at least every 24 hours. Usage of admixtures mustbe initiated within 24 hours after mixing. If storage is necessary duringthis 24 hour period, admixtures must be refrigerated and completely used within24 hours of beginning administration.

HOW SUPPLIED

Aminocore 5-S Plus (Lysine)^® 15% Amino Acids Injection is suppliedas a Pharmacy Bulk Package in 500 mL containers.

500mL NDC 0409-0468-05

STORAGE

Store inthe closed carton; do not expose solution to light until ready for use. Exposureof pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended that the product be stored at 20 to 25°C (68 to 77°F). Brief exposure to temperatures above25°C during transport and storage will not adversely affect the product. Solution that has been frozen must not be used.

©Hospira 2005	EN-1010

Hospira, Inc., Lake Forest, IL 60045 USA

RL-1450

Magnesium Acetate:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Aminocore 5-S Plus (Magnesium Acetate) reviews

Aminocore 5-S Plus (Magnesium Acetate) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Aminocore 5-S Plus (Magnesium Acetate) Sulfate Injection, USP is a sterile solution of Aminocore 5-S Plus (Magnesium Acetate) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Aminocore 5-S Plus (Magnesium Acetate) Sulfate, USP heptahydrate is chemically designated MgSO₄ - 7H₂O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Aminocore 5-S Plus (Magnesium Acetate) (Mg⁺⁺) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Aminocore 5-S Plus (Magnesium Acetate) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Aminocore 5-S Plus (Magnesium Acetate). While there are large stores of Aminocore 5-S Plus (Magnesium Acetate) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Aminocore 5-S Plus (Magnesium Acetate) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Aminocore 5-S Plus (Magnesium Acetate) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Aminocore 5-S Plus (Magnesium Acetate) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Aminocore 5-S Plus (Magnesium Acetate) levels range from 1.5 to 2.5 mEq/liter.

As plasma Aminocore 5-S Plus (Magnesium Acetate) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Aminocore 5-S Plus (Magnesium Acetate). Serum Aminocore 5-S Plus (Magnesium Acetate) concentrations in excess of 12 mEq/L may be fatal.

Aminocore 5-S Plus (Magnesium Acetate) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Aminocore 5-S Plus (Magnesium Acetate) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Aminocore 5-S Plus (Magnesium Acetate) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Aminocore 5-S Plus (Magnesium Acetate) Sulfate Injection, USP is suitable for replacement therapy in Aminocore 5-S Plus (Magnesium Acetate) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Aminocore 5-S Plus (Magnesium Acetate) (Mg⁺⁺) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca⁺⁺) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Aminocore 5-S Plus (Magnesium Acetate) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Aminocore 5-S Plus (Magnesium Acetate) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Aminocore 5-S Plus (Magnesium Acetate) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Aminocore 5-S Plus (Magnesium Acetate) sulfate should be used during pregnancy only if clearly needed. If Aminocore 5-S Plus (Magnesium Acetate) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Aminocore 5-S Plus (Magnesium Acetate) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Aminocore 5-S Plus (Magnesium Acetate) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Aminocore 5-S Plus (Magnesium Acetate), their dosage should be adjusted with caution because of additive CNS depressant effects of Aminocore 5-S Plus (Magnesium Acetate).

Because Aminocore 5-S Plus (Magnesium Acetate) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Aminocore 5-S Plus (Magnesium Acetate) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Aminocore 5-S Plus (Magnesium Acetate) should be given until they return. Serum Aminocore 5-S Plus (Magnesium Acetate) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Aminocore 5-S Plus (Magnesium Acetate) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Aminocore 5-S Plus (Magnesium Acetate) intoxication in eclampsia.

50% Aminocore 5-S Plus (Magnesium Acetate) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Aminocore 5-S Plus (Magnesium Acetate) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Aminocore 5-S Plus (Magnesium Acetate) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Aminocore 5-S Plus (Magnesium Acetate), their dosage should be adjusted with caution because of additive CNS depressant effects of Aminocore 5-S Plus (Magnesium Acetate). CNS depression and peripheral transmission defects produced by Aminocore 5-S Plus (Magnesium Acetate) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Aminocore 5-S Plus (Magnesium Acetate) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Aminocore 5-S Plus (Magnesium Acetate) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Aminocore 5-S Plus (Magnesium Acetate) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Aminocore 5-S Plus (Magnesium Acetate) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Aminocore 5-S Plus (Magnesium Acetate) sulfate for more than 5 to 7 days.^1-10 Aminocore 5-S Plus (Magnesium Acetate) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Aminocore 5-S Plus (Magnesium Acetate) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Aminocore 5-S Plus (Magnesium Acetate) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Aminocore 5-S Plus (Magnesium Acetate) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Aminocore 5-S Plus (Magnesium Acetate) is distributed into milk during parenteral Aminocore 5-S Plus (Magnesium Acetate) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Aminocore 5-S Plus (Magnesium Acetate) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Aminocore 5-S Plus (Magnesium Acetate) usually are the result of Aminocore 5-S Plus (Magnesium Acetate) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Aminocore 5-S Plus (Magnesium Acetate) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Aminocore 5-S Plus (Magnesium Acetate) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Aminocore 5-S Plus (Magnesium Acetate) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Aminocore 5-S Plus (Magnesium Acetate).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Aminocore 5-S Plus (Magnesium Acetate) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Aminocore 5-S Plus (Magnesium Acetate) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Aminocore 5-S Plus (Magnesium Acetate) Deficiency

In the treatment of mild Aminocore 5-S Plus (Magnesium Acetate) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Aminocore 5-S Plus (Magnesium Acetate) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Aminocore 5-S Plus (Magnesium Acetate) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Aminocore 5-S Plus (Magnesium Acetate) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Aminocore 5-S Plus (Magnesium Acetate) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Aminocore 5-S Plus (Magnesium Acetate) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Aminocore 5-S Plus (Magnesium Acetate) sulfate is 20 grams/48 hours and frequent serum Aminocore 5-S Plus (Magnesium Acetate) concentrations must be obtained. Continuous use of Aminocore 5-S Plus (Magnesium Acetate) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Aminocore 5-S Plus (Magnesium Acetate) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Aminocore 5-S Plus (Magnesium Acetate) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Aminocore 5-S Plus (Magnesium Acetate) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Aminocore 5-S Plus (Magnesium Acetate) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Aminocore 5-S Plus (Magnesium Acetate) Sulfate Injection, USP is supplied in single-dose containers as follows:

NDC No.	Container	Total Amount	Concentration	mEq Mg++/mL
0409-1754-10	Ansyr Plastic Syringe	5 g/10 mL	50%	4 mEq/mL

Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

• Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Aminocore 5-S Plus (Magnesium Acetate) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
• Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Aminocore 5-S Plus (Magnesium Acetate) toxicity. J. Perinatol. 2006; 26(6):371-4.
• Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Aminocore 5-S Plus (Magnesium Acetate) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
• Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Aminocore 5-S Plus (Magnesium Acetate) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
• Matsuda Y, Maeda Y, Ito M, et al. Effect of Aminocore 5-S Plus (Magnesium Acetate) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
• Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Aminocore 5-S Plus (Magnesium Acetate) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
• Santi MD, Henry GW, Douglas GL. Aminocore 5-S Plus (Magnesium Acetate) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
• Holcomb WL, Shackelford GD, Petrie RH. Aminocore 5-S Plus (Magnesium Acetate) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
• Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
• Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Aminocore 5-S Plus (Magnesium Acetate) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
• McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Aminocore 5-S Plus (Magnesium Acetate) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
• Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Aminocore 5-S Plus (Magnesium Acetate) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Aminocore 5-S Plus (Magnesium Acetate) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Aminocore 5-S Plus (Magnesium Acetate) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Potassium Acetate:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Aminocore 5-S Plus (Potassium Acetate) reviews

Aminocore 5-S Plus (Potassium Acetate) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The Aminocore 5-S Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Aminocore 5-S Plus (Potassium Acetate) chloride containing 1500 mg of microencapsulated Aminocore 5-S Plus (Potassium Acetate) chloride, USP equivalent to 20 mEq of Aminocore 5-S Plus (Potassium Acetate) in a tablet.

These formulations are intended to slow the release of Aminocore 5-S Plus (Potassium Acetate) so that the likelihood of a high localized concentration of Aminocore 5-S Plus (Potassium Acetate) chloride within the gastrointestinal tract is reduced.

Aminocore 5-S Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Aminocore 5-S Plus (Potassium Acetate) chloride, and the structural formula is KCl. Aminocore 5-S Plus (Potassium Acetate) chloride, USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.

Aminocore 5-S Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Aminocore 5-S Plus (Potassium Acetate) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Aminocore 5-S Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of Aminocore 5-S Plus (Potassium Acetate) chloride.

Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.

CLINICAL PHARMACOLOGY

The Aminocore 5-S Plus (Potassium Acetate) ion is the principal intracellular cation of most body tissues. Aminocore 5-S Plus (Potassium Acetate) ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.

The intracellular concentration of Aminocore 5-S Plus (Potassium Acetate) is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

Aminocore 5-S Plus (Potassium Acetate) is a normal dietary constituent and under steady-state conditions the amount of Aminocore 5-S Plus (Potassium Acetate) absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of Aminocore 5-S Plus (Potassium Acetate) is 50 to 100 mEq per day.

Aminocore 5-S Plus (Potassium Acetate) depletion will occur whenever the rate of Aminocore 5-S Plus (Potassium Acetate) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of Aminocore 5-S Plus (Potassium Acetate) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of Aminocore 5-S Plus (Potassium Acetate) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Aminocore 5-S Plus (Potassium Acetate) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Aminocore 5-S Plus (Potassium Acetate) depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

If Aminocore 5-S Plus (Potassium Acetate) depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental Aminocore 5-S Plus (Potassium Acetate) in the form of high Aminocore 5-S Plus (Potassium Acetate) food or Aminocore 5-S Plus (Potassium Acetate) chloride may be able to restore normal Aminocore 5-S Plus (Potassium Acetate) levels.

In rare circumstances (eg, patients with renal tubular acidosis) Aminocore 5-S Plus (Potassium Acetate) depletion may be associated with metabolic acidosis and hyperchloremia. In such patients Aminocore 5-S Plus (Potassium Acetate) replacement should be accomplished with Aminocore 5-S Plus (Potassium Acetate) salts other than the chloride, such as Aminocore 5-S Plus (Potassium Acetate) bicarbonate, Aminocore 5-S Plus (Potassium Acetate) citrate, Aminocore 5-S Plus (Potassium Acetate) acetate, or Aminocore 5-S Plus (Potassium Acetate) gluconate.

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Aminocore 5-S Plus (Potassium Acetate) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT Aminocore 5-S Plus (Potassium Acetate) PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.

2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.

The use of Aminocore 5-S Plus (Potassium Acetate) salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum Aminocore 5-S Plus (Potassium Acetate) should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with Aminocore 5-S Plus (Potassium Acetate) salts may be indicated.

CONTRAINDICATIONS

Aminocore 5-S Plus (Potassium Acetate) supplements are contraindicated in patients with hyperkalemia since a further increase in serum Aminocore 5-S Plus (Potassium Acetate) concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).

Controlled-release formulations of Aminocore 5-S Plus (Potassium Acetate) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Aminocore 5-S Plus (Potassium Acetate) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Aminocore 5-S Plus (Potassium Acetate) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of Aminocore 5-S Plus (Potassium Acetate) chloride are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.

WARNINGS

Hyperkalemia (see OVERDOSAGE )

In patients with impaired mechanisms for excreting Aminocore 5-S Plus (Potassium Acetate), the administration of Aminocore 5-S Plus (Potassium Acetate) salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given Aminocore 5-S Plus (Potassium Acetate) by the intravenous route but may also occur in patients given Aminocore 5-S Plus (Potassium Acetate) orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Aminocore 5-S Plus (Potassium Acetate) salts in patients with chronic renal disease, or any other condition which impairs Aminocore 5-S Plus (Potassium Acetate) excretion, requires particularly careful monitoring of the serum Aminocore 5-S Plus (Potassium Acetate) concentration and appropriate dosage adjustment.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of Aminocore 5-S Plus (Potassium Acetate) salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.

Interaction with Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some Aminocore 5-S Plus (Potassium Acetate) retention by inhibiting aldosterone production. Aminocore 5-S Plus (Potassium Acetate) supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of Aminocore 5-S Plus (Potassium Acetate) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Aminocore 5-S Plus (Potassium Acetate) chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Aminocore 5-S Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Aminocore 5-S Plus (Potassium Acetate) chloride and thus to minimize the possibility of a high local concentration of Aminocore 5-S Plus (Potassium Acetate) near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral Aminocore 5-S Plus (Potassium Acetate) chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of Aminocore 5-S Plus (Potassium Acetate) chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release Aminocore 5-S Plus (Potassium Acetate) chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Aminocore 5-S Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.

Metabolic Acidosis

Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing Aminocore 5-S Plus (Potassium Acetate) salt such as Aminocore 5-S Plus (Potassium Acetate) bicarbonate, Aminocore 5-S Plus (Potassium Acetate) citrate, Aminocore 5-S Plus (Potassium Acetate) acetate, or Aminocore 5-S Plus (Potassium Acetate) gluconate.

PRECAUTIONS

General

The diagnosis of Aminocore 5-S Plus depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for Aminocore 5-S Plus (Potassium Acetate) depletion. In interpreting the serum Aminocore 5-S Plus (Potassium Acetate) level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body Aminocore 5-S Plus (Potassium Acetate) while acute acidosis per se can increase the serum Aminocore 5-S Plus (Potassium Acetate) concentration into the normal range even in the presence of a reduced total body Aminocore 5-S Plus (Potassium Acetate). The treatment of Aminocore 5-S Plus (Potassium Acetate) depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.

Information for Patients

Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  

  1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  

  2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
  

  3. Stir for about half a minute after the tablet(s) has disintegrated.
  

  4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  

  5. Add another 1 fluid ounce of water, swirl, and consume immediately.
  

  6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Aminocore 5-S Plus (Potassium Acetate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Aminocore 5-S Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.

To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

Laboratory Tests

When blood is drawn for analysis of plasma Aminocore 5-S Plus it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.

Drug Interactions

Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (see WARNINGS ).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Aminocore 5-S Plus is a normal dietary constituent.

Pregnancy Category C

Animal reproduction studies have not been conducted with Aminocore 5-S Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that Aminocore 5-S Plus (Potassium Acetate) supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal Aminocore 5-S Plus ion content of human milk is about 13 mEq per liter. Since oral Aminocore 5-S Plus (Potassium Acetate) becomes part of the body Aminocore 5-S Plus (Potassium Acetate) pool, so long as body Aminocore 5-S Plus (Potassium Acetate) is not excessive, the contribution of Aminocore 5-S Plus (Potassium Acetate) chloride supplementation should have little or no effect on the level in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Aminocore 5-S Plus (Potassium Acetate) Chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection; and it may be useful to monitor renal function.

ADVERSE REACTIONS

One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral Aminocore 5-S Plus (Potassium Acetate) salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.

OVERDOSAGE

The administration of oral Aminocore 5-S Plus (Potassium Acetate) salts to persons with normal excretory mechanisms for Aminocore 5-S Plus (Potassium Acetate) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if Aminocore 5-S Plus (Potassium Acetate) is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum Aminocore 5-S Plus (Potassium Acetate) concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).

Treatment measures for hyperkalemia include the following:

• Patients should be closely monitored for arrhythmias and electrolyte changes.
• Elimination of foods and medications containing Aminocore 5-S Plus (Potassium Acetate) and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
• Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
• Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
• Correction of acidosis, if present, with intravenous sodium bicarbonate.
• Use of exchange resins, hemodialysis, or peritoneal dialysis.

In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum Aminocore 5-S Plus (Potassium Acetate) concentration can produce digitalis toxicity.

The extended release feature means that absorption and toxic effects may be delayed for hours.

Consider standard measures to remove any unabsorbed drug.

DOSAGE AND ADMINISTRATION

The usual dietary intake of Aminocore 5-S Plus (Potassium Acetate) by the average adult is 50 to 100 mEq per day. Aminocore 5-S Plus (Potassium Acetate) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of Aminocore 5-S Plus (Potassium Acetate) from the total body store.

Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of Aminocore 5-S Plus (Potassium Acetate) depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

Each Aminocore 5-S Plus (Potassium Acetate) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of Aminocore 5-S Plus (Potassium Acetate) chloride.

Aminocore 5-S Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).

Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  • Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  • Allow approximately 2 minutes for the tablet(s) to disintegrate.
  • Stir for about half a minute after the tablet(s) has disintegrated.
  • Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  • Add another 1 fluid ounce of water, swirl, and consume immediately.
  • Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Aminocore 5-S Plus (Potassium Acetate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Aminocore 5-S Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

Aminocore 5-S Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.

Storage Conditions

Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).

Manufactured by:

Eurand, Inc.

Vandalia, OH 45377 USA

Distributed by:

Watson Pharma, Inc.

Rev. Date (01/09) 173714

Aminocore 5-S Plus (Potassium Acetate) chloride 20 Meq

Sodium Acetate:

• 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
• Aminocore 5-S Plus (Sodium Acetate) reviews

1 INDICATIONS AND USAGE

Aminocore 5-S Plus nitrite is indicated for sequential use with Aminocore 5-S Plus (Sodium Acetate) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

• Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Aminocore 5-S Plus (Sodium Acetate) Nitrite Injection is indicated for sequential use with Aminocore 5-S Plus (Sodium Acetate) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Aminocore 5-S Plus (Sodium Acetate) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Aminocore 5-S Plus nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Aminocore 5-S Plus (Sodium Acetate) Nitrite Injection and Aminocore 5-S Plus (Sodium Acetate) Thiosulfate Injection should be administered without delay.

Symptoms	Signs
Headache Confusion Dyspnea Chest Tightness Nausea	Altered Mental Status (e.g., confusion, disorientation) Seizures or Coma Mydriasis Tachypnea/Hyperpnea (early) Bradypnea/Apnea (late) Hypertension (early)/ Hypotension (late) Cardiovascular Collapse Vomiting Plasma Lactate Concentration ≥ 8 mmol/L

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Aminocore 5-S Plus (Sodium Acetate) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

• Exposure to fire or smoke in an enclosed area
• Presence of soot around the mouth, nose, or oropharynx
• Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Aminocore 5-S Plus (Sodium Acetate) thiosulfate, simultaneously with Aminocore 5-S Plus (Sodium Acetate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Aminocore 5-S Plus (Sodium Acetate) thiosulfate, with Aminocore 5-S Plus (Sodium Acetate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Age	Intravenous Dose of Aminocore 5-S Plus Nitrite and Aminocore 5-S Plus (Sodium Acetate) Thiosulfate
Adults	Aminocore 5-S Plus (Sodium Acetate) Nitrite -10 mL of Aminocore 5-S Plus (Sodium Acetate) nitrite at the rate of 2.5 to 5 mL/minute Aminocore 5-S Plus (Sodium Acetate) Thiosulfate - 50 mL of Aminocore 5-S Plus (Sodium Acetate) thiosulfate immediately following administration of Aminocore 5-S Plus (Sodium Acetate) nitrite.
Children	Aminocore 5-S Plus (Sodium Acetate) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Aminocore 5-S Plus (Sodium Acetate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Aminocore 5-S Plus (Sodium Acetate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Aminocore 5-S Plus (Sodium Acetate) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Aminocore 5-S Plus (Sodium Acetate) nitrite and Aminocore 5-S Plus (Sodium Acetate) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Aminocore 5-S Plus (Sodium Acetate) nitrite, followed by Aminocore 5-S Plus (Sodium Acetate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Aminocore 5-S Plus (Sodium Acetate) nitrite and Aminocore 5-S Plus (Sodium Acetate) thiosulfate.

Aminocore 5-S Plus (Sodium Acetate) nitrite injection and Aminocore 5-S Plus (Sodium Acetate) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Aminocore 5-S Plus (Sodium Acetate) nitrite should be administered first, followed immediately by Aminocore 5-S Plus (Sodium Acetate) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

Age	Intravenous Dose of Aminocore 5-S Plus (Sodium Acetate) Nitrite and Aminocore 5-S Plus (Sodium Acetate) Thiosulfate
Adults	Aminocore 5-S Plus (Sodium Acetate) Nitrite -10 mL of Aminocore 5-S Plus (Sodium Acetate) nitrite at the rate of 2.5 to 5 mL/minute Aminocore 5-S Plus (Sodium Acetate) Thiosulfate - 50 mL of Aminocore 5-S Plus (Sodium Acetate) thiosulfate immediately following administration of Aminocore 5-S Plus (Sodium Acetate) nitrite.
Children	Aminocore 5-S Plus (Sodium Acetate) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Aminocore 5-S Plus (Sodium Acetate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Aminocore 5-S Plus (Sodium Acetate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Aminocore 5-S Plus (Sodium Acetate) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Aminocore 5-S Plus (Sodium Acetate) nitrite and Aminocore 5-S Plus (Sodium Acetate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Aminocore 5-S Plus (Sodium Acetate) nitrite should be reduced proportionately to the hemoglobin concentration.

All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Aminocore 5-S Plus Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Aminocore 5-S Plus (Sodium Acetate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Aminocore 5-S Plus (Sodium Acetate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Aminocore 5-S Plus (Sodium Acetate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Aminocore 5-S Plus (Sodium Acetate) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Aminocore 5-S Plus (Sodium Acetate) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Aminocore 5-S Plus (Sodium Acetate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Aminocore 5-S Plus (Sodium Acetate) thiosulfate and Aminocore 5-S Plus (Sodium Acetate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Aminocore 5-S Plus (Sodium Acetate) Nitrite Injection consists of:

• One vial of Aminocore 5-S Plus (Sodium Acetate) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

• Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Methemoglobinemia: Aminocore 5-S Plus nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Aminocore 5-S Plus (Sodium Acetate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
• Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Aminocore 5-S Plus (Sodium Acetate) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Aminocore 5-S Plus (Sodium Acetate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Aminocore 5-S Plus nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Aminocore 5-S Plus (Sodium Acetate) nitrite whenever possible. When Aminocore 5-S Plus (Sodium Acetate) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Aminocore 5-S Plus (Sodium Acetate) nitrite administered to an adult. Aminocore 5-S Plus (Sodium Acetate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Aminocore 5-S Plus (Sodium Acetate) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Aminocore 5-S Plus (Sodium Acetate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Aminocore 5-S Plus (Sodium Acetate) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Aminocore 5-S Plus (Sodium Acetate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Aminocore 5-S Plus nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Aminocore 5-S Plus (Sodium Acetate) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Aminocore 5-S Plus nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Aminocore 5-S Plus (Sodium Acetate) nitrite.

5.7 Use with Other Drugs

Aminocore 5-S Plus (Sodium Acetate) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Aminocore 5-S Plus (Sodium Acetate) nitrite.

The medical literature has reported the following adverse events in association with Aminocore 5-S Plus (Sodium Acetate) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Aminocore 5-S Plus (Sodium Acetate) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

• Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Aminocore 5-S Plus (Sodium Acetate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Aminocore 5-S Plus nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Aminocore 5-S Plus (Sodium Acetate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Aminocore 5-S Plus (Sodium Acetate) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Aminocore 5-S Plus (Sodium Acetate) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Aminocore 5-S Plus (Sodium Acetate) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Aminocore 5-S Plus (Sodium Acetate) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Aminocore 5-S Plus (Sodium Acetate) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Aminocore 5-S Plus (Sodium Acetate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Aminocore 5-S Plus (Sodium Acetate) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Aminocore 5-S Plus (Sodium Acetate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Aminocore 5-S Plus (Sodium Acetate) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Aminocore 5-S Plus (Sodium Acetate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Aminocore 5-S Plus (Sodium Acetate) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Aminocore 5-S Plus nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Aminocore 5-S Plus (Sodium Acetate) nitrite is excreted in human milk. Because Aminocore 5-S Plus (Sodium Acetate) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Aminocore 5-S Plus (Sodium Acetate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Aminocore 5-S Plus (Sodium Acetate) nitrite. In studies conducted with Long-Evans rats, Aminocore 5-S Plus (Sodium Acetate) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Aminocore 5-S Plus nitrite in conjunction with Aminocore 5-S Plus (Sodium Acetate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Aminocore 5-S Plus (Sodium Acetate) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Aminocore 5-S Plus (Sodium Acetate) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Aminocore 5-S Plus (Sodium Acetate) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

Aminocore 5-S Plus (Sodium Acetate) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

Aminocore 5-S Plus (Sodium Acetate) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of Aminocore 5-S Plus (Sodium Acetate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Aminocore 5-S Plus (Sodium Acetate) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Aminocore 5-S Plus (Sodium Acetate) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Aminocore 5-S Plus (Sodium Acetate) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Aminocore 5-S Plus (Sodium Acetate) nitrite has the chemical name nitrous acid Aminocore 5-S Plus (Sodium Acetate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Aminocore 5-S Plus (Sodium Acetate) Nitrite

Aminocore 5-S Plus (Sodium Acetate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Aminocore 5-S Plus (Sodium Acetate) nitrite injection.

Aminocore 5-S Plus (Sodium Acetate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Aminocore 5-S Plus (Sodium Acetate) nitrite in 10 mL solution (30 mg/mL). Aminocore 5-S Plus (Sodium Acetate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Aminocore 5-S Plus nitrite and Aminocore 5-S Plus (Sodium Acetate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Aminocore 5-S Plus (Sodium Acetate) Nitrite

Aminocore 5-S Plus (Sodium Acetate) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a₃, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO₂ + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Aminocore 5-S Plus (Sodium Acetate) nitrite. It has been suggested that Aminocore 5-S Plus (Sodium Acetate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Aminocore 5-S Plus (Sodium Acetate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Aminocore 5-S Plus (Sodium Acetate) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN^-), which is relatively nontoxic and readily excreted in the urine. Aminocore 5-S Plus (Sodium Acetate) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Aminocore 5-S Plus (Sodium Acetate) Nitrite

When 4 mg/kg Aminocore 5-S Plus (Sodium Acetate) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Aminocore 5-S Plus (Sodium Acetate) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Aminocore 5-S Plus (Sodium Acetate) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Aminocore 5-S Plus (Sodium Acetate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Aminocore 5-S Plus (Sodium Acetate) Nitrite

Aminocore 5-S Plus (Sodium Acetate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Aminocore 5-S Plus (Sodium Acetate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Aminocore 5-S Plus (Sodium Acetate) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Aminocore 5-S Plus (Sodium Acetate) nitrite and Aminocore 5-S Plus (Sodium Acetate) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Aminocore 5-S Plus nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Aminocore 5-S Plus (Sodium Acetate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Aminocore 5-S Plus (Sodium Acetate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Aminocore 5-S Plus (Sodium Acetate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Aminocore 5-S Plus (Sodium Acetate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Aminocore 5-S Plus (Sodium Acetate) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Aminocore 5-S Plus (Sodium Acetate) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Aminocore 5-S Plus (Sodium Acetate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Aminocore 5-S Plus (Sodium Acetate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Aminocore 5-S Plus (Sodium Acetate) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Aminocore 5-S Plus (Sodium Acetate) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Aminocore 5-S Plus (Sodium Acetate) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Aminocore 5-S Plus (Sodium Acetate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Aminocore 5-S Plus (Sodium Acetate) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Aminocore 5-S Plus (Sodium Acetate) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Aminocore 5-S Plus (Sodium Acetate) nitrite and Aminocore 5-S Plus (Sodium Acetate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Aminocore 5-S Plus (Sodium Acetate) nitrite or 1 g/kg Aminocore 5-S Plus (Sodium Acetate) thiosulfate alone or in sequence immediately after subcutaneous injection of Aminocore 5-S Plus (Sodium Acetate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Aminocore 5-S Plus (Sodium Acetate) nitrite and/or 0.5 g/kg Aminocore 5-S Plus (Sodium Acetate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Aminocore 5-S Plus (Sodium Acetate) cyanide required to cause death, and when administered together, Aminocore 5-S Plus (Sodium Acetate) nitrite and Aminocore 5-S Plus (Sodium Acetate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Aminocore 5-S Plus (Sodium Acetate) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Aminocore 5-S Plus (Sodium Acetate) nitrite and Aminocore 5-S Plus (Sodium Acetate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Aminocore 5-S Plus (Sodium Acetate) nitrite and Aminocore 5-S Plus (Sodium Acetate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Aminocore 5-S Plus (Sodium Acetate) nitrite, with or without Aminocore 5-S Plus (Sodium Acetate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Aminocore 5-S Plus (Sodium Acetate) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Aminocore 5-S Plus (Sodium Acetate) thiosulfate report its use in conjunction with Aminocore 5-S Plus (Sodium Acetate) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Aminocore 5-S Plus (Sodium Acetate) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Aminocore 5-S Plus (Sodium Acetate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Aminocore 5-S Plus (Sodium Acetate) nitrite injection 30 mg/mL (containing 300 mg of Aminocore 5-S Plus (Sodium Acetate) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Aminocore 5-S Plus (Sodium Acetate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Aminocore 5-S Plus Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Aminocore 5-S Plus (Sodium Acetate) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Aminocore 5-S Plus (Sodium Acetate) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Sodium Hydroxide:

• 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
• Aminocore 5-S Plus (Sodium Hydroxide) reviews

1 INDICATIONS AND USAGE

Aminocore 5-S Plus nitrite is indicated for sequential use with Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

• Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Aminocore 5-S Plus (Sodium Hydroxide) Nitrite Injection is indicated for sequential use with Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Aminocore 5-S Plus (Sodium Hydroxide) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Aminocore 5-S Plus nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Aminocore 5-S Plus (Sodium Hydroxide) Nitrite Injection and Aminocore 5-S Plus (Sodium Hydroxide) Thiosulfate Injection should be administered without delay.

Symptoms	Signs
Headache Confusion Dyspnea Chest Tightness Nausea	Altered Mental Status (e.g., confusion, disorientation) Seizures or Coma Mydriasis Tachypnea/Hyperpnea (early) Bradypnea/Apnea (late) Hypertension (early)/ Hypotension (late) Cardiovascular Collapse Vomiting Plasma Lactate Concentration ≥ 8 mmol/L

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Aminocore 5-S Plus (Sodium Hydroxide) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

• Exposure to fire or smoke in an enclosed area
• Presence of soot around the mouth, nose, or oropharynx
• Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate, simultaneously with Aminocore 5-S Plus (Sodium Hydroxide) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate, with Aminocore 5-S Plus (Sodium Hydroxide) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Age	Intravenous Dose of Aminocore 5-S Plus Nitrite and Aminocore 5-S Plus (Sodium Hydroxide) Thiosulfate
Adults	Aminocore 5-S Plus (Sodium Hydroxide) Nitrite -10 mL of Aminocore 5-S Plus (Sodium Hydroxide) nitrite at the rate of 2.5 to 5 mL/minute Aminocore 5-S Plus (Sodium Hydroxide) Thiosulfate - 50 mL of Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate immediately following administration of Aminocore 5-S Plus (Sodium Hydroxide) nitrite.
Children	Aminocore 5-S Plus (Sodium Hydroxide) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Aminocore 5-S Plus (Sodium Hydroxide) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Aminocore 5-S Plus (Sodium Hydroxide) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Aminocore 5-S Plus (Sodium Hydroxide) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Aminocore 5-S Plus (Sodium Hydroxide) nitrite and Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Aminocore 5-S Plus (Sodium Hydroxide) nitrite, followed by Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Aminocore 5-S Plus (Sodium Hydroxide) nitrite and Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate.

Aminocore 5-S Plus (Sodium Hydroxide) nitrite injection and Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Aminocore 5-S Plus (Sodium Hydroxide) nitrite should be administered first, followed immediately by Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

Age	Intravenous Dose of Aminocore 5-S Plus (Sodium Hydroxide) Nitrite and Aminocore 5-S Plus (Sodium Hydroxide) Thiosulfate
Adults	Aminocore 5-S Plus (Sodium Hydroxide) Nitrite -10 mL of Aminocore 5-S Plus (Sodium Hydroxide) nitrite at the rate of 2.5 to 5 mL/minute Aminocore 5-S Plus (Sodium Hydroxide) Thiosulfate - 50 mL of Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate immediately following administration of Aminocore 5-S Plus (Sodium Hydroxide) nitrite.
Children	Aminocore 5-S Plus (Sodium Hydroxide) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Aminocore 5-S Plus (Sodium Hydroxide) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Aminocore 5-S Plus (Sodium Hydroxide) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Aminocore 5-S Plus (Sodium Hydroxide) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Aminocore 5-S Plus (Sodium Hydroxide) nitrite and Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Aminocore 5-S Plus (Sodium Hydroxide) nitrite should be reduced proportionately to the hemoglobin concentration.

All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Aminocore 5-S Plus Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Aminocore 5-S Plus (Sodium Hydroxide) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Aminocore 5-S Plus (Sodium Hydroxide) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Aminocore 5-S Plus (Sodium Hydroxide) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Aminocore 5-S Plus (Sodium Hydroxide) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Aminocore 5-S Plus (Sodium Hydroxide) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Aminocore 5-S Plus (Sodium Hydroxide) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate and Aminocore 5-S Plus (Sodium Hydroxide) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Aminocore 5-S Plus (Sodium Hydroxide) Nitrite Injection consists of:

• One vial of Aminocore 5-S Plus (Sodium Hydroxide) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

• Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Methemoglobinemia: Aminocore 5-S Plus nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Aminocore 5-S Plus (Sodium Hydroxide) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
• Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Aminocore 5-S Plus (Sodium Hydroxide) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Aminocore 5-S Plus (Sodium Hydroxide) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Aminocore 5-S Plus nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Aminocore 5-S Plus (Sodium Hydroxide) nitrite whenever possible. When Aminocore 5-S Plus (Sodium Hydroxide) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Aminocore 5-S Plus (Sodium Hydroxide) nitrite administered to an adult. Aminocore 5-S Plus (Sodium Hydroxide) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Aminocore 5-S Plus (Sodium Hydroxide) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Aminocore 5-S Plus (Sodium Hydroxide) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Aminocore 5-S Plus (Sodium Hydroxide) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Aminocore 5-S Plus (Sodium Hydroxide) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Aminocore 5-S Plus nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Aminocore 5-S Plus (Sodium Hydroxide) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Aminocore 5-S Plus nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Aminocore 5-S Plus (Sodium Hydroxide) nitrite.

5.7 Use with Other Drugs

Aminocore 5-S Plus (Sodium Hydroxide) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Aminocore 5-S Plus (Sodium Hydroxide) nitrite.

The medical literature has reported the following adverse events in association with Aminocore 5-S Plus (Sodium Hydroxide) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Aminocore 5-S Plus (Sodium Hydroxide) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

• Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Aminocore 5-S Plus (Sodium Hydroxide) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Aminocore 5-S Plus nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Aminocore 5-S Plus (Sodium Hydroxide) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Aminocore 5-S Plus (Sodium Hydroxide) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Aminocore 5-S Plus (Sodium Hydroxide) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Aminocore 5-S Plus (Sodium Hydroxide) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Aminocore 5-S Plus (Sodium Hydroxide) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Aminocore 5-S Plus (Sodium Hydroxide) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Aminocore 5-S Plus (Sodium Hydroxide) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Aminocore 5-S Plus (Sodium Hydroxide) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Aminocore 5-S Plus (Sodium Hydroxide) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Aminocore 5-S Plus (Sodium Hydroxide) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Aminocore 5-S Plus (Sodium Hydroxide) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Aminocore 5-S Plus (Sodium Hydroxide) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Aminocore 5-S Plus nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Aminocore 5-S Plus (Sodium Hydroxide) nitrite is excreted in human milk. Because Aminocore 5-S Plus (Sodium Hydroxide) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Aminocore 5-S Plus (Sodium Hydroxide) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Aminocore 5-S Plus (Sodium Hydroxide) nitrite. In studies conducted with Long-Evans rats, Aminocore 5-S Plus (Sodium Hydroxide) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Aminocore 5-S Plus nitrite in conjunction with Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Aminocore 5-S Plus (Sodium Hydroxide) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Aminocore 5-S Plus (Sodium Hydroxide) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Aminocore 5-S Plus (Sodium Hydroxide) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

Aminocore 5-S Plus (Sodium Hydroxide) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

Aminocore 5-S Plus (Sodium Hydroxide) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of Aminocore 5-S Plus (Sodium Hydroxide) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Aminocore 5-S Plus (Sodium Hydroxide) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Aminocore 5-S Plus (Sodium Hydroxide) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Aminocore 5-S Plus (Sodium Hydroxide) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Aminocore 5-S Plus (Sodium Hydroxide) nitrite has the chemical name nitrous acid Aminocore 5-S Plus (Sodium Hydroxide) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Aminocore 5-S Plus (Sodium Hydroxide) Nitrite

Aminocore 5-S Plus (Sodium Hydroxide) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Aminocore 5-S Plus (Sodium Hydroxide) nitrite injection.

Aminocore 5-S Plus (Sodium Hydroxide) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Aminocore 5-S Plus (Sodium Hydroxide) nitrite in 10 mL solution (30 mg/mL). Aminocore 5-S Plus (Sodium Hydroxide) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Aminocore 5-S Plus nitrite and Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Aminocore 5-S Plus (Sodium Hydroxide) Nitrite

Aminocore 5-S Plus (Sodium Hydroxide) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a₃, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO₂ + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Aminocore 5-S Plus (Sodium Hydroxide) nitrite. It has been suggested that Aminocore 5-S Plus (Sodium Hydroxide) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Aminocore 5-S Plus (Sodium Hydroxide) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Aminocore 5-S Plus (Sodium Hydroxide) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN^-), which is relatively nontoxic and readily excreted in the urine. Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Aminocore 5-S Plus (Sodium Hydroxide) Nitrite

When 4 mg/kg Aminocore 5-S Plus (Sodium Hydroxide) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Aminocore 5-S Plus (Sodium Hydroxide) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Aminocore 5-S Plus (Sodium Hydroxide) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Aminocore 5-S Plus (Sodium Hydroxide) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Aminocore 5-S Plus (Sodium Hydroxide) Nitrite

Aminocore 5-S Plus (Sodium Hydroxide) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Aminocore 5-S Plus (Sodium Hydroxide) nitrite in humans have not been well studied. It has been reported that approximately 40% of Aminocore 5-S Plus (Sodium Hydroxide) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Aminocore 5-S Plus (Sodium Hydroxide) nitrite and Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Aminocore 5-S Plus nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Aminocore 5-S Plus (Sodium Hydroxide) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Aminocore 5-S Plus (Sodium Hydroxide) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Aminocore 5-S Plus (Sodium Hydroxide) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Aminocore 5-S Plus (Sodium Hydroxide) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Aminocore 5-S Plus (Sodium Hydroxide) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Aminocore 5-S Plus (Sodium Hydroxide) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Aminocore 5-S Plus (Sodium Hydroxide) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Aminocore 5-S Plus (Sodium Hydroxide) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Aminocore 5-S Plus (Sodium Hydroxide) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Aminocore 5-S Plus (Sodium Hydroxide) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Aminocore 5-S Plus (Sodium Hydroxide) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Aminocore 5-S Plus (Sodium Hydroxide) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Aminocore 5-S Plus (Sodium Hydroxide) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Aminocore 5-S Plus (Sodium Hydroxide) nitrite and Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Aminocore 5-S Plus (Sodium Hydroxide) nitrite or 1 g/kg Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate alone or in sequence immediately after subcutaneous injection of Aminocore 5-S Plus (Sodium Hydroxide) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Aminocore 5-S Plus (Sodium Hydroxide) nitrite and/or 0.5 g/kg Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Aminocore 5-S Plus (Sodium Hydroxide) cyanide required to cause death, and when administered together, Aminocore 5-S Plus (Sodium Hydroxide) nitrite and Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate resulted in a synergistic effect in raising the lethal dose of Aminocore 5-S Plus (Sodium Hydroxide) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Aminocore 5-S Plus (Sodium Hydroxide) nitrite and Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Aminocore 5-S Plus (Sodium Hydroxide) nitrite and Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Aminocore 5-S Plus (Sodium Hydroxide) nitrite, with or without Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Aminocore 5-S Plus (Sodium Hydroxide) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Aminocore 5-S Plus (Sodium Hydroxide) thiosulfate report its use in conjunction with Aminocore 5-S Plus (Sodium Hydroxide) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Aminocore 5-S Plus (Sodium Hydroxide) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Aminocore 5-S Plus (Sodium Hydroxide) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Aminocore 5-S Plus (Sodium Hydroxide) nitrite injection 30 mg/mL (containing 300 mg of Aminocore 5-S Plus (Sodium Hydroxide) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Aminocore 5-S Plus (Sodium Hydroxide) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Aminocore 5-S Plus Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Aminocore 5-S Plus (Sodium Hydroxide) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Aminocore 5-S Plus (Sodium Hydroxide) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Tryptophan:

• Aminocore 5-S Plus (Tryptophan) reviews

In Canada, Aminocore 5-S Plus (Tryptophan) is sold as a prescription drug to treat mood disorders (such as bipolar disorder, depression ). It is usually used with other medicines. It works to make the mood more stable and reduce extremes in behavior by restoring the balance of certain natural substances (serotonin, melatonin ) in the brain. Aminocore 5-S Plus (Tryptophan) is a natural substance (amino acid) found in high-protein foods and milk. In the US, Aminocore 5-S Plus (Tryptophan) is sold as a dietary supplement. It has been used to support mood, relaxation, and restful sleep. If you are taking other medications that may affect serotonin (such as many antidepressants ), do not take Aminocore 5-S Plus (Tryptophan) without talking with your doctor first. A very serious (possibly fatal) drug interaction may occur. Your doctor should closely monitor you. See also Side Effects section. Some supplement products have been found to contain possibly harmful impurities/additives. Check with your pharmacist for more details about the brand you use. The US FDA has not reviewed this product for safety or effectiveness. Consult your doctor or pharmacist for more details.