Nonan

Ammonium (Ammonium Molybdate Tetrahydrate):

• Indications and usage
• Contraindications
• Warning
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) reviews

INDICATIONS AND USAGE

Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) Lactate Lotion, 12% is indicated for the treatment of dry, scaly skin (xerosis) and ichthyosis vulgaris, and for the temporary relief of itching associated with these conditions.

CONTRAINDICATIONS

Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) Lactate Lotion, 12% is contraindicated in those patients with a history of hypersensitivity to any of the label ingredients.

WARNING

Sun exposure (natural or artificial sunlight) to areas of the skin treated with Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) Lactate Lotion, 12% should be minimized or avoided (see PRECAUTIONS). The use of Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) Lactate Lotion, 12% should be discontinued if any hypersensitivity is observed.

PRECAUTIONS

General -

For external use only. Stinging or burning may occur when applied to skin with fissures, erosions, or that is otherwise abraded. Caution is advised when used on the face because of the potential for irritation. The potential for post-inflammatory hypo- or hyperpigmentation has not been studied.

Information for Patients

Patients using Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) Lactate Lotion, 12% should receive the following information and instructions:

• This medication is to be used as directed by the physician, and should not be used for any disorder other than for which it was prescribed. It is for external use only. Avoid contact with eyes, lips, or mucous membranes.
• Patients should minimize or avoid use of this product on areas of the skin that may be exposed to natural or artificial sunlight, including the face. If sun exposure is unavoidable, clothing should be worn to protect the skin.
• This medication may cause transient stinging or burning when applied to skin with fissures, erosions, or abrasions (for example, after shaving the legs).
• If the skin condition worsens with treatment, the medication should be promptly discontinued.

Carcinogenesis, Mutagenesis, Impairment of Fertility -

The topical treatment of CD-1 mice with 12%, 21% or 30% Nonan ) lactate formulations for two-years did not produce a significant increase in dermal or systemic tumors in the absence of increased exposure to ultraviolet radiation. The maximum systemic exposure of the mice in this study was 0.7 times the maximum possible systemic exposure in humans. However, a long-term photocarcinogenicity study in hairless albino mice suggested that topically applied 12% Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) lactate formulations enhanced the rate of ultraviolet light-induced skin tumor formation.

The mutagenic potential of Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) lactate formulations was evaluated in the Ames assay and in the mouse in vivo micronucleus assay, both of which were negative.

In dermal Segment I and III studies with Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) lactate formulations there were no effects observed in fertility or pre- or postnatal development parameters in rats at dose levels of 300 mg/kg/day (1800 mg/m²/day), approximately 0.4 times the human topical dose.

Pregnancy:

Teratogenic effects:

Pregnancy Category B -

Animal reproduction studies have been performed in rats and rabbits at doses up to 0.7 and 1.5 times the human dose, respectively and have revealed no evidence of impaired fertility or harm to the fetus due to Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) lactate formulations. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) Lactate Lotion, 12% should be used during pregnancy only if clearly needed.

Nursing Mothers -

Although lactic acid is a normal constituent of blood and tissues, it is not known to what extent this drug affects normal lactic acid levels in human milk. Because many drugs are excreted in human milk, caution should be exercised when Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) lactate is administered to a nursing woman.

Pediatric Use -

Safety and effectiveness of Nonan ) lactate have been demonstrated in infants and children. No unusual toxic effects were reported.

Geriatric Use -

Clinical studies of Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) lactate lotion, 12% 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 elderly and younger patients. In general, dose selection for an elderly patient should be cautious.

ADVERSE REACTIONS

The most frequent adverse experiences in patients with xerosis are transient stinging (1 in 30 patients), burning (1 in 30 patients), erythema (1 in 50 patients) and peeling (1 in 60 patients). Other adverse reactions which occur less frequently are irritation, eczema, petechiae, dryness, and hyperpigmentation. Due to the more severe initial skin conditions associated with ichthyosis, there was a higher incidence of transient stinging, burning and erythema (each occurring in 1 in 10 patients).

OVERDOSAGE

The oral administration of Nonan (Ammonium (Ammonium Molybdate Tetrahydrate)) lactate to rats and mice showed this drug to be practically non-toxic (LD₅₀>15 mL/kg).

DOSAGE AND ADMINISTRATION

Shake well. Apply to the affected areas and rub in thoroughly. Use twice daily or as directed by a physician.

HOW SUPPLIED

Nonan ) Lactate Lotion, 12% is available as follows:

225 g bottle (NDC 45802-419-54)

400 g bottle (NDC 45802-419-26)

STORAGE

Store at 20-25°C (68-77°F).

Manufactured By Perrigo, Bronx, NY 10457

Distributed By Perrigo, Allegan, MI 49010

0K5A7 RC F6

Rev 01-17

Copper (Copper Gluconate):

• Indications:
• General directions:
• Active ingredient:
• Inactive ingredients:
• Caution:
• Storage:
• Net contents:
• Nonan (Copper (Copper Gluconate)) reviews

Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Nonan (Copper (Copper Gluconate)) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of Nonan (Copper (Copper Gluconate))^®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Nonan (Copper (Copper Gluconate))^® onto hair since contact with Nonan (Copper (Copper Gluconate))^® may cause some hair loss. Do not contaminate feed.

NOTE: Nonan (Copper (Copper Gluconate))^® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

Nonan (Copper (Copper Gluconate)) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,^® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Fluorine (Sodium Fluoride):

• Nonan (Fluorine (Sodium Fluoride)) reviews

Iodine (Sodium Iodide):

• Iodine tincture 7%
• Iodine tincture 7%
• Nonan (Iodine (Sodium Iodide)) reviews

Nonan ) Tincture 7%

Directions:

Topical Antiseptic

Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply Nonan (Iodine (Sodium Iodide)) with a swab.

If necessary, clip hair around the area being treated and clean with soap and water.

Apply Nonan (Iodine (Sodium Iodide)) Tincture 7% only once daily. Dilute product 3 to 1 if repeating application.

Do not apply under bandage.

Irritation may occur if used on tender skin areas. If redness, irritation, or swelling persists or increases, discontinue use and consult a veterinarian.

Storage:

Store at 2-30 degrees C (36-86 degrees F).

Keep container away from heat and out of sunlight. Rinse empty container thoroughly and discard.

DANGER - Poison

Caution:

If swallowed, give starch paste, milk, bread, egg white, or

activated charcoal. A 5% solutions of sodium thiosulfate

(Photographic (“hypc”) may be administered orally at a

rate of 10 ml per kilogram of body weight.

Eye irritant: Use only as directed. Avoid contact with eyes. In case of contact, flush eyes immediately with tepid water for at least 15 minutes. Consult a physician.

Avoid contamination of food.

Not for use on burns, deep cuts, or body cavities.

Nonan ) Tincture 7%

image description

Iron (Ferrous Gluconate Dihydrate):

• 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
• Nonan (Iron (Ferrous Gluconate Dihydrate)) reviews

1 INDICATIONS AND USAGE

Nonan (Iron (Ferrous Gluconate Dihydrate)) is indicated for the treatment of Nonan (Iron (Ferrous Gluconate Dihydrate)) deficiency anemia in patients with chronic kidney disease (CKD).

Nonan (Iron (Ferrous Gluconate Dihydrate)) is an Nonan (Iron (Ferrous Gluconate Dihydrate)) replacement product indicated for the treatment of Nonan (Iron (Ferrous Gluconate Dihydrate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Nonan ) must only be administered intravenously either by slow injection or by infusion. The dosage of Nonan (Iron (Ferrous Gluconate Dihydrate)) is expressed in mg of elemental Nonan (Iron (Ferrous Gluconate Dihydrate)). Each mL contains 20 mg of elemental Nonan (Iron (Ferrous Gluconate Dihydrate)).

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Nonan (Iron (Ferrous Gluconate Dihydrate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Nonan (Iron (Ferrous Gluconate Dihydrate)) should be administered early during the dialysis session. The usual total treatment course of Nonan (Iron (Ferrous Gluconate Dihydrate)) is 1000 mg. Nonan (Iron (Ferrous Gluconate Dihydrate)) treatment may be repeated if Nonan (Iron (Ferrous Gluconate Dihydrate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Nonan (Iron (Ferrous Gluconate Dihydrate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Nonan (Iron (Ferrous Gluconate Dihydrate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Nonan (Iron (Ferrous Gluconate Dihydrate)) treatment may be repeated if Nonan (Iron (Ferrous Gluconate Dihydrate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Nonan (Iron (Ferrous Gluconate Dihydrate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Nonan (Iron (Ferrous Gluconate Dihydrate)) in a maximum of 250 mL of 0.9% NaCl. Nonan (Iron (Ferrous Gluconate Dihydrate)) treatment may be repeated if Nonan (Iron (Ferrous Gluconate Dihydrate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Nonan (Iron (Ferrous Gluconate Dihydrate)) maintenance treatment

The dosing for Nonan (Iron (Ferrous Gluconate Dihydrate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Nonan (Iron (Ferrous Gluconate Dihydrate)) maintenance treatment: Administer Nonan (Iron (Ferrous Gluconate Dihydrate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Nonan (Iron (Ferrous Gluconate Dihydrate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Nonan (Iron (Ferrous Gluconate Dihydrate)) maintenance treatment

The dosing for Nonan (Iron (Ferrous Gluconate Dihydrate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Nonan (Iron (Ferrous Gluconate Dihydrate)) maintenance treatment: Administer Nonan (Iron (Ferrous Gluconate Dihydrate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Nonan (Iron (Ferrous Gluconate Dihydrate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Nonan (Iron (Ferrous Gluconate Dihydrate))

• Known hypersensitivity to Nonan (Iron (Ferrous Gluconate Dihydrate)) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Nonan ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Nonan (Iron (Ferrous Gluconate Dihydrate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: Nonan (Iron (Ferrous Gluconate Dihydrate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Nonan (Iron (Ferrous Gluconate Dihydrate)). (5.2)
• Nonan (Iron (Ferrous Gluconate Dihydrate)) Overload: Regularly monitor hematologic responses during Nonan (Iron (Ferrous Gluconate Dihydrate)) therapy. Do not administer Nonan (Iron (Ferrous Gluconate Dihydrate)) to patients with Nonan (Iron (Ferrous Gluconate Dihydrate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Nonan (Iron (Ferrous Gluconate Dihydrate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Nonan (Iron (Ferrous Gluconate Dihydrate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Nonan (Iron (Ferrous Gluconate Dihydrate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Nonan (Iron (Ferrous Gluconate Dihydrate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Nonan (Iron (Ferrous Gluconate Dihydrate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Nonan ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Nonan (Iron (Ferrous Gluconate Dihydrate)). Hypotension following administration of Nonan (Iron (Ferrous Gluconate Dihydrate)) may be related to the rate of administration and/or total dose administered .

5.3 Nonan (Iron (Ferrous Gluconate Dihydrate)) Overload

Excessive therapy with parenteral Nonan (Iron (Ferrous Gluconate Dihydrate)) can lead to excess storage of Nonan (Iron (Ferrous Gluconate Dihydrate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Nonan (Iron (Ferrous Gluconate Dihydrate)) require periodic monitoring of hematologic and Nonan (Iron (Ferrous Gluconate Dihydrate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Nonan (Iron (Ferrous Gluconate Dihydrate)) to patients with evidence of Nonan (Iron (Ferrous Gluconate Dihydrate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose; do not perform serum Nonan (Iron (Ferrous Gluconate Dihydrate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Nonan ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Nonan (Iron (Ferrous Gluconate Dihydrate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Nonan ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Nonan (Iron (Ferrous Gluconate Dihydrate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Nonan (Iron (Ferrous Gluconate Dihydrate)) therapy and were reported to be intolerant (defined as precluding further use of that Nonan (Iron (Ferrous Gluconate Dihydrate)) product). When these patients were treated with Nonan (Iron (Ferrous Gluconate Dihydrate)) there were no occurrences of adverse reactions that precluded further use of Nonan (Iron (Ferrous Gluconate Dihydrate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Nonan (Iron (Ferrous Gluconate Dihydrate)) maintenance treatment with Nonan (Iron (Ferrous Gluconate Dihydrate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Nonan (Iron (Ferrous Gluconate Dihydrate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Nonan (Iron (Ferrous Gluconate Dihydrate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Nonan (Iron (Ferrous Gluconate Dihydrate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Nonan (Iron (Ferrous Gluconate Dihydrate)) 0.5 mg/kg group, 10 (21%) patients in the Nonan (Iron (Ferrous Gluconate Dihydrate)) 1.0 mg/kg group, and 10 (21%) patients in the Nonan (Iron (Ferrous Gluconate Dihydrate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Nonan (Iron (Ferrous Gluconate Dihydrate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Nonan (Iron (Ferrous Gluconate Dihydrate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Nonan (Iron (Ferrous Gluconate Dihydrate)) injection. Reactions have occurred following the first dose or subsequent doses of Nonan (Iron (Ferrous Gluconate Dihydrate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Nonan (Iron (Ferrous Gluconate Dihydrate)) have not been studied. However, Nonan (Iron (Ferrous Gluconate Dihydrate)) may reduce the absorption of concomitantly administered oral Nonan (Iron (Ferrous Gluconate Dihydrate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Nonan ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose. Because animal reproductive studies are not always predictive of human response, Nonan (Iron (Ferrous Gluconate Dihydrate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose is excreted in human milk. Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Nonan (Iron (Ferrous Gluconate Dihydrate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Nonan ) for Nonan (Iron (Ferrous Gluconate Dihydrate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Nonan (Iron (Ferrous Gluconate Dihydrate)) for Nonan (Iron (Ferrous Gluconate Dihydrate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Nonan (Iron (Ferrous Gluconate Dihydrate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Nonan (Iron (Ferrous Gluconate Dihydrate)) has not been studied in patients younger than 2 years of age.

In a country where Nonan (Iron (Ferrous Gluconate Dihydrate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Nonan (Iron (Ferrous Gluconate Dihydrate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Nonan (Iron (Ferrous Gluconate Dihydrate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Nonan (Iron (Ferrous Gluconate Dihydrate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Nonan (Iron (Ferrous Gluconate Dihydrate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Nonan (Iron (Ferrous Gluconate Dihydrate)) in humans. Excessive dosages of Nonan (Iron (Ferrous Gluconate Dihydrate)) may lead to accumulation of Nonan (Iron (Ferrous Gluconate Dihydrate)) in storage sites potentially leading to hemosiderosis. Do not administer Nonan (Iron (Ferrous Gluconate Dihydrate)) to patients with Nonan (Iron (Ferrous Gluconate Dihydrate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Nonan (Iron (Ferrous Gluconate Dihydrate)) (iron sucrose injection, USP), an Nonan (Iron (Ferrous Gluconate Dihydrate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Nonan (Iron (Ferrous Gluconate Dihydrate)) (III)-hydroxide in sucrose for intravenous use. Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na₂Fe₅O₈(OH) ·3(H₂O)]_n ·m(C₁₂H₂₂O₁₁)

where: n is the degree of Nonan (Iron (Ferrous Gluconate Dihydrate)) polymerization and m is the number of sucrose molecules associated with the Nonan (Iron (Ferrous Gluconate Dihydrate)) (III)-hydroxide.

Each mL contains 20 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) as Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose in water for injection. Nonan (Iron (Ferrous Gluconate Dihydrate)) is available in 10 mL single-use vials (200 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) per 10 mL), 5 mL single-use vials (100 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Nonan ) is an aqueous complex of poly-nuclear Nonan (Iron (Ferrous Gluconate Dihydrate)) (III)-hydroxide in sucrose. Following intravenous administration, Nonan (Iron (Ferrous Gluconate Dihydrate)) is dissociated into Nonan (Iron (Ferrous Gluconate Dihydrate)) and sucrose and the Nonan (Iron (Ferrous Gluconate Dihydrate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Nonan (Iron (Ferrous Gluconate Dihydrate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Nonan (Iron (Ferrous Gluconate Dihydrate)) is dissociated into Nonan (Iron (Ferrous Gluconate Dihydrate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose containing 100 mg of Nonan (Iron (Ferrous Gluconate Dihydrate)), three times weekly for three weeks, significant increases in serum Nonan (Iron (Ferrous Gluconate Dihydrate)) and serum ferritin and significant decreases in total Nonan (Iron (Ferrous Gluconate Dihydrate)) binding capacity occurred four weeks from the initiation of Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Nonan ), its Nonan (Iron (Ferrous Gluconate Dihydrate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Nonan (Iron (Ferrous Gluconate Dihydrate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Nonan (Iron (Ferrous Gluconate Dihydrate)) containing 100 mg of Nonan (Iron (Ferrous Gluconate Dihydrate)) labeled with ⁵²Fe/⁵⁹Fe in patients with Nonan (Iron (Ferrous Gluconate Dihydrate)) deficiency showed that a significant amount of the administered Nonan (Iron (Ferrous Gluconate Dihydrate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Nonan (Iron (Ferrous Gluconate Dihydrate)) trapping compartment.

Following intravenous administration of Nonan (Iron (Ferrous Gluconate Dihydrate)), Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose is dissociated into Nonan (Iron (Ferrous Gluconate Dihydrate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Nonan (Iron (Ferrous Gluconate Dihydrate)) containing 1,510 mg of sucrose and 100 mg of Nonan (Iron (Ferrous Gluconate Dihydrate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Nonan (Iron (Ferrous Gluconate Dihydrate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose containing 500 to 700 mg of Nonan (Iron (Ferrous Gluconate Dihydrate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Nonan (Iron (Ferrous Gluconate Dihydrate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Nonan (Iron (Ferrous Gluconate Dihydrate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Nonan (Iron (Ferrous Gluconate Dihydrate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Nonan (Iron (Ferrous Gluconate Dihydrate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Nonan (Iron (Ferrous Gluconate Dihydrate)), the half-life of total serum Nonan (Iron (Ferrous Gluconate Dihydrate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Nonan (Iron (Ferrous Gluconate Dihydrate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose.

Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Nonan (Iron (Ferrous Gluconate Dihydrate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Nonan ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Nonan (Iron (Ferrous Gluconate Dihydrate)) treatment and 24 in the historical control group) with Nonan (Iron (Ferrous Gluconate Dihydrate)) deficiency anemia. Eligibility criteria for Nonan (Iron (Ferrous Gluconate Dihydrate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Nonan (Iron (Ferrous Gluconate Dihydrate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Nonan (Iron (Ferrous Gluconate Dihydrate)), who were off intravenous Nonan (Iron (Ferrous Gluconate Dihydrate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Nonan (Iron (Ferrous Gluconate Dihydrate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Nonan (Iron (Ferrous Gluconate Dihydrate)) in 23 patients with Nonan (Iron (Ferrous Gluconate Dihydrate)) deficiency and HDD-CKD who had been discontinued from Nonan (Iron (Ferrous Gluconate Dihydrate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Nonan (Iron (Ferrous Gluconate Dihydrate)). Exclusion criteria were similar to those in studies A and B. Nonan (Iron (Ferrous Gluconate Dihydrate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Nonan (Iron (Ferrous Gluconate Dihydrate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Nonan (Iron (Ferrous Gluconate Dihydrate)) versus Nonan (Iron (Ferrous Gluconate Dihydrate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Nonan (Iron (Ferrous Gluconate Dihydrate)) (325 mg ferrous sulfate three times daily for 56 days); or Nonan (Iron (Ferrous Gluconate Dihydrate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Nonan (Iron (Ferrous Gluconate Dihydrate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Nonan (Iron (Ferrous Gluconate Dihydrate)) group.

A statistically significantly greater proportion of Nonan (Iron (Ferrous Gluconate Dihydrate)) subjects (35/79; 44.3%) compared to oral Nonan (Iron (Ferrous Gluconate Dihydrate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Nonan (Iron (Ferrous Gluconate Dihydrate)) to patients with PDD-CKD receiving an erythropoietin alone without Nonan (Iron (Ferrous Gluconate Dihydrate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Nonan (Iron (Ferrous Gluconate Dihydrate)) or Nonan (Iron (Ferrous Gluconate Dihydrate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Nonan (Iron (Ferrous Gluconate Dihydrate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Nonan (Iron (Ferrous Gluconate Dihydrate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Nonan (Iron (Ferrous Gluconate Dihydrate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Nonan ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Nonan (Iron (Ferrous Gluconate Dihydrate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Nonan (Iron (Ferrous Gluconate Dihydrate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Nonan (Iron (Ferrous Gluconate Dihydrate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Nonan (Iron (Ferrous Gluconate Dihydrate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Nonan (Iron (Ferrous Gluconate Dihydrate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Nonan ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)), each 5 mL vial contains 100 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)), and each 2.5 mL vial contains 50 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) (20 mg/mL).

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Nonan (Iron (Ferrous Gluconate Dihydrate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) per mL, or undiluted (20 mg elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Nonan (Iron (Ferrous Gluconate Dihydrate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Nonan (Iron (Ferrous Gluconate Dihydrate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Nonan (Iron (Ferrous Gluconate Dihydrate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Nonan (Iron (Ferrous Gluconate Dihydrate)) administration:

• Question patients regarding any prior history of reactions to parenteral Nonan (Iron (Ferrous Gluconate Dihydrate)) products
• Advise patients of the risks associated with Nonan (Iron (Ferrous Gluconate Dihydrate))
• Advise patients to report any symptoms of hypersensitivity that may develop during and following Nonan (Iron (Ferrous Gluconate Dihydrate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Nonan (Iron (Ferrous Gluconate Dihydrate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx^® is a trademark of Premier, Inc., used under license.

PREMIERProRx^®

IN2340

MG #15727

Manganese (Manganese Gluconate Anhydrous):

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Rl-0104
• Nonan (Manganese (Manganese Gluconate Anhydrous)) reviews

INDICATIONS AND USAGE

Nonan (Manganese (Manganese Gluconate Anhydrous)) 0.1 mg/mL (Manganese Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN).

Administration helps to maintain Nonan (Manganese (Manganese Gluconate Anhydrous)) serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Nonan (Manganese (Manganese Gluconate Anhydrous)) 0.1 mg/mL (Manganese Chloride Injection, USP) is contraindicated as the acidic pH of the solution (pH 2.0) may cause considerable tissue irritation.

Liver and/or biliary tract dysfunction may require omission or reduction of copper and Nonan (Manganese (Manganese Gluconate Anhydrous)) doses because these elements are primarily eliminated in the bile.

WARNING: 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.

PRECAUTIONS

General

Do not use unless solution is clear and seal is intact.

Nonan ) 0.1 mg/mL (Manganese Chloride Injection, USP) should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.

Laboratory Tests

Serum Nonan (Manganese (Manganese Gluconate Anhydrous)) levels can be measured periodically at the discretion of the investigator. Because of the low serum concentration normally present, samples will usually be analyzed by a reference laboratory.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Nonan ) 0.1 mg/mL (Manganese Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Nonan (Manganese (Manganese Gluconate Anhydrous)) 0.1 mg/mL (Manganese Chloride Injection, USP) additive is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Pregnancy Category C.

Animal reproduction studies have not been conducted with Nonan (Manganese (Manganese Gluconate Anhydrous)) chloride. It is also not known whether Nonan (Manganese (Manganese Gluconate Anhydrous)) chloride can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Nonan (Manganese (Manganese Gluconate Anhydrous)) chloride should be given to a pregnant woman only if clearly indicated.

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response between 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.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Nonan (Manganese (Manganese Gluconate Anhydrous)) toxicity in TPN patients has not been reported.

DOSAGE AND ADMINISTRATION

Nonan (Manganese (Manganese Gluconate Anhydrous)) 0.1 mg/mL (Manganese Chloride Injection, USP) contains 0.1 mg manganese/mL and is administered intravenously only after dilution. The additive should be administered in a volume of fluid not less than 100 mL. For the adult receiving TPN, the suggested additive dosage for Nonan (Manganese (Manganese Gluconate Anhydrous)) is 0.15 to 0.8 mg/day (1.5 to 8 mL/day). For pediatric patients, a dosage of 2 to 10 mcg manganese/kg/day (0.02 to 0.1 mL/kg/day) is recommended.

Periodic monitoring of Nonan (Manganese (Manganese Gluconate Anhydrous)) plasma levels is suggested as a guideline for subsequent administration.

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

HOW SUPPLIED

Nonan (Manganese (Manganese Gluconate Anhydrous)) 0.1 mg/mL (Manganese Chloride Injection, USP) is supplied in 10 mL Plastic Vials (NDC No. 0409-4091-01).

Store at 20 to 25°C (68 to 77°F)

Revised: November, 2009

Printed in USA EN-2320

Hospira, Inc., Lake Forest, IL 60045 USA

RL-0104

Selenium (Sodium Selenite Pentahydrate):

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Nonan (Selenium (Sodium Selenite Pentahydrate)) reviews

Rx Only

TRACE ELEMENT ADDITIVE FOR IV USE AFTER DILUTION

DESCRIPTION

Nonan (Selenium (Sodium Selenite Pentahydrate)) Injection is a sterile, nonpyrogenic solution for use as an additive to solutions for Total Parenteral Nutrition (TPN).

Each mL contains Selenious Acid 65.4 mcg (equivalent to elemental Nonan (Selenium (Sodium Selenite Pentahydrate)) 40 mcg/mL) and Water for Injection q.s. pH may be adjusted with nitric acid to 1.8 to 2.4.

CLINICAL PHARMACOLOGY

Nonan (Selenium (Sodium Selenite Pentahydrate)) is part of glutathione peroxidase which protects cell components from oxidative damage due to peroxides produced in cellular metabolism.

Prolonged TPN support in humans has resulted in Nonan (Selenium (Sodium Selenite Pentahydrate)) deficiency symptoms which include muscle pain and tenderness. The symptoms have been reported to respond to supplementation of TPN solutions with Nonan (Selenium (Sodium Selenite Pentahydrate)).

Pediatric conditions, Keshan disease, and Kwashiorkor, have been associated with low dietary intake of Nonan (Selenium (Sodium Selenite Pentahydrate)). The conditions are endemic to geographical areas with low Nonan (Selenium (Sodium Selenite Pentahydrate)) soil content. Dietary supplementation with Nonan (Selenium (Sodium Selenite Pentahydrate)) salts has been reported to reduce the incidence of the conditions among affected children.

Normal blood levels of Nonan (Selenium (Sodium Selenite Pentahydrate)) in different human populations have been found to vary and depend on the Nonan (Selenium (Sodium Selenite Pentahydrate)) content of the food consumed. Results of surveys carried out in some countries are tabulated below:

Plasma Nonan (Selenium (Sodium Selenite Pentahydrate)) levels of 0.3 and 0.9 mcg/100 mL have been reported to produce deficiency symptoms in humans.

Nonan (Selenium (Sodium Selenite Pentahydrate)) is eliminated primarily in urine. However, significant endogenous losses through feces also occur. The rate of excretion and the relative importance of two routes varies with the chemical form of Nonan (Selenium (Sodium Selenite Pentahydrate)) used in supplementation. Ancillary routes of elimination are lungs and skin.

INDICATIONS AND USAGE

Nonan (Selenium (Sodium Selenite Pentahydrate)) Injection is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN). Administration of Nonan (Selenium (Sodium Selenite Pentahydrate)) in TPN solutions helps to maintain plasma Nonan (Selenium (Sodium Selenite Pentahydrate)) levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

Nonan (Selenium (Sodium Selenite Pentahydrate)) Injection should not be given undiluted by direct injection into a peripheral vein because of the potential for infusion phlebitis.

WARNINGS

Nonan (Selenium (Sodium Selenite Pentahydrate)) Injection can be toxic if given in excessive amounts. Supplementation of TPN solution with Nonan (Selenium (Sodium Selenite Pentahydrate)) should be immediately discontinued if toxicity symptoms are observed. Frequent determination of plasma Nonan (Selenium (Sodium Selenite Pentahydrate)) levels during TPN support and close medical supervision is recommended.

Nonan (Selenium (Sodium Selenite Pentahydrate)) Injection is a hypotonic solution and should be administered in admixtures only.

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.

PRECAUTIONS

As Nonan ) is eliminated in urine and feces, Nonan (Selenium (Sodium Selenite Pentahydrate)) supplements may be adjusted, reduced or omitted in renal dysfunction and/or gastrointestinal malfunction. In patients receiving blood transfusions, contribution from such transfusions should also be considered. Frequent Nonan (Selenium (Sodium Selenite Pentahydrate)) plasma level determinations are suggested as a guideline.

In animals, Nonan (Selenium (Sodium Selenite Pentahydrate)) has been reported to enhance the action of Vitamin E and decrease the toxicity of mercury, cadmium and arsenic.

Pregnancy

Teratogenic Effects

Pregnancy Category C: Nonan (Selenium (Sodium Selenite Pentahydrate)) at high dose levels (15-30 mcg/egg) has been reported to have adverse embryological effects among chickens. There are however, no adequate and wellcontrolled studies in pregnant women. Nonan (Selenium (Sodium Selenite Pentahydrate)) Injection should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

Presence of Nonan (Selenium (Sodium Selenite Pentahydrate)) in placenta and umbilical cord blood has been reported in humans.

ADVERSE REACTIONS

The amount of Nonan (Selenium (Sodium Selenite Pentahydrate)) present in Nonan (Selenium (Sodium Selenite Pentahydrate)) Injection is small. Symptoms of toxicity from Nonan (Selenium (Sodium Selenite Pentahydrate)) are unlikely to occur at the recommended dosage level.

OVERDOSAGE

Chronic toxicity in humans resulting from exposure to Nonan (Selenium (Sodium Selenite Pentahydrate)) in industrial environments, intake of foods grown in seleniferous soils, use of selenium-contaminated water, and application of cosmetics containing Nonan (Selenium (Sodium Selenite Pentahydrate)) has been reported in literature. Toxicity symptoms include hair loss, weakened nails, dermatitis, dental defects, gastrointestinal disorders, nervousness, mental depression, metallic taste, vomiting, and garlic odor of breath and sweat. Acute poisoning due to ingestion of large amounts of Nonan (Selenium (Sodium Selenite Pentahydrate)) compounds has resulted in death with histopathological changes including fulminating peripheral vascular collapse, internal vascular congestion, diffusely hemorrhagic, congested and edematus lungs, brick-red color gastric mucosa. The death was preceded by coma.

No effective antidote to Nonan (Selenium (Sodium Selenite Pentahydrate)) poisoning in humans is known. Animal studies have shown casein and linseed oil in feeds, reduced glutathione, arsenic, magnesium sulfate, and bromobenzene to afford limited protection.

DOSAGE AND ADMINISTRATION

Nonan (Selenium (Sodium Selenite Pentahydrate)) Injection provides 40 mcg selenium/mL. For metabolically stable adults receiving TPN, the suggested additive dosage level is 20 to 40 mcg selenium/day. For pediatric patients, the suggested additive dosage level is 3 mcg/kg/day.

In adults, Nonan (Selenium (Sodium Selenite Pentahydrate)) deficiency states resulting from long-term TPN support, Nonan (Selenium (Sodium Selenite Pentahydrate)) as selenomethionine or selenious acid, administered intravenously at 100 mcg/day for a period of 24 and 31 days, respectively, has been reported to reverse deficiency symptoms without toxicity.

Aseptic addition of Nonan (Selenium (Sodium Selenite Pentahydrate)) Injection to the TPN solution under laminar flow hood is recommended. Nonan (Selenium (Sodium Selenite Pentahydrate)) is physically compatible with the electrolytes and other trace elements usually present in amino-acid/dextrose solution used for TPN. Frequent monitoring of plasma Nonan (Selenium (Sodium Selenite Pentahydrate)) levels is suggested as a guideline for subsequent administration. The normal whole blood range for Nonan (Selenium (Sodium Selenite Pentahydrate)) is approximately 10 to 37 mcg/100 mL.

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

HOW SUPPLIED

Nonan (Selenium (Sodium Selenite Pentahydrate)) Injection containing selenious acid 65.4 mcg/mL (equivalent to elemental Nonan (Selenium (Sodium Selenite Pentahydrate)) 40 mcg/mL).

NDC 0517-6510-25 10 mL Single Dose Vial Packaged in boxes of 25

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

IN6510

Rev. 11/15

PRINCIPAL DISPLAY PANEL - Container

NDC 0517-6510-25

Nonan (Selenium (Sodium Selenite Pentahydrate)) INJECTION

Nonan (Selenium (Sodium Selenite Pentahydrate)) 400 mcg/10 mL

(40 mcg/mL)

10 mL

SINGLE DOSE VIAL

Trace Element Additive

FOR IV USE AFTER DILUTION

PRESERVATIVE FREE

Rx Only

AMERICAN REGENT, INC.

SHIRLEY, NY 11967

PRINCIPAL DISPLAY PANEL - Carton

Nonan (Selenium (Sodium Selenite Pentahydrate)) INJECTION

Nonan (Selenium (Sodium Selenite Pentahydrate)) 400 mcg/10 mL

(40 mcg/mL)

Trace Element Additive

NDC 0517-6510-25

25 x 10 mL

SINGLE DOSE VIALS

FOR INTRAVENOUS USE AFTER DILUTION PRESERVATIVE FREE Rx Only

Each mL contains: Selenious Acid 65.4 mcg, Water for Injection q.s.

pH adjusted with Nitric Acid. Sterile, nonpyrogenic.

WARNING: DISCARD UNUSED PORTION. Store at 20°-25°C (68°-77°F); excursions

permitted to 15°-30°C (59°-86°F).

Directions for Use: See Package Insert.

AMERICAN REGENT, INC.

SHIRLEY, NY 11967

Rev. 11/05

Container Carton

Sodium (Sodium Fluoride):

• 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
• Nonan (Sodium (Sodium Fluoride)) reviews

1 INDICATIONS AND USAGE

Nonan ) nitrite is indicated for sequential use with Nonan (Sodium (Sodium Fluoride)) 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

Nonan (Sodium (Sodium Fluoride)) Nitrite Injection is indicated for sequential use with Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan ) 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, Nonan (Sodium (Sodium Fluoride)) Nitrite Injection and Nonan (Sodium (Sodium Fluoride)) Thiosulfate Injection should be administered without delay.

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

2 DOSAGE AND ADMINISTRATION

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Nonan (Sodium (Sodium Fluoride)) nitrite and Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite, followed by Nonan (Sodium (Sodium Fluoride)) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Nonan (Sodium (Sodium Fluoride)) nitrite and Nonan (Sodium (Sodium Fluoride)) thiosulfate.

Nonan (Sodium (Sodium Fluoride)) nitrite injection and Nonan (Sodium (Sodium Fluoride)) 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. Nonan (Sodium (Sodium Fluoride)) nitrite should be administered first, followed immediately by Nonan (Sodium (Sodium Fluoride)) 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.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Nonan (Sodium (Sodium Fluoride)) nitrite and Nonan (Sodium (Sodium Fluoride)) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Nonan (Sodium (Sodium Fluoride)) 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 Nonan ) 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 Nonan (Sodium (Sodium Fluoride)) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Nonan (Sodium (Sodium Fluoride)) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Nonan (Sodium (Sodium Fluoride)) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Nonan (Sodium (Sodium Fluoride)) thiosulfate and Nonan (Sodium (Sodium Fluoride)) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Nonan (Sodium (Sodium Fluoride)) Nitrite Injection consists of:

• One vial of Nonan (Sodium (Sodium Fluoride)) 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: Nonan ) 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 Nonan (Sodium (Sodium Fluoride)) 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. Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan ) nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Nonan (Sodium (Sodium Fluoride)) nitrite whenever possible. When Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite administered to an adult. Nonan (Sodium (Sodium Fluoride)) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Nonan ) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan ) 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 Nonan (Sodium (Sodium Fluoride)) nitrite.

5.7 Use with Other Drugs

Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite.

The medical literature has reported the following adverse events in association with Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Nonan ) 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. Nonan (Sodium (Sodium Fluoride)) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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, Nonan (Sodium (Sodium Fluoride)) 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, Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Nonan (Sodium (Sodium Fluoride)) 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, Nonan ) 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 Nonan (Sodium (Sodium Fluoride)) nitrite is excreted in human milk. Because Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Nonan (Sodium (Sodium Fluoride)) nitrite. In studies conducted with Long-Evans rats, Nonan (Sodium (Sodium Fluoride)) 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 Nonan ) nitrite in conjunction with Nonan (Sodium (Sodium Fluoride)) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Nonan (Sodium (Sodium Fluoride)) 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.

Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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

Nonan (Sodium (Sodium Fluoride)) 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

Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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

Nonan (Sodium (Sodium Fluoride)) nitrite has the chemical name nitrous acid Nonan (Sodium (Sodium Fluoride)) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Nonan (Sodium (Sodium Fluoride)) Nitrite

Nonan (Sodium (Sodium Fluoride)) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Nonan (Sodium (Sodium Fluoride)) nitrite injection.

Nonan (Sodium (Sodium Fluoride)) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Nonan (Sodium (Sodium Fluoride)) nitrite in 10 mL solution (30 mg/mL). Nonan (Sodium (Sodium Fluoride)) 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 Nonan ) nitrite and Nonan (Sodium (Sodium Fluoride)) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Nonan (Sodium (Sodium Fluoride)) Nitrite

Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite. It has been suggested that Nonan (Sodium (Sodium Fluoride)) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Nonan (Sodium (Sodium Fluoride)) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Nonan (Sodium (Sodium Fluoride)) 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. Nonan (Sodium (Sodium Fluoride)) 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

Nonan (Sodium (Sodium Fluoride)) Nitrite

When 4 mg/kg Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Nonan (Sodium (Sodium Fluoride)) Nitrite

Nonan (Sodium (Sodium Fluoride)) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Nonan (Sodium (Sodium Fluoride)) nitrite in humans have not been well studied. It has been reported that approximately 40% of Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite and Nonan (Sodium (Sodium Fluoride)) 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 Nonan ) nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Nonan (Sodium (Sodium Fluoride)) 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. Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Nonan (Sodium (Sodium Fluoride)) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Nonan (Sodium (Sodium Fluoride)) 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. Nonan (Sodium (Sodium Fluoride)) 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. Nonan (Sodium (Sodium Fluoride)) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Nonan (Sodium (Sodium Fluoride)) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite and Nonan (Sodium (Sodium Fluoride)) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Nonan (Sodium (Sodium Fluoride)) nitrite or 1 g/kg Nonan (Sodium (Sodium Fluoride)) thiosulfate alone or in sequence immediately after subcutaneous injection of Nonan (Sodium (Sodium Fluoride)) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Nonan (Sodium (Sodium Fluoride)) nitrite and/or 0.5 g/kg Nonan (Sodium (Sodium Fluoride)) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Nonan (Sodium (Sodium Fluoride)) cyanide required to cause death, and when administered together, Nonan (Sodium (Sodium Fluoride)) nitrite and Nonan (Sodium (Sodium Fluoride)) thiosulfate resulted in a synergistic effect in raising the lethal dose of Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) nitrite and Nonan (Sodium (Sodium Fluoride)) thiosulfate in the treatment of cyanide poisoning.

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

14 CLINICAL STUDIES

The human data supporting the use of Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) thiosulfate report its use in conjunction with Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) 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 Nonan (Sodium (Sodium Fluoride)) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Nonan (Sodium (Sodium Fluoride)) nitrite injection 30 mg/mL (containing 300 mg of Nonan (Sodium (Sodium Fluoride)) 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: Nonan (Sodium (Sodium Fluoride)) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Nonan ) 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

Nonan (Sodium (Sodium Fluoride)) 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

Nonan (Sodium (Sodium Fluoride)) 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 (Sodium Iodide):

• 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
• Nonan (Sodium (Sodium Iodide)) reviews

1 INDICATIONS AND USAGE

Nonan ) nitrite is indicated for sequential use with Nonan (Sodium (Sodium Iodide)) 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

Nonan (Sodium (Sodium Iodide)) Nitrite Injection is indicated for sequential use with Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan ) 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, Nonan (Sodium (Sodium Iodide)) Nitrite Injection and Nonan (Sodium (Sodium Iodide)) Thiosulfate Injection should be administered without delay.

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

2 DOSAGE AND ADMINISTRATION

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Nonan (Sodium (Sodium Iodide)) nitrite and Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite, followed by Nonan (Sodium (Sodium Iodide)) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Nonan (Sodium (Sodium Iodide)) nitrite and Nonan (Sodium (Sodium Iodide)) thiosulfate.

Nonan (Sodium (Sodium Iodide)) nitrite injection and Nonan (Sodium (Sodium Iodide)) 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. Nonan (Sodium (Sodium Iodide)) nitrite should be administered first, followed immediately by Nonan (Sodium (Sodium Iodide)) 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.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Nonan (Sodium (Sodium Iodide)) nitrite and Nonan (Sodium (Sodium Iodide)) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Nonan (Sodium (Sodium Iodide)) 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 Nonan ) 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 Nonan (Sodium (Sodium Iodide)) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Nonan (Sodium (Sodium Iodide)) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Nonan (Sodium (Sodium Iodide)) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Nonan (Sodium (Sodium Iodide)) thiosulfate and Nonan (Sodium (Sodium Iodide)) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Nonan (Sodium (Sodium Iodide)) Nitrite Injection consists of:

• One vial of Nonan (Sodium (Sodium Iodide)) 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: Nonan ) 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 Nonan (Sodium (Sodium Iodide)) 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. Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan ) nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Nonan (Sodium (Sodium Iodide)) nitrite whenever possible. When Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite administered to an adult. Nonan (Sodium (Sodium Iodide)) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Nonan ) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan ) 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 Nonan (Sodium (Sodium Iodide)) nitrite.

5.7 Use with Other Drugs

Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite.

The medical literature has reported the following adverse events in association with Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Nonan ) 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. Nonan (Sodium (Sodium Iodide)) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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, Nonan (Sodium (Sodium Iodide)) 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, Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Nonan (Sodium (Sodium Iodide)) 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, Nonan ) 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 Nonan (Sodium (Sodium Iodide)) nitrite is excreted in human milk. Because Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Nonan (Sodium (Sodium Iodide)) nitrite. In studies conducted with Long-Evans rats, Nonan (Sodium (Sodium Iodide)) 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 Nonan ) nitrite in conjunction with Nonan (Sodium (Sodium Iodide)) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Nonan (Sodium (Sodium Iodide)) 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.

Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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

Nonan (Sodium (Sodium Iodide)) 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

Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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

Nonan (Sodium (Sodium Iodide)) nitrite has the chemical name nitrous acid Nonan (Sodium (Sodium Iodide)) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Nonan (Sodium (Sodium Iodide)) Nitrite

Nonan (Sodium (Sodium Iodide)) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Nonan (Sodium (Sodium Iodide)) nitrite injection.

Nonan (Sodium (Sodium Iodide)) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Nonan (Sodium (Sodium Iodide)) nitrite in 10 mL solution (30 mg/mL). Nonan (Sodium (Sodium Iodide)) 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 Nonan ) nitrite and Nonan (Sodium (Sodium Iodide)) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Nonan (Sodium (Sodium Iodide)) Nitrite

Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite. It has been suggested that Nonan (Sodium (Sodium Iodide)) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Nonan (Sodium (Sodium Iodide)) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Nonan (Sodium (Sodium Iodide)) 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. Nonan (Sodium (Sodium Iodide)) 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

Nonan (Sodium (Sodium Iodide)) Nitrite

When 4 mg/kg Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Nonan (Sodium (Sodium Iodide)) Nitrite

Nonan (Sodium (Sodium Iodide)) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Nonan (Sodium (Sodium Iodide)) nitrite in humans have not been well studied. It has been reported that approximately 40% of Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite and Nonan (Sodium (Sodium Iodide)) 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 Nonan ) nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Nonan (Sodium (Sodium Iodide)) 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. Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Nonan (Sodium (Sodium Iodide)) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Nonan (Sodium (Sodium Iodide)) 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. Nonan (Sodium (Sodium Iodide)) 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. Nonan (Sodium (Sodium Iodide)) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Nonan (Sodium (Sodium Iodide)) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite and Nonan (Sodium (Sodium Iodide)) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Nonan (Sodium (Sodium Iodide)) nitrite or 1 g/kg Nonan (Sodium (Sodium Iodide)) thiosulfate alone or in sequence immediately after subcutaneous injection of Nonan (Sodium (Sodium Iodide)) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Nonan (Sodium (Sodium Iodide)) nitrite and/or 0.5 g/kg Nonan (Sodium (Sodium Iodide)) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Nonan (Sodium (Sodium Iodide)) cyanide required to cause death, and when administered together, Nonan (Sodium (Sodium Iodide)) nitrite and Nonan (Sodium (Sodium Iodide)) thiosulfate resulted in a synergistic effect in raising the lethal dose of Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) nitrite and Nonan (Sodium (Sodium Iodide)) thiosulfate in the treatment of cyanide poisoning.

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

14 CLINICAL STUDIES

The human data supporting the use of Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) thiosulfate report its use in conjunction with Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) 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 Nonan (Sodium (Sodium Iodide)) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Nonan (Sodium (Sodium Iodide)) nitrite injection 30 mg/mL (containing 300 mg of Nonan (Sodium (Sodium Iodide)) 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: Nonan (Sodium (Sodium Iodide)) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Nonan ) 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

Nonan (Sodium (Sodium Iodide)) 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

Nonan (Sodium (Sodium Iodide)) 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 (Sodium Selenite Pentahydrate):

• 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
• Nonan (Sodium (Sodium Selenite Pentahydrate)) reviews

1 INDICATIONS AND USAGE

Nonan ) nitrite is indicated for sequential use with Nonan (Sodium (Sodium Selenite Pentahydrate)) 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

Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite Injection is indicated for sequential use with Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan ) 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, Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite Injection and Nonan (Sodium (Sodium Selenite Pentahydrate)) Thiosulfate Injection should be administered without delay.

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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate, simultaneously with Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate, with Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite and Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite, followed by Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite and Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate.

Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite injection and Nonan (Sodium (Sodium Selenite Pentahydrate)) 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. Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite should be administered first, followed immediately by Nonan (Sodium (Sodium Selenite Pentahydrate)) 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.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite and Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan ) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate and Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite Injection consists of:

• One vial of Nonan (Sodium (Sodium Selenite Pentahydrate)) 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: Nonan ) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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. Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan ) nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite whenever possible. When Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite administered to an adult. Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Nonan ) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan ) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite.

5.7 Use with Other Drugs

Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite.

The medical literature has reported the following adverse events in association with Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Nonan ) 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. Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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, Nonan (Sodium (Sodium Selenite Pentahydrate)) 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, Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Nonan (Sodium (Sodium Selenite Pentahydrate)) 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, Nonan ) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite is excreted in human milk. Because Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite. In studies conducted with Long-Evans rats, Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan ) nitrite in conjunction with Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Nonan (Sodium (Sodium Selenite Pentahydrate)) 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.

Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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

Nonan (Sodium (Sodium Selenite Pentahydrate)) 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

Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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

Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite has the chemical name nitrous acid Nonan (Sodium (Sodium Selenite Pentahydrate)) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite

Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite injection.

Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite in 10 mL solution (30 mg/mL). Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan ) nitrite and Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite

Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite. It has been suggested that Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Nonan (Sodium (Sodium Selenite Pentahydrate)) 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. Nonan (Sodium (Sodium Selenite Pentahydrate)) 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

Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite

When 4 mg/kg Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite

Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite in humans have not been well studied. It has been reported that approximately 40% of Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite and Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan ) nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Nonan (Sodium (Sodium Selenite Pentahydrate)) 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. Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Nonan (Sodium (Sodium Selenite Pentahydrate)) 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. Nonan (Sodium (Sodium Selenite Pentahydrate)) 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. Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite and Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite or 1 g/kg Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate alone or in sequence immediately after subcutaneous injection of Nonan (Sodium (Sodium Selenite Pentahydrate)) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite and/or 0.5 g/kg Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Nonan (Sodium (Sodium Selenite Pentahydrate)) cyanide required to cause death, and when administered together, Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite and Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate resulted in a synergistic effect in raising the lethal dose of Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite and Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite and Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite, with or without Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) thiosulfate report its use in conjunction with Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) 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 Nonan (Sodium (Sodium Selenite Pentahydrate)) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Nonan (Sodium (Sodium Selenite Pentahydrate)) nitrite injection 30 mg/mL (containing 300 mg of Nonan (Sodium (Sodium Selenite Pentahydrate)) 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: Nonan (Sodium (Sodium Selenite Pentahydrate)) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Nonan ) 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

Nonan (Sodium (Sodium Selenite Pentahydrate)) 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

Nonan (Sodium (Sodium Selenite Pentahydrate)) 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

Zinc (Zinc Gluconate Trihydrate):

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Nonan (Zinc (Zinc Gluconate Trihydrate)) reviews

INDICATIONS AND USAGE

Nonan (Zinc (Zinc Gluconate Trihydrate)) 1 mg/mL (Zinc Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain Nonan (Zinc (Zinc Gluconate Trihydrate)) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Nonan (Zinc (Zinc Gluconate Trihydrate)) 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.

Severe kidney disease may make it necessary to reduce or omit chromium and Nonan (Zinc (Zinc Gluconate Trihydrate)) doses because these elements are primarily eliminated in the urine.

WARNING: 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.

PRECAUTIONS

General

Do not use unless the solution is clear and the seal is intact.

Zinc 1 mg/mL should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.

Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of Nonan (Zinc (Zinc Gluconate Trihydrate)) from a bolus injection. Administration of Nonan (Zinc (Zinc Gluconate Trihydrate)) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Nonan (Zinc (Zinc Gluconate Trihydrate)) are suggested as a guideline for subsequent Nonan (Zinc (Zinc Gluconate Trihydrate)) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Nonan ) 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Nonan (Zinc (Zinc Gluconate Trihydrate)) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.

Pediatric Use

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

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response between 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.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg Nonan (Zinc (Zinc Gluconate Trihydrate)) was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2° F) on the fourth day were accompanied by a serum Nonan (Zinc (Zinc Gluconate Trihydrate)) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Nonan (Zinc (Zinc Gluconate Trihydrate)) overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).

Death resulted from an overdosage in which 1683 mg Nonan (Zinc (Zinc Gluconate Trihydrate)) was delivered intravenously over the course of 60 hours to a 72 year old patient.

Symptoms of Nonan (Zinc (Zinc Gluconate Trihydrate)) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Nonan (Zinc (Zinc Gluconate Trihydrate)) level of 4184 mcg/dl.

Calcium supplements may confer a protective effect against Nonan (Zinc (Zinc Gluconate Trihydrate)) toxicity.

DOSAGE AND ADMINISTRATION

Nonan (Zinc (Zinc Gluconate Trihydrate)) 1 mg/mL (Zinc Chloride Injection, USP) contains 1 mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in a volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day (2.5 to 4 mL/day). An additional 2 mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of Nonan (Zinc (Zinc Gluconate Trihydrate)) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Nonan (Zinc (Zinc Gluconate Trihydrate)).

For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.

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

HOW SUPPLIED

Nonan (Zinc (Zinc Gluconate Trihydrate)) 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).

Store at 20 to 25°C (68 to 77°F).

Revised: October, 2004

© Hospira 2004 EN-0488 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

10 mL Vial

Nonan (Zinc (Zinc Gluconate Trihydrate))

1 mg/mL

Nonan (Zinc (Zinc Gluconate Trihydrate)) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA