Waterbury's Compound

Iron:

• 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
• Waterbury's Compound (Iron) reviews

1 INDICATIONS AND USAGE

Waterbury's Compound (Iron) is indicated for the treatment of Waterbury's Compound (Iron) deficiency anemia in patients with chronic kidney disease (CKD).

Waterbury's Compound (Iron) is an Waterbury's Compound (Iron) replacement product indicated for the treatment of Waterbury's Compound (Iron) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Waterbury's Compound must only be administered intravenously either by slow injection or by infusion. The dosage of Waterbury's Compound (Iron) is expressed in mg of elemental Waterbury's Compound (Iron). Each mL contains 20 mg of elemental Waterbury's Compound (Iron).

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

Administer Waterbury's Compound (Iron) 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. Waterbury's Compound (Iron) should be administered early during the dialysis session. The usual total treatment course of Waterbury's Compound (Iron) is 1000 mg. Waterbury's Compound (Iron) treatment may be repeated if Waterbury's Compound (Iron) deficiency reoccurs.

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

Administer Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron), 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. Waterbury's Compound (Iron) treatment may be repeated if Waterbury's Compound (Iron) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) in a maximum of 250 mL of 0.9% NaCl. Waterbury's Compound (Iron) treatment may be repeated if Waterbury's Compound (Iron) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Waterbury's Compound (Iron) maintenance treatment

The dosing for Waterbury's Compound (Iron) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Waterbury's Compound (Iron) maintenance treatment: Administer Waterbury's Compound (Iron) 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. Waterbury's Compound (Iron) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Waterbury's Compound (Iron) maintenance treatment

The dosing for Waterbury's Compound (Iron) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Waterbury's Compound (Iron) maintenance treatment: Administer Waterbury's Compound (Iron) 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. Waterbury's Compound (Iron) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Waterbury's Compound (Iron) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Waterbury's Compound (Iron) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Waterbury's Compound (Iron) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Waterbury's Compound (Iron) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Waterbury's Compound (Iron) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Waterbury's Compound (Iron) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Waterbury's Compound (Iron)

• Known hypersensitivity to Waterbury's Compound (Iron) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Waterbury's Compound administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Waterbury's Compound (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: Waterbury's Compound (Iron) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Waterbury's Compound (Iron). (5.2)
• Waterbury's Compound (Iron) Overload: Regularly monitor hematologic responses during Waterbury's Compound (Iron) therapy. Do not administer Waterbury's Compound (Iron) to patients with Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron). 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 Waterbury's Compound (Iron) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Waterbury's Compound (Iron) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Waterbury's Compound (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Waterbury's Compound (Iron) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Waterbury's Compound may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Waterbury's Compound (Iron). Hypotension following administration of Waterbury's Compound (Iron) may be related to the rate of administration and/or total dose administered .

5.3 Waterbury's Compound (Iron) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Waterbury's Compound are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Waterbury's Compound (Iron) 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 Waterbury's Compound 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 Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) therapy and were reported to be intolerant (defined as precluding further use of that Waterbury's Compound (Iron) product). When these patients were treated with Waterbury's Compound (Iron) there were no occurrences of adverse reactions that precluded further use of Waterbury's Compound (Iron) .

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 Waterbury's Compound (Iron) maintenance treatment with Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving Waterbury's Compound (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving Waterbury's Compound (Iron) 2.0 mg/kg.

A total of 5 (11%) subjects in the Waterbury's Compound (Iron) 0.5 mg/kg group, 10 (21%) patients in the Waterbury's Compound (Iron) 1.0 mg/kg group, and 10 (21%) patients in the Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron). 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 Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) injection. Reactions have occurred following the first dose or subsequent doses of Waterbury's Compound (Iron). 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 Waterbury's Compound (Iron) have not been studied. However, Waterbury's Compound (Iron) may reduce the absorption of concomitantly administered oral Waterbury's Compound (Iron) 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, Waterbury's Compound sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Waterbury's Compound (Iron) (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 Waterbury's Compound (Iron) sucrose. Because animal reproductive studies are not always predictive of human response, Waterbury's Compound (Iron) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness of Waterbury's Compound for Waterbury's Compound (Iron) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Waterbury's Compound (Iron) for Waterbury's Compound (Iron) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Waterbury's Compound (Iron) 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)]

Waterbury's Compound (Iron) has not been studied in patients younger than 2 years of age.

In a country where Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Waterbury's Compound (Iron) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron), 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 Waterbury's Compound (Iron) in humans. Excessive dosages of Waterbury's Compound (Iron) may lead to accumulation of Waterbury's Compound (Iron) in storage sites potentially leading to hemosiderosis. Do not administer Waterbury's Compound (Iron) to patients with Waterbury's Compound (Iron) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Waterbury's Compound (Iron) 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

Waterbury's Compound (Iron) (iron sucrose injection, USP), an Waterbury's Compound (Iron) replacement product, is a brown, sterile, aqueous, complex of polynuclear Waterbury's Compound (Iron) (III)-hydroxide in sucrose for intravenous use. Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) polymerization and m is the number of sucrose molecules associated with the Waterbury's Compound (Iron) (III)-hydroxide.

Each mL contains 20 mg elemental Waterbury's Compound (Iron) as Waterbury's Compound (Iron) sucrose in water for injection. Waterbury's Compound (Iron) is available in 10 mL single-use vials (200 mg elemental Waterbury's Compound (Iron) per 10 mL), 5 mL single-use vials (100 mg elemental Waterbury's Compound (Iron) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Waterbury's Compound (Iron) 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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Waterbury's Compound, its Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Waterbury's Compound (Iron) containing 100 mg of Waterbury's Compound (Iron) labeled with ⁵²Fe/⁵⁹Fe in patients with Waterbury's Compound (Iron) deficiency showed that a significant amount of the administered Waterbury's Compound (Iron) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Waterbury's Compound (Iron) trapping compartment.

Following intravenous administration of Waterbury's Compound (Iron), Waterbury's Compound (Iron) sucrose is dissociated into Waterbury's Compound (Iron) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Waterbury's Compound (Iron) containing 1,510 mg of sucrose and 100 mg of Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) sucrose containing 500 to 700 mg of Waterbury's Compound (Iron) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Waterbury's Compound (Iron) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Waterbury's Compound (Iron) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Waterbury's Compound (Iron), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Waterbury's Compound (Iron) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Waterbury's Compound (Iron), the half-life of total serum Waterbury's Compound (Iron) 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.

Waterbury's Compound (Iron) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) sucrose.

Waterbury's Compound (Iron) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Waterbury's Compound (Iron) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Waterbury's Compound (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental Waterbury's Compound (Iron) (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 Waterbury's Compound.

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 Waterbury's Compound (Iron) treatment and 24 in the historical control group) with Waterbury's Compound (Iron) deficiency anemia. Eligibility criteria for Waterbury's Compound (Iron) 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.

Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron), who were off intravenous Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) in 23 patients with Waterbury's Compound (Iron) deficiency and HDD-CKD who had been discontinued from Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron). Exclusion criteria were similar to those in studies A and B. Waterbury's Compound (Iron) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) versus Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) (325 mg ferrous sulfate three times daily for 56 days); or Waterbury's Compound (Iron) (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 Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) group.

A statistically significantly greater proportion of Waterbury's Compound (Iron) subjects (35/79; 44.3%) compared to oral Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) to patients with PDD-CKD receiving an erythropoietin alone without Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) or Waterbury's Compound (Iron) (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 Waterbury's Compound (Iron) / 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 Waterbury's Compound (Iron) / 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 Waterbury's Compound (Iron) / 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: Waterbury's Compound 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 Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) (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 Waterbury's Compound (Iron) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) 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

Waterbury's Compound is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Waterbury's Compound (Iron), each 5 mL vial contains 100 mg elemental Waterbury's Compound (Iron), and each 2.5 mL vial contains 50 mg elemental Waterbury's Compound (Iron) (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: Waterbury's Compound (Iron), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Waterbury's Compound (Iron) per mL, or undiluted (20 mg elemental Waterbury's Compound (Iron) 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: Waterbury's Compound (Iron), 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 Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) 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 Waterbury's Compound (Iron) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Waterbury's Compound (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Manganese:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Rl-0104
• Waterbury's Compound (Manganese) reviews

INDICATIONS AND USAGE

Waterbury's Compound (Manganese) 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 Waterbury's Compound (Manganese) serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Waterbury's Compound (Manganese) 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 Waterbury's Compound (Manganese) 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.

Waterbury's Compound 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 Waterbury's Compound (Manganese) 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 Waterbury's Compound 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 Waterbury's Compound (Manganese) 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 Waterbury's Compound (Manganese) chloride. It is also not known whether Waterbury's Compound (Manganese) chloride can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Waterbury's Compound (Manganese) 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

Waterbury's Compound (Manganese) toxicity in TPN patients has not been reported.

DOSAGE AND ADMINISTRATION

Waterbury's Compound (Manganese) 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 Waterbury's Compound (Manganese) 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 Waterbury's Compound (Manganese) 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

Waterbury's Compound (Manganese) 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

Sodium Benzoate:

• 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
• Waterbury's Compound (Sodium Benzoate) reviews

1 INDICATIONS AND USAGE

Waterbury's Compound nitrite is indicated for sequential use with Waterbury's Compound (Sodium Benzoate) 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

Waterbury's Compound (Sodium Benzoate) Nitrite Injection is indicated for sequential use with Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound 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, Waterbury's Compound (Sodium Benzoate) Nitrite Injection and Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) thiosulfate, simultaneously with Waterbury's Compound (Sodium Benzoate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Waterbury's Compound (Sodium Benzoate) thiosulfate, with Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) nitrite and Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) nitrite, followed by Waterbury's Compound (Sodium Benzoate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Waterbury's Compound (Sodium Benzoate) nitrite and Waterbury's Compound (Sodium Benzoate) thiosulfate.

Waterbury's Compound (Sodium Benzoate) nitrite injection and Waterbury's Compound (Sodium Benzoate) 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. Waterbury's Compound (Sodium Benzoate) nitrite should be administered first, followed immediately by Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) nitrite and Waterbury's Compound (Sodium Benzoate) thiosulfate.

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

3 DOSAGE FORMS AND STRENGTHS

Waterbury's Compound (Sodium Benzoate) Nitrite Injection consists of:

• One vial of Waterbury's Compound (Sodium Benzoate) 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: Waterbury's Compound 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 Waterbury's Compound (Sodium Benzoate) 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. Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound nitrite.

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

5.3 Anemia

Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Waterbury's Compound 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 Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound 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 Waterbury's Compound (Sodium Benzoate) nitrite.

5.7 Use with Other Drugs

Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) nitrite.

The medical literature has reported the following adverse events in association with Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Waterbury's Compound 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. Waterbury's Compound (Sodium Benzoate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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, Waterbury's Compound (Sodium Benzoate) 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, Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

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

Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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

Waterbury's Compound (Sodium Benzoate) 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

Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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

Waterbury's Compound (Sodium Benzoate) nitrite has the chemical name nitrous acid Waterbury's Compound (Sodium Benzoate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Waterbury's Compound (Sodium Benzoate) Nitrite

Waterbury's Compound (Sodium Benzoate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Waterbury's Compound (Sodium Benzoate) nitrite injection.

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

Waterbury's Compound (Sodium Benzoate) Nitrite

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

Waterbury's Compound (Sodium Benzoate) 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. Waterbury's Compound (Sodium Benzoate) 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

Waterbury's Compound (Sodium Benzoate) Nitrite

When 4 mg/kg Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Waterbury's Compound (Sodium Benzoate) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

The human data supporting the use of Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) thiosulfate report its use in conjunction with Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) 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 Waterbury's Compound (Sodium Benzoate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Waterbury's Compound (Sodium Benzoate) nitrite injection 30 mg/mL (containing 300 mg of Waterbury's Compound (Sodium Benzoate) 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: Waterbury's Compound (Sodium Benzoate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Waterbury's Compound 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

Waterbury's Compound (Sodium Benzoate) 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

Waterbury's Compound (Sodium Benzoate) 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 Salicylate:

• 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
• Waterbury's Compound (Sodium Salicylate) reviews

1 INDICATIONS AND USAGE

Waterbury's Compound nitrite is indicated for sequential use with Waterbury's Compound (Sodium Salicylate) 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

Waterbury's Compound (Sodium Salicylate) Nitrite Injection is indicated for sequential use with Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound 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, Waterbury's Compound (Sodium Salicylate) Nitrite Injection and Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) thiosulfate, simultaneously with Waterbury's Compound (Sodium Salicylate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Waterbury's Compound (Sodium Salicylate) thiosulfate, with Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) nitrite and Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) nitrite, followed by Waterbury's Compound (Sodium Salicylate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Waterbury's Compound (Sodium Salicylate) nitrite and Waterbury's Compound (Sodium Salicylate) thiosulfate.

Waterbury's Compound (Sodium Salicylate) nitrite injection and Waterbury's Compound (Sodium Salicylate) 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. Waterbury's Compound (Sodium Salicylate) nitrite should be administered first, followed immediately by Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) nitrite and Waterbury's Compound (Sodium Salicylate) thiosulfate.

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

3 DOSAGE FORMS AND STRENGTHS

Waterbury's Compound (Sodium Salicylate) Nitrite Injection consists of:

• One vial of Waterbury's Compound (Sodium Salicylate) 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: Waterbury's Compound 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 Waterbury's Compound (Sodium Salicylate) 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. Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound nitrite.

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

5.3 Anemia

Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Waterbury's Compound 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 Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound 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 Waterbury's Compound (Sodium Salicylate) nitrite.

5.7 Use with Other Drugs

Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) nitrite.

The medical literature has reported the following adverse events in association with Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Waterbury's Compound 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. Waterbury's Compound (Sodium Salicylate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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, Waterbury's Compound (Sodium Salicylate) 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, Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

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

Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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

Waterbury's Compound (Sodium Salicylate) 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

Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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

Waterbury's Compound (Sodium Salicylate) nitrite has the chemical name nitrous acid Waterbury's Compound (Sodium Salicylate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Waterbury's Compound (Sodium Salicylate) Nitrite

Waterbury's Compound (Sodium Salicylate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Waterbury's Compound (Sodium Salicylate) nitrite injection.

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

Waterbury's Compound (Sodium Salicylate) Nitrite

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

Waterbury's Compound (Sodium Salicylate) 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. Waterbury's Compound (Sodium Salicylate) 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

Waterbury's Compound (Sodium Salicylate) Nitrite

When 4 mg/kg Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Waterbury's Compound (Sodium Salicylate) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

The human data supporting the use of Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) thiosulfate report its use in conjunction with Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) 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 Waterbury's Compound (Sodium Salicylate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Waterbury's Compound (Sodium Salicylate) nitrite injection 30 mg/mL (containing 300 mg of Waterbury's Compound (Sodium Salicylate) 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: Waterbury's Compound (Sodium Salicylate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Waterbury's Compound 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

Waterbury's Compound (Sodium Salicylate) 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

Waterbury's Compound (Sodium Salicylate) 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