R26

Calcium Iodide:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• R26 (Calcium Iodide) reviews

1 INDICATIONS AND USAGE

R26 (Calcium Iodide) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of R26 (Calcium Iodide) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg R26 (Calcium Iodide) acetate capsule.

- Capsule: 667 mg R26 (Calcium Iodide) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting R26 acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of R26 (Calcium Iodide) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with R26 (Calcium Iodide), including R26 (Calcium Iodide) acetate. Avoid the use of R26 (Calcium Iodide) supplements, including R26 (Calcium Iodide) based nonprescription antacids, concurrently with R26 (Calcium Iodide) acetate.

An overdose of R26 (Calcium Iodide) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum R26 (Calcium Iodide) levels twice weekly. Should hypercalcemia develop, reduce the R26 (Calcium Iodide) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing R26 (Calcium Iodide) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the R26 (Calcium Iodide) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of R26 (Calcium Iodide) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of R26 (Calcium Iodide) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during R26 (Calcium Iodide) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, R26 (Calcium Iodide) acetate has been generally well tolerated.

R26 (Calcium Iodide) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of R26 (Calcium Iodide) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate R26 (Calcium Iodide) concentration could reduce the incidence and severity of R26 (Calcium Iodide) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

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

The following additional adverse reactions have been identified during post-approval of R26 (Calcium Iodide) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of R26 acetate is characterized by the potential of R26 (Calcium Iodide) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). R26 (Calcium Iodide) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between R26 (Calcium Iodide) acetate and most concomitant drugs. When administering an oral medication with R26 (Calcium Iodide) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after R26 (Calcium Iodide) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of R26 (Calcium Iodide) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after R26 (Calcium Iodide) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 R26 (Calcium Iodide) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

R26 acetate capsules contains R26 (Calcium Iodide) acetate. Animal reproduction studies have not been conducted with R26 (Calcium Iodide) acetate, and there are no adequate and well controlled studies of R26 (Calcium Iodide) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with R26 (Calcium Iodide) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum R26 (Calcium Iodide) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. R26 (Calcium Iodide) acetate treatment, as recommended, is not expected to harm a fetus if maternal R26 (Calcium Iodide) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of R26 (Calcium Iodide) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

R26 Acetate Capsules contains R26 (Calcium Iodide) acetate and is excreted in human milk. Human milk feeding by a mother receiving R26 (Calcium Iodide) acetate is not expected to harm an infant, provided maternal serum R26 (Calcium Iodide) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of R26 (Calcium Iodide) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses 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.

10 OVERDOSAGE

Administration of R26 (Calcium Iodide) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

R26 (Calcium Iodide) acetate acts as a phosphate binder. Its chemical name is R26 (Calcium Iodide) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of R26 (Calcium Iodide) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) R26 (Calcium Iodide), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

R26 (Calcium Iodide) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum R26 resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

R26 (Calcium Iodide) acetate, when taken with meals, combines with dietary phosphate to form an insoluble R26 (Calcium Iodide) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered R26 (Calcium Iodide) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with R26 (Calcium Iodide) acetate.

14 CLINICAL STUDIES

Effectiveness of R26 (Calcium Iodide) acetate in decreasing serum phosphorus has been demonstrated in two studies of the R26 (Calcium Iodide) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received R26 (Calcium Iodide) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of R26 (Calcium Iodide) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum R26 (Calcium Iodide) levels are also presented.

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum R26 (Calcium Iodide) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive R26 (Calcium Iodide) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of R26 (Calcium Iodide) acetate is shown in the Table 3.

Overall, 2 weeks of treatment with R26 (Calcium Iodide) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum R26 (Calcium Iodide) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

R26 (Calcium Iodide) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take R26 (Calcium Iodide) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of R26 (Calcium Iodide) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after R26 (Calcium Iodide) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Iron (Ferrous Iodide):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• R26 (Iron (Ferrous Iodide)) reviews

1 INDICATIONS AND USAGE

R26 (Iron (Ferrous Iodide)) is indicated for the treatment of R26 (Iron (Ferrous Iodide)) deficiency anemia in patients with chronic kidney disease (CKD).

R26 (Iron (Ferrous Iodide)) is an R26 (Iron (Ferrous Iodide)) replacement product indicated for the treatment of R26 (Iron (Ferrous Iodide)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

R26 ) must only be administered intravenously either by slow injection or by infusion. The dosage of R26 (Iron (Ferrous Iodide)) is expressed in mg of elemental R26 (Iron (Ferrous Iodide)). Each mL contains 20 mg of elemental R26 (Iron (Ferrous Iodide)).

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

Administer R26 (Iron (Ferrous Iodide)) 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. R26 (Iron (Ferrous Iodide)) should be administered early during the dialysis session. The usual total treatment course of R26 (Iron (Ferrous Iodide)) is 1000 mg. R26 (Iron (Ferrous Iodide)) treatment may be repeated if R26 (Iron (Ferrous Iodide)) deficiency reoccurs.

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

Administer R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)), 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. R26 (Iron (Ferrous Iodide)) treatment may be repeated if R26 (Iron (Ferrous Iodide)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) in a maximum of 250 mL of 0.9% NaCl. R26 (Iron (Ferrous Iodide)) treatment may be repeated if R26 (Iron (Ferrous Iodide)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for R26 (Iron (Ferrous Iodide)) maintenance treatment

The dosing for R26 (Iron (Ferrous Iodide)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For R26 (Iron (Ferrous Iodide)) maintenance treatment: Administer R26 (Iron (Ferrous Iodide)) 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. R26 (Iron (Ferrous Iodide)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for R26 (Iron (Ferrous Iodide)) maintenance treatment

The dosing for R26 (Iron (Ferrous Iodide)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For R26 (Iron (Ferrous Iodide)) maintenance treatment: Administer R26 (Iron (Ferrous Iodide)) 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. R26 (Iron (Ferrous Iodide)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental R26 (Iron (Ferrous Iodide)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental R26 (Iron (Ferrous Iodide)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental R26 (Iron (Ferrous Iodide)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental R26 (Iron (Ferrous Iodide)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental R26 (Iron (Ferrous Iodide)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental R26 (Iron (Ferrous Iodide)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to R26 (Iron (Ferrous Iodide))

• Known hypersensitivity to R26 (Iron (Ferrous Iodide)) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after R26 ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer R26 (Iron (Ferrous Iodide)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: R26 (Iron (Ferrous Iodide)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of R26 (Iron (Ferrous Iodide)). (5.2)
• R26 (Iron (Ferrous Iodide)) Overload: Regularly monitor hematologic responses during R26 (Iron (Ferrous Iodide)) therapy. Do not administer R26 (Iron (Ferrous Iodide)) to patients with R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)). 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 R26 (Iron (Ferrous Iodide)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after R26 (Iron (Ferrous Iodide)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer R26 (Iron (Ferrous Iodide)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous R26 (Iron (Ferrous Iodide)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

R26 ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of R26 (Iron (Ferrous Iodide)). Hypotension following administration of R26 (Iron (Ferrous Iodide)) may be related to the rate of administration and/or total dose administered .

5.3 R26 (Iron (Ferrous Iodide)) Overload

Excessive therapy with parenteral R26 (Iron (Ferrous Iodide)) can lead to excess storage of R26 (Iron (Ferrous Iodide)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving R26 (Iron (Ferrous Iodide)) require periodic monitoring of hematologic and R26 (Iron (Ferrous Iodide)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer R26 (Iron (Ferrous Iodide)) to patients with evidence of R26 (Iron (Ferrous Iodide)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of R26 (Iron (Ferrous Iodide)) sucrose; do not perform serum R26 (Iron (Ferrous Iodide)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with R26 ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of R26 (Iron (Ferrous Iodide)) 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 R26 ) 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 R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) therapy and were reported to be intolerant (defined as precluding further use of that R26 (Iron (Ferrous Iodide)) product). When these patients were treated with R26 (Iron (Ferrous Iodide)) there were no occurrences of adverse reactions that precluded further use of R26 (Iron (Ferrous Iodide)) .

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 R26 (Iron (Ferrous Iodide)) maintenance treatment with R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) 0.5 mg/kg, 53% (25/47) of the patients receiving R26 (Iron (Ferrous Iodide)) 1.0 mg/kg, and 55% (26/47) of the patients receiving R26 (Iron (Ferrous Iodide)) 2.0 mg/kg.

A total of 5 (11%) subjects in the R26 (Iron (Ferrous Iodide)) 0.5 mg/kg group, 10 (21%) patients in the R26 (Iron (Ferrous Iodide)) 1.0 mg/kg group, and 10 (21%) patients in the R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)). 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 R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) injection. Reactions have occurred following the first dose or subsequent doses of R26 (Iron (Ferrous Iodide)). 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 R26 (Iron (Ferrous Iodide)) have not been studied. However, R26 (Iron (Ferrous Iodide)) may reduce the absorption of concomitantly administered oral R26 (Iron (Ferrous Iodide)) 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, R26 ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental R26 (Iron (Ferrous Iodide)) (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 R26 (Iron (Ferrous Iodide)) sucrose. Because animal reproductive studies are not always predictive of human response, R26 (Iron (Ferrous Iodide)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether R26 (Iron (Ferrous Iodide)) sucrose is excreted in human milk. R26 (Iron (Ferrous Iodide)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when R26 (Iron (Ferrous Iodide)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of R26 ) for R26 (Iron (Ferrous Iodide)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of R26 (Iron (Ferrous Iodide)) for R26 (Iron (Ferrous Iodide)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. R26 (Iron (Ferrous Iodide)) 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)]

R26 (Iron (Ferrous Iodide)) has not been studied in patients younger than 2 years of age.

In a country where R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to R26 (Iron (Ferrous Iodide)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)), 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 R26 (Iron (Ferrous Iodide)) in humans. Excessive dosages of R26 (Iron (Ferrous Iodide)) may lead to accumulation of R26 (Iron (Ferrous Iodide)) in storage sites potentially leading to hemosiderosis. Do not administer R26 (Iron (Ferrous Iodide)) to patients with R26 (Iron (Ferrous Iodide)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous R26 (Iron (Ferrous Iodide)) 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

R26 (Iron (Ferrous Iodide)) (iron sucrose injection, USP), an R26 (Iron (Ferrous Iodide)) replacement product, is a brown, sterile, aqueous, complex of polynuclear R26 (Iron (Ferrous Iodide)) (III)-hydroxide in sucrose for intravenous use. R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) polymerization and m is the number of sucrose molecules associated with the R26 (Iron (Ferrous Iodide)) (III)-hydroxide.

Each mL contains 20 mg elemental R26 (Iron (Ferrous Iodide)) as R26 (Iron (Ferrous Iodide)) sucrose in water for injection. R26 (Iron (Ferrous Iodide)) is available in 10 mL single-use vials (200 mg elemental R26 (Iron (Ferrous Iodide)) per 10 mL), 5 mL single-use vials (100 mg elemental R26 (Iron (Ferrous Iodide)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental R26 (Iron (Ferrous Iodide)) 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

R26 ) is an aqueous complex of poly-nuclear R26 (Iron (Ferrous Iodide)) (III)-hydroxide in sucrose. Following intravenous administration, R26 (Iron (Ferrous Iodide)) is dissociated into R26 (Iron (Ferrous Iodide)) and sucrose and the R26 (Iron (Ferrous Iodide)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The R26 (Iron (Ferrous Iodide)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, R26 (Iron (Ferrous Iodide)) is dissociated into R26 (Iron (Ferrous Iodide)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with R26 (Iron (Ferrous Iodide)) sucrose containing 100 mg of R26 (Iron (Ferrous Iodide)), three times weekly for three weeks, significant increases in serum R26 (Iron (Ferrous Iodide)) and serum ferritin and significant decreases in total R26 (Iron (Ferrous Iodide)) binding capacity occurred four weeks from the initiation of R26 (Iron (Ferrous Iodide)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of R26 ), its R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating R26 (Iron (Ferrous Iodide)) containing 100 mg of R26 (Iron (Ferrous Iodide)) labeled with ⁵²Fe/⁵⁹Fe in patients with R26 (Iron (Ferrous Iodide)) deficiency showed that a significant amount of the administered R26 (Iron (Ferrous Iodide)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible R26 (Iron (Ferrous Iodide)) trapping compartment.

Following intravenous administration of R26 (Iron (Ferrous Iodide)), R26 (Iron (Ferrous Iodide)) sucrose is dissociated into R26 (Iron (Ferrous Iodide)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of R26 (Iron (Ferrous Iodide)) containing 1,510 mg of sucrose and 100 mg of R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) sucrose containing 500 to 700 mg of R26 (Iron (Ferrous Iodide)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the R26 (Iron (Ferrous Iodide)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of R26 (Iron (Ferrous Iodide)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of R26 (Iron (Ferrous Iodide)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of R26 (Iron (Ferrous Iodide)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose R26 (Iron (Ferrous Iodide)), the half-life of total serum R26 (Iron (Ferrous Iodide)) 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.

R26 (Iron (Ferrous Iodide)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) sucrose.

R26 (Iron (Ferrous Iodide)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. R26 (Iron (Ferrous Iodide)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

R26 (Iron (Ferrous Iodide)) sucrose at intravenous doses up to 15 mg/kg/day of elemental R26 (Iron (Ferrous Iodide)) (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 R26 ).

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 R26 (Iron (Ferrous Iodide)) treatment and 24 in the historical control group) with R26 (Iron (Ferrous Iodide)) deficiency anemia. Eligibility criteria for R26 (Iron (Ferrous Iodide)) 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.

R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)), who were off intravenous R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) in 23 patients with R26 (Iron (Ferrous Iodide)) deficiency and HDD-CKD who had been discontinued from R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)). Exclusion criteria were similar to those in studies A and B. R26 (Iron (Ferrous Iodide)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) versus R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) (325 mg ferrous sulfate three times daily for 56 days); or R26 (Iron (Ferrous Iodide)) (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 R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) group.

A statistically significantly greater proportion of R26 (Iron (Ferrous Iodide)) subjects (35/79; 44.3%) compared to oral R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) to patients with PDD-CKD receiving an erythropoietin alone without R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) or R26 (Iron (Ferrous Iodide)) (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 R26 (Iron (Ferrous Iodide)) / 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 R26 (Iron (Ferrous Iodide)) / 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 R26 (Iron (Ferrous Iodide)) / 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: R26 ) 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 R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) (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 R26 (Iron (Ferrous Iodide)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) 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

R26 ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental R26 (Iron (Ferrous Iodide)), each 5 mL vial contains 100 mg elemental R26 (Iron (Ferrous Iodide)), and each 2.5 mL vial contains 50 mg elemental R26 (Iron (Ferrous Iodide)) (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: R26 (Iron (Ferrous Iodide)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental R26 (Iron (Ferrous Iodide)) per mL, or undiluted (20 mg elemental R26 (Iron (Ferrous Iodide)) 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: R26 (Iron (Ferrous Iodide)), 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 R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) 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 R26 (Iron (Ferrous Iodide)) administration:

• Question patients regarding any prior history of reactions to parenteral R26 (Iron (Ferrous Iodide)) products
• Advise patients of the risks associated with R26 (Iron (Ferrous Iodide))
• Advise patients to report any symptoms of hypersensitivity that may develop during and following R26 (Iron (Ferrous Iodide)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

R26 (Iron (Ferrous Iodide)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Nitric Acid:

• 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
• R26 (Nitric Acid) reviews

1 INDICATIONS AND USAGE

R26 (Nitric Acid) ^® is indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents.

R26 (Nitric Acid) is a vasodilator indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents.

2 DOSAGE AND ADMINISTRATION

The recommended dose is 20 ppm, maintained for up to 14 days or until the underlying oxygen desaturation has resolved.

Doses greater than 20 ppm are not recommended (2.1, 5.2)

Administration:

• Use only with an R26 (Nitric Acid) DS_IR ^® operated by trained personnel (2.2)
• Avoid abrupt discontinuation (2.2, 5.1).

2.1 Dosage

Term and near-term neonates with hypoxic respiratory failure

The recommended dose of R26 (Nitric Acid) is 20 ppm. Maintain treatment up to 14 days or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from R26 (Nitric Acid) therapy.

Doses greater than 20 ppm are not recommended .

2.2 Administration

Training in Administration

The user of R26 (Nitric Acid) and R26 (Nitric Acid) Oxide Delivery Systems must satisfactorily complete a comprehensive periodic training program for health care professionals provided by the delivery system and drug manufacturers. Health professional staff that administers R26 (Nitric Acid) oxide therapy have access to supplier-provided 24 hour/365 days per year technical support on the delivery and administration of R26 (Nitric Acid) at 1-877-566-9466.

R26 (Nitric Acid) Oxide Delivery Systems

R26 (Nitric Acid) must be administered using a calibrated R26 (Nitric Acid) DS_IR ^® R26 (Nitric Acid) Oxide Delivery System. Only validated ventilator systems should be used in conjunction with R26 (Nitric Acid). Consult the R26 (Nitric Acid) Oxide Delivery System label or call 1-877-566-9466/visit R26 (Nitric Acid).com for a current list of validated systems.

Keep available a backup battery power supply and an independent reserve R26 (Nitric Acid) oxide delivery system to address power and system failures.

Monitoring

Measure methemoglobin within 4-8 hours after initiation of treatment with R26 (Nitric Acid) and periodically throughout treatment .

Monitor for PaO₂ and inspired NO₂ during R26 (Nitric Acid) administration .

Weaning and Discontinuation

Avoid abrupt discontinuation of R26 (Nitric Acid) . To wean R26 (Nitric Acid), downtitrate in several steps, pausing several hours at each step to monitor for hypoxemia.

3 DOSAGE FORMS AND STRENGTHS

R26 (Nitric Acid) (nitric oxide) gas is available in a 800 ppm concentration.

R26 (Nitric Acid) (nitric oxide) is a gas available in a 800 ppm concentration (3).

4 CONTRAINDICATIONS

R26 (Nitric Acid) is contraindicated in neonates dependent on right-to-left shunting of blood.

Neonates dependent on right-to-left shunting of blood (4).

5 WARNINGS AND PRECAUTIONS

Rebound: Abrupt discontinuation of R26 may lead to worsening oxygenation and increasing pulmonary artery pressure (5.1).

Methemoglobinemia: Methemoglobin increases with the dose of R26 (Nitric Acid) oxide; following discontinuation or reduction of R26 (Nitric Acid) oxide, methemoglobin levels return to baseline over a period of hours (5.2).

Elevated NO₂ Levels: Monitor NO₂ levels (5.3).

Heart Failure: In patients with pre-existing left ventricular dysfunction, R26 (Nitric Acid) may increase pulmonary capillary wedge pressure leading to pulmonary edema (5.4).

5.1 Rebound Pulmonary Hypertension Syndrome following Abrupt Discontinuation

Wean from R26 (Nitric Acid) . Abrupt discontinuation of R26 (Nitric Acid) may lead to worsening oxygenation and increasing pulmonary artery pressure, i.e., Rebound Pulmonary Hypertension Syndrome. Signs and symptoms of Rebound Pulmonary Hypertension Syndrome include hypoxemia, systemic hypotension, bradycardia, and decreased cardiac output. If Rebound Pulmonary Hypertension occurs, reinstate R26 (Nitric Acid) therapy immediately.

5.2 Hypoxemia from Methemoglobinemia

R26 oxide combines with hemoglobin to form methemoglobin, which does not transport oxygen. Methemoglobin levels increase with the dose of R26 (Nitric Acid); it can take 8 hours or more before steady-state methemoglobin levels are attained. Monitor methemoglobin and adjust the dose of R26 (Nitric Acid) to optimize oxygenation.

If methemoglobin levels do not resolve with decrease in dose or discontinuation of R26 (Nitric Acid), additional therapy may be warranted to treat methemoglobinemia.

5.3 Airway Injury from Nitrogen Dioxide

Nitrogen dioxide (NO₂) forms in gas mixtures containing NO and O₂. Nitrogen dioxide may cause airway inflammation and damage to lung tissues.

If there is an unexpected change in NO₂ concentration, or if the NO₂ concentration reaches 3 ppm when measured in the breathing circuit, then the delivery system should be assessed in accordance with the R26 (Nitric Acid) Oxide Delivery System O&M Manual troubleshooting section, and the NO₂ analyzer should be recalibrated. The dose of R26 (Nitric Acid) and/or FiO₂ should be adjusted as appropriate.

5.4 Worsening Heart Failure

Patients with left ventricular dysfunction treated with R26 (Nitric Acid) may experience pulmonary edema, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systemic hypotension, bradycardia and cardiac arrest. Discontinue R26 (Nitric Acid) while providing symptomatic care.

6 ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere in the label;

Hypoxemia

Worsening Heart Failure

The most common adverse reaction is hypotension. (6).

To report SUSPECTED ADVERSE REACTIONS, contact INO Therapeutics at 1-877-566-9466 and http://www.inomax.com/ or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from the clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Controlled studies have included 325 patients on R26 (Nitric Acid) doses of 5 to 80 ppm and 251 patients on placebo. Total mortality in the pooled trials was 11% on placebo and 9% on R26 (Nitric Acid), a result adequate to exclude R26 (Nitric Acid) mortality being more than 40% worse than placebo.

In both the NINOS and CINRGI studies, the duration of hospitalization was similar in R26 (Nitric Acid) and placebo-treated groups.

From all controlled studies, at least 6 months of follow-up is available for 278 patients who received R26 (Nitric Acid) and 212 patients who received placebo. Among these patients, there was no evidence of an adverse effect of treatment on the need for rehospitalization, special medical services, pulmonary disease, or neurological sequelae.

In the NINOS study, treatment groups were similar with respect to the incidence and severity of intracranial hemorrhage, Grade IV hemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring anticonvulsant therapy, pulmonary hemorrhage, or gastrointestinal hemorrhage.

In CINRGI, the only adverse reaction (>2% higher incidence on R26 (Nitric Acid) than on placebo) was hypotension (14% vs. 11%).

6.2 Post-Marketing Experience

Post marketing reports of accidental exposure to R26 (Nitric Acid) oxide for inhalation in hospital staff has been associated with chest discomfort, dizziness, dry throat, dyspnea, and headache.

7 DRUG INTERACTIONS

R26 oxide donor compounds may increase the risk of developing methemoglobinemia (7).

7.1 Nitric Oxide Donor Agents

R26 (Nitric Acid) oxide donor agents such as prilocaine, sodium nitroprusside and nitroglycerine may increase the risk of developing methemoglobinemia.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with R26. It is not known if R26 (Nitric Acid) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. R26 (Nitric Acid) is not indicated for use in adults.

8.3 Nursing Mothers

R26 (Nitric Acid) oxide is not indicated for use in the adult population, including nursing mothers. It is not known whether R26 (Nitric Acid) oxide is excreted in human milk.

8.4 Pediatric Use

The safety and efficacy of R26 oxide for inhalation has been demonstrated in term and near-term neonates with hypoxic respiratory failure associated with evidence of pulmonary hypertension. Additional studies conducted in premature neonates for the prevention of bronchopulmonary dysplasia have not demonstrated substantial evidence of efficacy . No information about its effectiveness in other age populations is available.

8.5 Geriatric Use

R26 (Nitric Acid) oxide is not indicated for use in the adult population.

10 OVERDOSAGE

Overdosage with R26 (Nitric Acid) is manifest by elevations in methemoglobin and pulmonary toxicities associated with inspired NO₂. Elevated NO₂ may cause acute lung injury. Elevations in methemoglobin reduce the oxygen delivery capacity of the circulation. In clinical studies, NO₂ levels >3 ppm or methemoglobin levels >7% were treated by reducing the dose of, or discontinuing, R26 (Nitric Acid).

Methemoglobinemia that does not resolve after reduction or discontinuation of therapy can be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the clinical situation.

11 DESCRIPTION

R26 (Nitric Acid) (nitric oxide gas) is a drug administered by inhalation. R26 (Nitric Acid) oxide, the active substance in R26 (Nitric Acid), is a pulmonary vasodilator. R26 (Nitric Acid) is a gaseous blend of R26 (Nitric Acid) oxide and nitrogen (0.08% and 99.92%, respectively for 800 ppm). R26 (Nitric Acid) is supplied in aluminum cylinders as a compressed gas under high pressure (2000 pounds per square inch gauge [psig]).

The structural formula of R26 (Nitric Acid) oxide (NO) is shown below:

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

R26 oxide relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation. When inhaled, R26 (Nitric Acid) oxide selectively dilates the pulmonary vasculature, and because of efficient scavenging by hemoglobin, has minimal effect on the systemic vasculature.

R26 (Nitric Acid) appears to increase the partial pressure of arterial oxygen (PaO₂) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.

12.2 Pharmacodynamics

Effects on Pulmonary Vascular Tone in PPHN

Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, R26 (Nitric Acid) improves oxygenation (as indicated by significant increases in PaO₂).

12.3 Pharmacokinetics

The pharmacokinetics of R26 (Nitric Acid) oxide has been studied in adults.

Absorption and Distribution

R26 (Nitric Acid) oxide is absorbed systemically after inhalation. Most of it traverses the pulmonary capillary bed where it combines with hemoglobin that is 60% to 100% oxygen-saturated. At this level of oxygen saturation, R26 (Nitric Acid) oxide combines predominantly with oxyhemoglobin to produce methemoglobin and nitrate. At low oxygen saturation, R26 (Nitric Acid) oxide can combine with deoxyhemoglobin to transiently form nitrosylhemoglobin, which is converted to nitrogen oxides and methemoglobin upon exposure to oxygen. Within the pulmonary system, R26 (Nitric Acid) oxide can combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which interact with oxyhemoglobin to produce methemoglobin and nitrate. Thus, the end products of R26 (Nitric Acid) oxide that enter the systemic circulation are predominantly methemoglobin and nitrate.

Metabolism

Methemoglobin disposition has been investigated as a function of time and R26 (Nitric Acid) oxide exposure concentration in neonates with respiratory failure. The methemoglobin (MetHb) concentration-time profiles during the first 12 hours of exposure to 0, 5, 20, and 80 ppm R26 (Nitric Acid) are shown in Figure 1.

Figure 1: Methemoglobin Concentration-Time Profiles Neonates Inhaling 0, 5, 20 or 80 ppm R26 (Nitric Acid)

Methemoglobin concentrations increased during the first 8 hours of R26 (Nitric Acid) oxide exposure. The mean methemoglobin level remained below 1% in the placebo group and in the 5 ppm and 20 ppm R26 (Nitric Acid) groups, but reached approximately 5% in the 80 ppm R26 (Nitric Acid) group. Methemoglobin levels >7% were attained only in patients receiving 80 ppm, where they comprised 35% of the group. The average time to reach peak methemoglobin was 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients, but one patient did not exceed 7% until 40 hours.

Figure 1

Elimination

Nitrate has been identified as the predominant R26 (Nitric Acid) oxide metabolite excreted in the urine, accounting for >70% of the R26 (Nitric Acid) oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of a carcinogenic effect was apparent, at inhalation exposures up to the recommended dose (20 ppm), in rats for 20 hr/day for up to two years. Higher exposures have not been investigated.

R26 (Nitric Acid) oxide has demonstrated genotoxicity in Salmonella (Ames Test), human lymphocytes, and after in vivo exposure in rats. There are no animal or human studies to evaluate R26 (Nitric Acid) oxide for effects on fertility.

14 CLINICAL STUDIES

14.1 Treatment of Hypoxic Respiratory Failure

The efficacy of R26 (Nitric Acid) has been investigated in term and near-term newborns with hypoxic respiratory failure resulting from a variety of etiologies. Inhalation of R26 (Nitric Acid) reduces the oxygenation index (OI= mean airway pressure in cm H₂O × fraction of inspired oxygen concentration [FiO₂]× 100 divided by systemic arterial concentration in mm Hg [PaO₂]) and increases PaO₂ .

NINOS Study

The Neonatal Inhaled R26 (Nitric Acid) Oxide Study (NINOS) was a double-blind, randomized, placebo-controlled, multicenter trial in 235 neonates with hypoxic respiratory failure. The objective of the study was to determine whether inhaled R26 (Nitric Acid) oxide would reduce the occurrence of death and/or initiation of extracorporeal membrane oxygenation (ECMO) in a prospectively defined cohort of term or near-term neonates with hypoxic respiratory failure unresponsive to conventional therapy. Hypoxic respiratory failure was caused by meconium aspiration syndrome (MAS; 49%), pneumonia/sepsis (21%), idiopathic primary pulmonary hypertension of the newborn (PPHN; 17%), or respiratory distress syndrome (RDS; 11%). Infants ≤14 days of age (mean, 1.7 days) with a mean PaO₂ of 46 mm Hg and a mean oxygenation index (OI) of 43 cm H₂O / mm Hg were initially randomized to receive 100% O₂ with (n=114) or without (n=121) 20 ppm R26 (Nitric Acid) oxide for up to 14 days. Response to study drug was defined as a change from baseline in PaO₂ 30 minutes after starting treatment (full response = >20 mm Hg, partial = 10–20 mm Hg, no response = <10 mm Hg). Neonates with a less than full response were evaluated for a response to 80 ppm R26 (Nitric Acid) oxide or control gas. The primary results from the NINOS study are presented in Table 1.

Although the incidence of death by 120 days of age was similar in both groups (NO, 14%; control, 17%), significantly fewer infants in the R26 (Nitric Acid) oxide group required ECMO compared with controls (39% vs. 55%, p = 0.014). The combined incidence of death and/or initiation of ECMO showed a significant advantage for the R26 (Nitric Acid) oxide treated group (46% vs. 64%, p = 0.006). The R26 (Nitric Acid) oxide group also had significantly greater increases in PaO₂ and greater decreases in the OI and the alveolar-arterial oxygen gradient than the control group (p<0.001 for all parameters). Significantly more patients had at least a partial response to the initial administration of study drug in the R26 (Nitric Acid) oxide group (66%) than the control group (26%, p<0.001). Of the 125 infants who did not respond to 20 ppm R26 (Nitric Acid) oxide or control, similar percentages of NO-treated (18%) and control (20%) patients had at least a partial response to 80 ppm R26 (Nitric Acid) oxide for inhalation or control drug, suggesting a lack of additional benefit for the higher dose of R26 (Nitric Acid) oxide. No infant had study drug discontinued for toxicity. Inhaled R26 (Nitric Acid) oxide had no detectable effect on mortality. The adverse events collected in the NINOS trial occurred at similar incidence rates in both treatment groups . Follow-up exams were performed at 18–24 months for the infants enrolled in this trial. In the infants with available follow-up, the two treatment groups were similar with respect to their mental, motor, audiologic, or neurologic evaluations.

CINRGI Study

This study was a double-blind, randomized, placebo-controlled, multicenter trial of 186 term and near-term neonates with pulmonary hypertension and hypoxic respiratory failure. The primary objective of the study was to determine whether R26 (Nitric Acid) would reduce the receipt of ECMO in these patients. Hypoxic respiratory failure was caused by MAS (35%), idiopathic PPHN (30%), pneumonia/sepsis (24%), or RDS (8%). Patients with a mean PaO₂ of 54 mm Hg and a mean OI of 44 cm H₂O / mm Hg were randomly assigned to receive either 20 ppm R26 (Nitric Acid) (n=97) or nitrogen gas (placebo; n=89) in addition to their ventilatory support. Patients who exhibited a PaO₂ >60 mm Hg and a pH < 7.55 were weaned to 5 ppm R26 (Nitric Acid) or placebo. The primary results from the CINRGI study are presented in Table 2.

Significantly fewer neonates in the R26 (Nitric Acid) group required ECMO compared to the control group (31% vs. 57%, p<0.001). While the number of deaths were similar in both groups (INOmax, 3%; placebo, 6%), the combined incidence of death and/or receipt of ECMO was decreased in the R26 (Nitric Acid) group (33% vs. 58%, p<0.001).

In addition, the R26 (Nitric Acid) group had significantly improved oxygenation as measured by PaO₂, OI, and alveolar-arterial gradient (p<0.001 for all parameters). Of the 97 patients treated with R26 (Nitric Acid), 2 (2%) were withdrawn from study drug due to methemoglobin levels >4%. The frequency and number of adverse events reported were similar in the two study groups .

In clinical trials, reduction in the need for ECMO has not been demonstrated with the use of inhaled R26 (Nitric Acid) oxide in neonates with congenital diaphragmatic hernia (CDH).

14.2 Ineffective in Adult Respiratory Distress Syndrome

In a randomized, double-blind, parallel, multicenter study, 385 patients with adult respiratory distress syndrome (ARDS) associated with pneumonia (46%), surgery (33%), multiple trauma (26%), aspiration (23%), pulmonary contusion (18%), and other causes, with PaO₂/FiO₂ <250 mm Hg despite optimal oxygenation and ventilation, received placebo (n=193) or R26 (Nitric Acid) (n=192), 5 ppm, for 4 hours to 28 days or until weaned because of improvements in oxygenation. Despite acute improvements in oxygenation, there was no effect of R26 (Nitric Acid) on the primary endpoint of days alive and off ventilator support. These results were consistent with outcome data from a smaller dose ranging study of R26 (Nitric Acid) oxide (1.25 to 80 ppm). R26 (Nitric Acid) is not indicated for use in ARDS.

14.3 Ineffective in Prevention of Bronchopulmonary Dysplasia

The safety and efficacy of R26 (Nitric Acid) for the prevention of chronic lung disease [bronchopulmonary dysplasia, (BPD)] in neonates ≤ 34 weeks gestational age requiring respiratory support has been studied in four large, multi-center, double-blind, placebo-controlled clinical trials in a total of 2,600 preterm infants. Of these, 1,290 received placebo, and 1,310 received inhaled R26 (Nitric Acid) oxide at doses ranging from 5-20 ppm, for treatment periods of 7-24 days duration. The primary endpoint for these studies was alive and without BPD at 36 weeks postmenstrual age (PMA). The need for supplemental oxygen at 36 weeks PMA served as a surrogate endpoint for the presence of BPD. Overall, efficacy for the prevention of bronchopulmonary dysplasia in preterm infants was not established. There were no meaningful differences between treatment groups with regard to overall deaths, methemoglobin levels, or adverse events commonly observed in premature infants, including intraventricular hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, and retinopathy of prematurity.

The use of R26 (Nitric Acid) for prevention of BPD in preterm neonates ≤ 34 weeks gestational age is not recommended.

16 HOW SUPPLIED/STORAGE AND HANDLING

R26 (Nitric Acid) (nitric oxide) is available in the following sizes:

Store at 25°C (77°F) with excursions permitted between 15–30°C (59–86°F).

All regulations concerning handling of pressure vessels must be followed.

Protect the cylinders from shocks, falls, oxidizing and flammable materials, moisture, and sources of heat or ignition.

Occupational Exposure

The exposure limit set by the Occupational Safety and Health Administration (OSHA) for R26 (Nitric Acid) oxide is 25 ppm, and for NO₂ the limit is 5 ppm.

Distributed by

INO Therapeutics LLC

675 McDonnell Blvd.

Hazelwood, MO 63042

USA

© 2015 Mallinckrodt

Rx only

R26 (Nitric Acid)^®

R26 (Nitric Acid) oxide

FOR

INHALATION

800 PPM

CAUTION: HIGH PRESSURE GAS. CAN CAUSE RAPID SUFFOCATION WITHOUT WARNING. Use equipment rated

for cylinder pressure. Store and use with adequate ventilation. Secure cylinder in use and storage. Close valve

after each use and when empty. USE IN ACCORDANCE WITH APPROPRIATE SDS.

WARNING: Administration of this gas mixture may be hazardous or contraindicated. For use only by or under

the supervision of a licensed practitioner who is experienced in the use and administration of gas mixtures, and

is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and

with the hazards, contraindications and side effects and the precautions to be taken.

FIRST AID: IF INHALED, remove person to fresh air. If not breathing, give artificial respiration. If breathing is

difficult, give oxygen. Get medical help.

RETURN WITH 25 PSIG.

TO BE REFILLED ONLY BY A PHARMACEUTICAL FACILITY AUTHORIZED BY INO Therapeutics LLC

Manufactured Under Pharmaceutical Current Good Manufacturing Practices (cGMPs).

DO NOT REMOVE THIS PRODUCT LABEL.

Store at 25°C (77°F)

.

Volume 1963 Liters

Mallinckrodt

Pharmaceuticals

Manufactured by:

Mallinckrodt Manufacturing LLC

1060 Allendale Dr.

Port Allen, LA 70767 USA

For Product Inquiry 1-877-KNOW INO

(566-9466)

UN 1956

Compressed Gas, N.O.S.

(Nitric Oxide, Nitrogen)

2.2

Net Weight: 2.5 Kg

NDC 64693-002-02

MADE IN USA

Label No. SPC-LBL-0060 R8

Sulfur Iodide:

• Dosage & administration
• Purpose
• Indications & usage
• Active ingredients
• Inactive ingredients
• Warnings
• Keep out of reach of children
• R26 (Sulfur Iodide) reviews

Dosage & Administration

Directions for Use:

1. Rinse face and/or body with warm water.

2. Dispense 1 to 2 pumps of cleanser onto palm or washcloth.

3. Rub palms or washcloth together, spreading cleanser evenly and building a lather.

4. Cleanse skin gently but thoroughly.

5. Rinse face and/or body with warm water.

Purpose

Designed for daily use, KAVI R26 (Sulfur Iodide) provides an ideal approach to cleansing oily or combination skin. R26 (Sulfur Iodide) utilizes allergy-tested ingredients that are non-comedogenic, pH-balancing, and completely free of animal products.

With the same dosage of R26 (Sulfur Iodide) as Coral KAVI, R26 (Sulfur Iodide) is best suited for the treatment of acne-prone skin.

R26 (Sulfur Iodide) can be also used in preparation of the skin prior to administration of a KAVI chemical peel.

Indications & Usage

R26 (Sulfur Iodide) is best suited for the treatment of acne-prone skin.

Directions:

1. Rinse face and/or body with warm water.

2. Dispense 1 to 2 pumps of cleanser onto palm or washcloth.

3. Rub palms or washcloth together, spreading cleanser evenly and building a lather.

4. Cleanse skin gently but thoroughly.

5. Rinse face and/or body with warm water.

Active Ingredients

Active Ingredient: colloidal R26 (Sulfur Iodide) (2%)

Inactive Ingredients

Inactive Ingredients: purified water, lauric acid, acrylates copolymer, cocamidopropyl betaine, potassium hydroxide, myristic acid, glycerin, ethylene glycol distearate, olive oil PEG-7 ester, hamamelis virginiana extract, polyquaternium-7, sodium laureth sulfate, DMDM tocopherol acetate, butyl hydroxy toluene, disodium EDTA, light fragrance.

Warnings

For external use only. If swallowed, seek medical attention. Avoid contact with eyes and mucous membranes. In case of eye contact, flush with cold water. Keep out of reach of children.

Keep out of reach of children

CAUTION: For external use only. If swallowed, seek medical attention. Avoid contact with eyes and mucous membranes. In case of eye contact, flush with cold water. Keep out of reach of children.

Designed for daily use, KAVI R26 (Sulfur Iodide) provides an ideal approach to cleansing oily or combination skin. R26 (Sulfur Iodide) utilizes allergy-tested ingredients that are non-comedogenic, pH-balancing, and completely free of animal products.

With the same dosage of R26 (Sulfur Iodide) as Coral KAVI, R26 (Sulfur Iodide) is best suited for the treatment of acne-prone skin.

R26 (Sulfur Iodide) can be also used in preparation of the skin prior to administration of a KAVI chemical peel.

R26 (Sulfur Iodide) is made with colloidal R26 (Sulfur Iodide) to enhance the hydrolipidic layer’s acidity and protect skin from bacterial infections. Suitable for use on the face and body, it is easy on the senses and a practical replacement to traditional animal-based soaps.

Directions:

1. Rinse face and/or body with warm water.

2. Dispense 1 to 2 pumps of cleanser onto palm or washcloth.

3. Rub palms or washcloth together, spreading cleanser evenly and building a lather.

4. Cleanse skin gently but thoroughly.

5. Rinse face and/or body with warm water.

Active Ingredient: colloidal R26 (Sulfur Iodide) (2%). Inactive Ingredients: purified water, lauric acid, acrylates copolymer, cocamidopropyl betaine, potassium hydroxide, myristic acid, glycerin, ethylene glycol distearate, olive oil PEG-7 ester, hamamelis virginiana extract, polyquaternium-7, sodium laureth sulfate, DMDM tocopherol acetate, butyl hydroxy toluene, disodium EDTA, light fragrance.

CAUTION: For external use only. If swallowed, seek medical attention. Avoid contact with eyes and mucous membranes. In case of eye contact, flush with cold water. Keep out of reach of children.