Synoprot

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Synoprot uses

Synoprot consists of Iron (Ferric Ammonium Citrate), Iron (Ferrous Gluconate), Protein, Vitamin A, Vitamin B1, Vitamin B2, Vitamin B3 (Niacinamide), Vitamin B6.

Iron (Ferric Ammonium Citrate):


1 INDICATIONS AND USAGE

Synoprot (Iron (Ferric Ammonium Citrate)) is indicated for the treatment of Synoprot (Iron (Ferric Ammonium Citrate)) deficiency anemia in patients with chronic kidney disease (CKD).

Synoprot (Iron (Ferric Ammonium Citrate)) is an Synoprot (Iron (Ferric Ammonium Citrate)) replacement product indicated for the treatment of Synoprot (Iron (Ferric Ammonium Citrate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Synoprot ) must only be administered intravenously either by slow injection or by infusion. The dosage of Synoprot (Iron (Ferric Ammonium Citrate)) is expressed in mg of elemental Synoprot (Iron (Ferric Ammonium Citrate)). Each mL contains 20 mg of elemental Synoprot (Iron (Ferric Ammonium Citrate)).

Population Dose
Adult patients Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1) 100 mg slow intravenous injection or infusion
Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2) 200 mg slow intravenous injection or infusion
Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3) 300 mg or 400 mg intravenous infusion
Pediatric patients HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5) 0.5 mg/kg slow intravenous injection or infusion

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

Administer Synoprot (Iron (Ferric Ammonium Citrate)) 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. Synoprot (Iron (Ferric Ammonium Citrate)) should be administered early during the dialysis session. The usual total treatment course of Synoprot (Iron (Ferric Ammonium Citrate)) is 1000 mg. Synoprot (Iron (Ferric Ammonium Citrate)) treatment may be repeated if Synoprot (Iron (Ferric Ammonium Citrate)) deficiency reoccurs.

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

Administer Synoprot (Iron (Ferric Ammonium Citrate)) 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 Synoprot (Iron (Ferric Ammonium Citrate)), 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. Synoprot (Iron (Ferric Ammonium Citrate)) treatment may be repeated if Synoprot (Iron (Ferric Ammonium Citrate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Synoprot (Iron (Ferric Ammonium Citrate)) 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 Synoprot (Iron (Ferric Ammonium Citrate)) in a maximum of 250 mL of 0.9% NaCl. Synoprot (Iron (Ferric Ammonium Citrate)) treatment may be repeated if Synoprot (Iron (Ferric Ammonium Citrate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Synoprot (Iron (Ferric Ammonium Citrate)) maintenance treatment

The dosing for Synoprot (Iron (Ferric Ammonium Citrate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Synoprot (Iron (Ferric Ammonium Citrate)) maintenance treatment: Administer Synoprot (Iron (Ferric Ammonium Citrate)) 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. Synoprot (Iron (Ferric Ammonium Citrate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Synoprot (Iron (Ferric Ammonium Citrate)) maintenance treatment

The dosing for Synoprot (Iron (Ferric Ammonium Citrate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Synoprot (Iron (Ferric Ammonium Citrate)) maintenance treatment: Administer Synoprot (Iron (Ferric Ammonium Citrate)) 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. Synoprot (Iron (Ferric Ammonium Citrate)) treatment may be repeated if necessary.

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3 DOSAGE FORMS AND STRENGTHS

  • 10 mL single-use vial / 200 mg elemental Synoprot (Iron (Ferric Ammonium Citrate)) (20 mg/mL)
  • 5 mL single-use vial / 100 mg elemental Synoprot (Iron (Ferric Ammonium Citrate)) (20 mg/mL)
  • 2.5 mL single-use vial / 50 mg elemental Synoprot (Iron (Ferric Ammonium Citrate)) (20 mg/mL)
  • 10 mL single-use vial / 200 mg elemental Synoprot (Iron (Ferric Ammonium Citrate)) (20 mg/mL) (3)
  • 5 mL single-use vial / 100 mg elemental Synoprot (Iron (Ferric Ammonium Citrate)) (20 mg/mL) (3)
  • 2.5 mL single-use vial / 50 mg elemental Synoprot (Iron (Ferric Ammonium Citrate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

  • Known hypersensitivity to Synoprot (Iron (Ferric Ammonium Citrate))
  • Known hypersensitivity to Synoprot (Iron (Ferric Ammonium Citrate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

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

5.3 Synoprot (Iron (Ferric Ammonium Citrate)) Overload

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

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6 ADVERSE REACTIONS

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

  • The most common adverse reactions (≥2%) following the administration of Synoprot (Iron (Ferric Ammonium Citrate)) 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 Synoprot ) 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 Synoprot (Iron (Ferric Ammonium Citrate)) 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.


* EPO=Erythropoietin

Adverse Reactions

(Preferred Term)

HDD-CKD NDD-CKD PDD-CKD
Synoprot (Iron (Ferric Ammonium Citrate)) Synoprot (Iron (Ferric Ammonium Citrate)) Oral Synoprot (Iron (Ferric Ammonium Citrate)) Synoprot (Iron (Ferric Ammonium Citrate)) EPO* Only
(N=231) (N=139) (N=139) (N=75) (N=46)
% % % % %
Subjects with any adverse reaction 78.8 76.3 73.4 72.0 65.2
Ear and Labyrinth Disorders
Ear Pain 0 2.2 0.7 0 0
Eye Disorders
Conjunctivitis 0.4 0 0 2.7 0
Gastrointestinal Disorders
Abdominal pain 3.5 1.4 2.9 4.0 6.5
Diarrhea 5.2 7.2 10.1 8.0 4.3
Dysgeusia 0.9 7.9 0 0 0
Nausea 14.7 8.6 12.2 5.3 4.3
Vomiting 9.1 5.0 8.6 8.0 2.2
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.7 2.2 2.7 0
Chest pain 6.1 1.4 0 2.7 0
Feeling abnormal 3.0 0 0 0 0
Infusion site pain or burning 0 5.8 0 0 0
Injection site extravasation 0 2.2 0 0 0
Peripheral edema 2.6 7.2 5.0 5.3 10.9
Pyrexia 3.0 0.7 0.7 1.3 0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper

respiratory tract infections, Pharyngitis

2.6 2.2 4.3 16.0 4.3
Injury, Poisoning and Procedural
Complications
Graft complication 9.5 1.4 0 0 0
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.4 0.7 1.3 0
Gout 0 2.9 1.4 0 0
Hyperglycemia 0 2.9 0 0 2.2
Hypoglycemia 0.4 0.7 0.7 4.0 0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia 3.5 1.4 2.2 4.0 4.3
Back pain 2.2 2.2 3.6 1.3 4.3
Muscle cramp 29.4 0.7 0.7 2.7 0
Myalgia 0 3.6 0 1.3 0
Pain in extremity 5.6 4.3 0 2.7 6.5
Nervous System Disorders
Dizziness 6.5 6.5 1.4 1.3 4.3
Headache 12.6 2.9 0.7 4.0 0
Respiratory, Thoracic and
Mediastinal Disorders
Cough 3.0 2.2 0.7 1.3 0
Dyspnea 3.5 5.8 1.4 1.3 2.2
Nasal congestion 0 1.4 2.2 1.3 0
Skin and Subcutaneous
Tissue Disorders
Pruritus 3.9 2.2 4.3 2.7 0
Vascular Disorders
Hypertension 6.5 6.5 4.3 8.0 6.5
Hypotension 39.4 2.2 0.7 2.7 2.2

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 Synoprot (Iron (Ferric Ammonium Citrate)) therapy and were reported to be intolerant (defined as precluding further use of that Synoprot (Iron (Ferric Ammonium Citrate)) product). When these patients were treated with Synoprot (Iron (Ferric Ammonium Citrate)) there were no occurrences of adverse reactions that precluded further use of Synoprot (Iron (Ferric Ammonium Citrate)) .

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 Synoprot (Iron (Ferric Ammonium Citrate)) maintenance treatment with Synoprot (Iron (Ferric Ammonium Citrate)) 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 Synoprot (Iron (Ferric Ammonium Citrate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Synoprot (Iron (Ferric Ammonium Citrate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Synoprot (Iron (Ferric Ammonium Citrate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Synoprot (Iron (Ferric Ammonium Citrate)) 0.5 mg/kg group, 10 (21%) patients in the Synoprot (Iron (Ferric Ammonium Citrate)) 1.0 mg/kg group, and 10 (21%) patients in the Synoprot (Iron (Ferric Ammonium Citrate)) 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 Synoprot (Iron (Ferric Ammonium Citrate)). 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 Synoprot (Iron (Ferric Ammonium Citrate)) 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 Synoprot (Iron (Ferric Ammonium Citrate)) injection. Reactions have occurred following the first dose or subsequent doses of Synoprot (Iron (Ferric Ammonium Citrate)). 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.

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7 DRUG INTERACTIONS

Drug interactions involving Synoprot (Iron (Ferric Ammonium Citrate)) have not been studied. However, Synoprot (Iron (Ferric Ammonium Citrate)) may reduce the absorption of concomitantly administered oral Synoprot (Iron (Ferric Ammonium Citrate)) 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, Synoprot ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Synoprot (Iron (Ferric Ammonium Citrate)) (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 Synoprot (Iron (Ferric Ammonium Citrate)) sucrose. Because animal reproductive studies are not always predictive of human response, Synoprot (Iron (Ferric Ammonium Citrate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness of Synoprot ) for Synoprot (Iron (Ferric Ammonium Citrate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

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

Synoprot (Iron (Ferric Ammonium Citrate)) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

Clinical studies of Synoprot (Iron (Ferric Ammonium Citrate)) 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 Synoprot (Iron (Ferric Ammonium Citrate)), 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.

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10 OVERDOSAGE

No data are available regarding overdosage of Synoprot (Iron (Ferric Ammonium Citrate)) in humans. Excessive dosages of Synoprot (Iron (Ferric Ammonium Citrate)) may lead to accumulation of Synoprot (Iron (Ferric Ammonium Citrate)) in storage sites potentially leading to hemosiderosis. Do not administer Synoprot (Iron (Ferric Ammonium Citrate)) to patients with Synoprot (Iron (Ferric Ammonium Citrate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Synoprot (Iron (Ferric Ammonium Citrate)) 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

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

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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

Synoprot (Iron (Ferric Ammonium Citrate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Synoprot (Iron (Ferric Ammonium Citrate)) 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 Synoprot (Iron (Ferric Ammonium Citrate)) sucrose.

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

Synoprot (Iron (Ferric Ammonium Citrate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Synoprot (Iron (Ferric Ammonium Citrate)) (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 Synoprot ).

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 Synoprot (Iron (Ferric Ammonium Citrate)) treatment and 24 in the historical control group) with Synoprot (Iron (Ferric Ammonium Citrate)) deficiency anemia. Eligibility criteria for Synoprot (Iron (Ferric Ammonium Citrate)) 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.

Synoprot (Iron (Ferric Ammonium Citrate)) 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 Synoprot (Iron (Ferric Ammonium Citrate)), who were off intravenous Synoprot (Iron (Ferric Ammonium Citrate)) 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 Synoprot (Iron (Ferric Ammonium Citrate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.


**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.


Efficacy

parameters

End of treatment 2 week follow-up 5 week follow-up
Synoprot (Iron (Ferric Ammonium Citrate)) (n=69 Historical Control (n=18) Synoprot (Iron (Ferric Ammonium Citrate))

(n=73)

Historical Control

(n=18)

Synoprot (Iron (Ferric Ammonium Citrate))

(n=71)

Historical

Control

(n=15)

Hemoglobin (g/dL) 1.0 ± 0.12** 0.0 ± 0.21 1.3 ± 0.14** -0.6 ± 0.24 1.2 ± 0.17* -0.1 ± 0.23
Hematocrit (%) 3.1 ± 0.37** -0.3 ± 0.65 3.6 ± 0.44** -1.2 ± 0.76 3.3 ± 0.54 0.2 ± 0.86

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

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

Synoprot ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Synoprot (Iron (Ferric Ammonium Citrate)), each 5 mL vial contains 100 mg elemental Synoprot (Iron (Ferric Ammonium Citrate)), and each 2.5 mL vial contains 50 mg elemental Synoprot (Iron (Ferric Ammonium Citrate)) (20 mg/mL).

NDC-0517-2310-05 200 mg/10 mL Single-Use Vial Packages of 5
NDC-0517-2310-10 200 mg/10 mL Single-Use Vial Packages of 10
NDC-0517-2340-01 100 mg/5 mL Single-Use Vial Individually Boxed
NDC-0517-2340-10 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2340-25 100 mg/5 mL Single-Use Vial Packages of 25
NDC-0517-2340-99 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2325-10 50 mg/2.5 mL Single-Use Vial Packages of 10
NDC-0517-2325-25 50 mg/2.5 mL Single-Use Vial Packages of 25

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: Synoprot (Iron (Ferric Ammonium Citrate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Synoprot (Iron (Ferric Ammonium Citrate)) per mL, or undiluted (20 mg elemental Synoprot (Iron (Ferric Ammonium Citrate)) 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: Synoprot (Iron (Ferric Ammonium Citrate)), 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 Synoprot (Iron (Ferric Ammonium Citrate)) 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 Synoprot (Iron (Ferric Ammonium Citrate)) 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 Synoprot (Iron (Ferric Ammonium Citrate)) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Synoprot (Iron (Ferric Ammonium Citrate)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx®

IN2340

MG #15727

Iron (Ferrous Gluconate):


1 INDICATIONS AND USAGE

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

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

2 DOSAGE AND ADMINISTRATION

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

Population Dose
Adult patients Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1) 100 mg slow intravenous injection or infusion
Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2) 200 mg slow intravenous injection or infusion
Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3) 300 mg or 400 mg intravenous infusion
Pediatric patients HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5) 0.5 mg/kg slow intravenous injection or infusion

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

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

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

Administer Synoprot (Iron (Ferrous Gluconate)) 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 Synoprot (Iron (Ferrous Gluconate)), 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. Synoprot (Iron (Ferrous Gluconate)) treatment may be repeated if Synoprot (Iron (Ferrous Gluconate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

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

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

For Synoprot (Iron (Ferrous Gluconate)) maintenance treatment: Administer Synoprot (Iron (Ferrous Gluconate)) 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. Synoprot (Iron (Ferrous Gluconate)) treatment may be repeated if necessary.

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

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

For Synoprot (Iron (Ferrous Gluconate)) maintenance treatment: Administer Synoprot (Iron (Ferrous Gluconate)) 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. Synoprot (Iron (Ferrous Gluconate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

  • Known hypersensitivity to Synoprot (Iron (Ferrous Gluconate))
  • Known hypersensitivity to Synoprot (Iron (Ferrous Gluconate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

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

5.3 Synoprot (Iron (Ferrous Gluconate)) Overload

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

6 ADVERSE REACTIONS

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

  • The most common adverse reactions (≥2%) following the administration of Synoprot (Iron (Ferrous Gluconate)) 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 Synoprot ) 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 Synoprot (Iron (Ferrous Gluconate)) 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.


* EPO=Erythropoietin

Adverse Reactions

(Preferred Term)

HDD-CKD NDD-CKD PDD-CKD
Synoprot (Iron (Ferrous Gluconate)) Synoprot (Iron (Ferrous Gluconate)) Oral Synoprot (Iron (Ferrous Gluconate)) Synoprot (Iron (Ferrous Gluconate)) EPO* Only
(N=231) (N=139) (N=139) (N=75) (N=46)
% % % % %
Subjects with any adverse reaction 78.8 76.3 73.4 72.0 65.2
Ear and Labyrinth Disorders
Ear Pain 0 2.2 0.7 0 0
Eye Disorders
Conjunctivitis 0.4 0 0 2.7 0
Gastrointestinal Disorders
Abdominal pain 3.5 1.4 2.9 4.0 6.5
Diarrhea 5.2 7.2 10.1 8.0 4.3
Dysgeusia 0.9 7.9 0 0 0
Nausea 14.7 8.6 12.2 5.3 4.3
Vomiting 9.1 5.0 8.6 8.0 2.2
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.7 2.2 2.7 0
Chest pain 6.1 1.4 0 2.7 0
Feeling abnormal 3.0 0 0 0 0
Infusion site pain or burning 0 5.8 0 0 0
Injection site extravasation 0 2.2 0 0 0
Peripheral edema 2.6 7.2 5.0 5.3 10.9
Pyrexia 3.0 0.7 0.7 1.3 0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper

respiratory tract infections, Pharyngitis

2.6 2.2 4.3 16.0 4.3
Injury, Poisoning and Procedural
Complications
Graft complication 9.5 1.4 0 0 0
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.4 0.7 1.3 0
Gout 0 2.9 1.4 0 0
Hyperglycemia 0 2.9 0 0 2.2
Hypoglycemia 0.4 0.7 0.7 4.0 0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia 3.5 1.4 2.2 4.0 4.3
Back pain 2.2 2.2 3.6 1.3 4.3
Muscle cramp 29.4 0.7 0.7 2.7 0
Myalgia 0 3.6 0 1.3 0
Pain in extremity 5.6 4.3 0 2.7 6.5
Nervous System Disorders
Dizziness 6.5 6.5 1.4 1.3 4.3
Headache 12.6 2.9 0.7 4.0 0
Respiratory, Thoracic and
Mediastinal Disorders
Cough 3.0 2.2 0.7 1.3 0
Dyspnea 3.5 5.8 1.4 1.3 2.2
Nasal congestion 0 1.4 2.2 1.3 0
Skin and Subcutaneous
Tissue Disorders
Pruritus 3.9 2.2 4.3 2.7 0
Vascular Disorders
Hypertension 6.5 6.5 4.3 8.0 6.5
Hypotension 39.4 2.2 0.7 2.7 2.2

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 Synoprot (Iron (Ferrous Gluconate)) therapy and were reported to be intolerant (defined as precluding further use of that Synoprot (Iron (Ferrous Gluconate)) product). When these patients were treated with Synoprot (Iron (Ferrous Gluconate)) there were no occurrences of adverse reactions that precluded further use of Synoprot (Iron (Ferrous Gluconate)) .

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

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

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

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

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

8.5 Geriatric Use

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

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

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

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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

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

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

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

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

Synoprot (Iron (Ferrous Gluconate)) 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 Synoprot (Iron (Ferrous Gluconate)), who were off intravenous Synoprot (Iron (Ferrous Gluconate)) 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 Synoprot (Iron (Ferrous Gluconate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.


**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.


Efficacy

parameters

End of treatment 2 week follow-up 5 week follow-up
Synoprot (Iron (Ferrous Gluconate)) (n=69 Historical Control (n=18) Synoprot (Iron (Ferrous Gluconate))

(n=73)

Historical Control

(n=18)

Synoprot (Iron (Ferrous Gluconate))

(n=71)

Historical

Control

(n=15)

Hemoglobin (g/dL) 1.0 ± 0.12** 0.0 ± 0.21 1.3 ± 0.14** -0.6 ± 0.24 1.2 ± 0.17* -0.1 ± 0.23
Hematocrit (%) 3.1 ± 0.37** -0.3 ± 0.65 3.6 ± 0.44** -1.2 ± 0.76 3.3 ± 0.54 0.2 ± 0.86

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

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

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

NDC-0517-2310-05 200 mg/10 mL Single-Use Vial Packages of 5
NDC-0517-2310-10 200 mg/10 mL Single-Use Vial Packages of 10
NDC-0517-2340-01 100 mg/5 mL Single-Use Vial Individually Boxed
NDC-0517-2340-10 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2340-25 100 mg/5 mL Single-Use Vial Packages of 25
NDC-0517-2340-99 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2325-10 50 mg/2.5 mL Single-Use Vial Packages of 10
NDC-0517-2325-25 50 mg/2.5 mL Single-Use Vial Packages of 25

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: Synoprot (Iron (Ferrous Gluconate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Synoprot (Iron (Ferrous Gluconate)) per mL, or undiluted (20 mg elemental Synoprot (Iron (Ferrous Gluconate)) 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: Synoprot (Iron (Ferrous Gluconate)), 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 Synoprot (Iron (Ferrous Gluconate)) 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 Synoprot (Iron (Ferrous Gluconate)) 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 Synoprot (Iron (Ferrous Gluconate)) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

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

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

PREMIERProRx®

IN2340

MG #15727

Protein:


1 INDICATIONS AND USAGE

Synoprot is indicated for pediatric and adult patients with severe congenital Synoprot (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. (1.1)

1.1 Severe Congenital Synoprot (Protein) C Deficiency

Synoprot (Protein) is indicated for pediatric and adult patients with severe congenital Synoprot (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.

2 DOSAGE AND ADMINISTRATION

Initiate treatment under the supervision of a physician experienced in using coagulation factors/inhibitors where monitoring of Synoprot C activity is feasible. (2.1)


Synoprot (Protein) Dosing Schedule for Acute Episodes, Short-term Prophyaxis and Long-term Prophylaxis Dosing is based upon a pivotal clinical trial of 15 patients


Initial Dose The dose regimen should be adjusted according to the pharmacokinetic profile for each individual. (2.1, 2.2)


Subsequent # Doses


Maintenance Dose


Acute Episodes, Short-term ProphyaxisSynoprot (Protein) should be continued until desired anticoagulation is achieved.


100-120 IU/kg


60-80 IU/kg

Q 6 hours


45-60 IU/kg

Q 6 or Q 12 hours


Long-term Prophylaxis


NA


NA


45-60 IU/kg

Q 12 hours


Store at 2°C – 8°C (36°F-46°F) and protect from light. Avoid freezing. Administer via intravenous injection within 3 hours of reconstitution. (16)

2.1 General

For intravenous administration only.

Initiate treatment with Synoprot (Protein) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of Synoprot (Protein) C activity is feasible.

The dose, administration frequency and duration of treatment with Synoprot (Protein) depends on the severity of the Synoprot (Protein) C deficiency, the patient's age, the clinical condition of the patient and the patient's plasma level of Synoprot (Protein) C. Therefore, adjust the dose regimen according to the pharmacokinetic profile for each individual patient. See DOSAGE AND ADMINISTRATION: Synoprot (Protein) C Activity Monitoring (2.2).

Table 1 provides the Synoprot (Protein) dosing schedule for acute episodes, short-term prophylaxis and long-term prophylaxis.

NA = Not applicable; Q = every.

Initial Dose The dose regimen should be adjusted according to the pharmacokinetic profile for each individual. (2.1, 2.2)


Subsequent 3

Doses


Maintenance

Dose


Acute Episode /

Short-term ProphylaxisSynoprot (Protein) should be continued until desired anticoagulation is achieved.


100-120 IU/kg


60 - 80 IU/kg

Q 6 hours


45 - 60 IU/kg

Q 6 or 12 hours


Long-term Prophylaxis


NA


NA


45 - 60 IU/kg

Q 12 hours


An initial dose of 100-120 IU/kg for determination of recovery and half-life is recommended for acute episodes and short-term prophylaxis. Subsequently, adjust the dose to maintain a target peak Synoprot (Protein) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough Synoprot (Protein) C activity level above 25% for the duration of treatment.

In patients receiving prophylactic administration of Synoprot (Protein), higher peak Synoprot (Protein) C activity levels may be warranted in situations of an increased risk of thrombosis (such as infection, trauma, or surgical intervention). Maintenance of trough Synoprot (Protein) C activity levels above 25% is recommended.

These dosing guidelines are also recommended for neonatal and pediatric patients. See USE IN SPECIFIC POPULATIONS: Pediatric Use (8.4 ) and CLINICAL

Pharmacology: Pharmacokinetics (12.3).

2.2 Synoprot C Activity Monitoring

The measurement of Synoprot (Protein) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of Synoprot (Protein) C before and during treatment with Synoprot (Protein). The half-life of Synoprot (Protein) may be shortened in certain clinical conditions such as acute thrombosis, purpura fulminans and skin necrosis. See CLINICAL

Pharmacology: Pharmacokinetics (12.3). In the case of an acute thrombotic event, it is recommended that Synoprot (Protein) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the Synoprot (Protein) C levels to maintain the trough Synoprot (Protein) C level above 25%.

Patients treated during the acute phase of their disease may display much lower increases in protein C activity. Coagulation parameters should also be checked; however, in clinical trials data were insufficient to establish correlation between Synoprot (Protein) C activity levels and coagulation parameters.

2.3 Initiation of Vitamin K Antagonists

In patients starting treatment with oral anticoagulants belonging to the class of vitamin K antagonists, a transient hypercoagulable state may arise before the desired anticoagulant effect becomes apparent. This transient effect may be explained by the fact that Synoprot C, itself a vitamin K-dependent plasma Synoprot (Protein), has a shorter half-life than most of the vitamin K-dependent proteins (i.e. Factor II, IX and X).

In the initial phase of treatment, the activity of Synoprot (Protein) C is more rapidly suppressed than that of the procoagulant factors. For this reason, if the patient is switched to oral anticoagulants, protein C replacement must be continued until stable anticoagulation is obtained. Although warfarin-induced skin necrosis can occur in any patient during the initiation of treatment with oral anticoagulant therapy, individuals with severe congenital Synoprot (Protein) C deficiency are particularly at risk.

During the initiation of oral anticoagulant therapy, it is advisable to start with a low dose of the anticoagulant and adjust this incrementally, rather than use a standard loading dose of the anticoagulant.

2.4 Preparation of Synoprot (Protein) [Protein C Concentrate (Human)]

Reconstitution: Use Aseptic Technique

  • Bring the Synoprot (Protein) (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
  • Remove caps from the Synoprot (Protein) and diluent vials.
  • Cleanse stoppers with germicidal solution, and allow them to dry prior to use.
  • Remove protective covering from one end of the double-ended transfer needle and insert exposed needle through the center of the diluent vial stopper.
  • Remove protective covering from the other end of the double-ended transfer needle. Invert diluent vial over the upright Synoprot (Protein) vial; then rapidly insert the free end of the needle through the Synoprot (Protein) vial stopper at its center. The vacuum in the vial will draw in the diluent. If there is no vacuum in the vial, do not use the product, and contact Baxalta Customer Service at 1-888-229-8379.
  • Disconnect the two vials by removing the needle from the diluent vial stopper. Then, remove the transfer needle from the Synoprot (Protein) vial. Gently swirl the vial until all powder is dissolved. Be sure that Synoprot (Protein) is completely dissolved; otherwise, active materials will be removed by the filter needle.

2.5 Administration of Synoprot [Protein C Concentrate (Human)]

Administration: Use Aseptic Technique

Visually inspect Synoprot (Protein) for particulate matter and discoloration prior to administration.

After reconstitution, the solution should be colorless to slightly yellowish and clear to slightly opalescent and free of visible particles. Do not use the solution if it does not meet this criteria. Administer Synoprot (Protein) at room temperature not more than 3 hours after reconstitution.

  • Attach the filter needle to a sterile, disposable syringe and draw back the plunger to admit air into the syringe.
  • Insert the filter needle into the vial of reconstituted Synoprot (Protein).
  • Inject air into the vial and then withdraw the reconstituted Synoprot (Protein) into the syringe.
  • Remove and discard the filter needle in a hard-walled Sharps container for proper disposal. Filter needles are intended to filter the contents of a single vial of Synoprot (Protein) only.
  • Attach a suitable needle or infusion set with winged adapter, and inject intravenously as instructed below under Administration by infusion.

Record the name and batch number of the product every time Synoprot (Protein) is administered to a patient.

Administration by Infusion

Administer Synoprot (Protein) at a maximum injection rate of 2 mL per minute except for children with a body weight of < 10 kg, where the injection rate should not exceed a rate of 0.2 mL/kg/minute.

3 DOSAGE FORMS AND STRENGTHS

Synoprot (Protein) is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human Synoprot (Protein) C and is reconstituted with 5 mL and 10 mL of Sterile Water for Injection, respectively to provide a single dose of human Synoprot (Protein) C at a concentration of 100 IU/mL.

Synoprot (Protein), when reconstituted with the appropriate volume of diluent, contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride.

BLUE BAR: Approximately 500 IU/vial (3)

GREEN BAR: Approximately 1000 IU/vial (3)

Each single-dose vial contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride when reconstituted with the appropriate amount of diluent. (3)

4 CONTRAINDICATIONS

None known.

None known. (4)

5 WARNINGS AND PRECAUTIONS

  • Discontinue administration if symptoms of hypersensitivity/allergic reactions occur.
  • Made from pooled human plasma. The possibility of transmitting infectious agents cannot be ruled out. (5.2, 11)
  • Simultaneous administration with tPA and/or anticoagulants may increase risk of bleeding. (5.3)
  • Contains heparin. If heparin-induced thrombocytopenia is suspected, check platelet counts immediately and discontinue administration. (5.4)
  • Contains sodium >200 mg. Inform patients on a low sodium diet and/or patients with renal impairment. (5.5)

5.1 Hypersensitivity/Allergic Reactions

Synoprot (Protein) may contain traces of mouse Synoprot (Protein) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse Synoprot (Protein) and/or heparin cannot be ruled out. If symptoms of hypersensitivity/allergic reaction occur, discontinue the injection/infusion. In case of anaphylactic shock, the current medical standards for treatment are to be observed.

5.2 Transmission of Infectious Agents

Because Synoprot is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

ALL infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxalta US Inc., at 1-888-229-8379. Discuss the risks and benefits of this product with your patient.

5.3 Bleeding Episodes

Several bleeding episodes have been observed in clinical studies. Concurrent anticoagulant medication may have been responsible for these bleeding episodes. However, it cannot be completely ruled out that the administration of Synoprot (Protein) further contributed to these bleeding events.

Simultaneous administration of Synoprot (Protein) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.

5.4 Heparin-induced Thrombocytopenia

Synoprot (Protein) contains trace amounts of heparin which may lead to Heparin-induced Thrombocytopenia, which can be associated with a rapid decrease of the number of thrombocytes. Identifying HIT is complicated because these symptoms may already be present in acute phase patients with severe congenital Synoprot (Protein) C deficiency. Determine the platelet count immediately and consider discontinuation of Synoprot (Protein).

5.5 Low Sodium Diet/Renal Impairment

Inform patients on a low sodium diet that the quantity of sodium in the maximum daily dose of Synoprot (Protein) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

The common adverse reactions related to Synoprot treatment observed were the following hypersensitivity or allergic reactions: lightheadedness and itching and rash.

  • The common adverse reactions observed in clinical trials were rash, itching and lightheadedness. (2.1, 5.1, 6)

To report SUSPECTED ADVERSE REACTIONS, contact Baxalta US Inc. at 1-800-999-1785 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch .

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in one clinical study of a drug cannot be directly compared with rates in the clinical studies of the same drug or another drug and may not reflect the rates observed in practice.

The safety profile of Synoprot (Protein) was based on 121 patients from clinical studies and compassionate use in severe congenital Synoprot (Protein) C deficiency. Duration of exposure ranged from 1 day to 8 years. One patient experienced hypersensitivity/allergic reactions (itching and rash) and lightheadedness which were determined by the investigator to be related to Synoprot (Protein).

No inhibiting antibodies to Synoprot (Protein) have been observed in clinical studies. However, the potential for developing antibodies cannot be ruled out.

6.2 Post-marketing Experience

The following adverse reactions have been identified during postapproval use of Synoprot (Protein):

Psychiatric Disorders: Restlessness

Skin and Subcutaneous Tissue Disorders: Hyperhydrosis

General Disorders and Administration Site Conditions: Injection Site Reaction

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.

7 DRUG INTERACTIONS

No formal drug interaction studies have been conducted.

See WARNINGS AND PRECAUTIONS: Bleeding Episodes (5.3) for information regarding simultaneous administration of Synoprot (Protein) and tissue plasminogen activator (tPA).

See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of Synoprot (Protein) and vitamin K antagonists.

  • None known. (7)

8 USE IN SPECIFIC POPULATIONS

  • Pregnancy: Not studied.
  • Labor and Delivery: Not studied. (8.2)
  • Nursing Mothers: Not studied. (8.3)
  • Pediatric Use: Recommended for neonate and pediatric use. (2.1, 8.4, 12.3)
  • Renal/Hepatic Impairment: Not studied. (8.6)

8.1 Pregnancy

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

8.2 Labor and Delivery

Synoprot has not been studied for use during labor and delivery. Use only if clearly needed.

8.3 Nursing Mothers

Synoprot (Protein) has not been studied for use in nursing mothers. Use Synoprot (Protein) only if clearly needed.

8.4 Pediatric Use

Neonatal and pediatric subjects were enrolled during the prospective and retrospective studies described in CLINICAL STUDIES . Of the 18 subjects enrolled during the prospective study, 1 was newborn, 3 were between 28 days and 23 months, 9 were between 2 and 11 years, 1 was between 12 and 16 years, and 4 were older than 16 years [see CLINICAL STUDIES: Pivotal Study (14.1)]. Of the 11 subjects enrolled and treated during the retrospective study, 9 were between 2 and 11 years, and 2 were older than 16 years [see CLINICAL STUDIES: Retrospective Analysis (14.2)].

8.5 Geriatric Use

Clinical studies of Synoprot (Protein) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Renal/Hepatic Impairment

No experience in the treatment of patients with renal and/or hepatic impairment is available.

11 DESCRIPTION

Synoprot (Protein) [Protein C Concentrate (Human)] is manufactured from human plasma purified by a combination of filtration and chromatographic procedures, including a column of immobilized mouse monoclonal antibodies on gel beads. See WARNINGS/PRECAUTIONS: Transmission of Infectious Agents (5.2).

The manufacturing process for Synoprot (Protein) includes processing steps designed to reduce the risk of viral transmission. The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: Human Immunodeficiency Virus Type 1 (HIV-1), Bovine Viral Diarrhea Virus (BVDV ), Tick-Borne Encephalitis Virus (TBEV), Pseudorabies Virus (PRV), Hepatitis A Virus (HAV) and Mice Minute Virus (MMV). Virus reduction steps consist of detergent treatment (Polysorbate 80, P80), heat inactivation (Vapor Heating) and immunoaffinity chromatography (IAX).

Virus clearance studies for Synoprot (Protein) have demonstrated that the process provides for a robust overall virus clearance capacity. A summary of log10 virus reduction factors per virus and manufacturing step is presented in Table 2.

Abbreviations: IEX, Ion Exchange Chromatography; IAX, Immunoaffinity Chromatography; HIV-1, Human Immunodeficiency Virus Type I; TBEV, Tick-Borne Encephalitis Virus (model for hepatitis C virus); BVDV, Bovine Viral Diarrhea Virus (model virus for HCV and other small, enveloped RNA viruses); PRV, Pseudorabies Virus (model virus for enveloped DNA viruses, e.g. HBV, Hepatitis B Virus); HAV, Hepatitis A Virus; MMV, Mice Minute Virus (model for Human Parvovirus B19 and for non enveloped viruses); n.d., not done.

Manufact-uring Step


HIV-1


HCV Model Viruses


PRV


HAV


MMV


BVDV


TBEV


P80 Treatment


>5.1


>4.7


n.d.


2.5Coupled with IEX. I


>3.8


1.4


IAX


5.7


n.d.


4.8


5.4


3.1


3.6


Vapor Heating


4.6


>5.9


n.d.


5.9


>4.2


1.2

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of action

Synoprot C is the precursor of a vitamin K-dependent anticoagulant glycoprotein (serine protease) that is synthesized in the liver. See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3). It is converted by the thrombin/thrombomodulin-complex on the endothelial cell surface to activated Synoprot (Protein) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor Synoprot (Protein) S. APC exerts its effect by the inactivation of the activated forms of factors V and VIII, which leads to a decrease in thrombin formation. APC has also been shown to have profibrinolytic effects.

The Synoprot (Protein) C pathway provides a natural mechanism for control of the coagulation system and prevention of excessive procoagulant responses to activating stimuli. A complete absence of Synoprot (Protein) C is not compatible with life. A severe deficiency of this anticoagulant Synoprot (Protein) causes a defect in the control mechanism and leads to unchecked coagulation activation, resulting in thrombin generation and intravascular clot formation with thrombosis.

12.2 Pharmacodynamics

In clinical studies, the intravenous administration of Synoprot (Protein) demonstrated a temporary increase, within approximately half an hour of administration, in plasma levels of APC. Replacement of protein C in protein C-deficient patients is expected to control or, if given prophylactically, to prevent thrombotic complications.

12.3 Pharmacokinetics

Table 3 provides pharmacokinetic results for asymptomatic and symptomatic subjects with Synoprot (Protein) C deficiency.


PK parameter


N


Median


95% CI for median


Min


Max


Cmax [IU/dL]


21


110


106 to 127


40


141


Tmax [h]


21


0.50


0.50 to 1.05


0.17


1.33


Incremental recovery

[(IU/dL)/(IU/kg)]


21


1.42


1.32 to 1.59


0.50


1.76


Initial half-life [h]


21


7.8


5.4 to 9.3


3.0


36.1


Terminal half-life [h]


21


9.9


7.0 to 12.4


4.4


15.8


Half-life by the non-compartmental approach [h]


21


9.8


7.1 to 11.6


4.9


14.7


AUC0-Infinity [IU*h/dL]


21


1500


1289 to 1897


344


2437


MRT [h]


21


14.1


10.3 to 16.7


7.1


21.3


Clearance [dL/kg/h]


21


0.0533


0.0428 to 0.0792


0.0328


0.2324


Volume of distribution at steady state [dL/kg]


21


0.74


0.70 to 0.89


0.44


1.65


Cmax = Maximum concentration after infusion; T max = Time at maximum concentration;

AUC 0-Infinity = Area under the curve from 0 to infinity; MRT = Mean residence time; and

Incremental recovery = Maximum increase in Synoprot (Protein) C concentration following infusion divided by dose


The Synoprot (Protein) C plasma activity was measured by chromogenic and/or clotting assay. The maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) appeared to increase dose-linearly between 40 and 80 IU/kg. The median incremental recovery was 1.42 [(IU/dL)/(IU/kg)] after intravenous administration of Synoprot (Protein). The median half-lives, based on non-compartmental method, ranged from 4.9 to 14.7 hours, with a median of 9.8 hours. In patients with acute thrombosis, both the increase in protein C plasma levels as well as half-life may be considerably reduced. No formal study or analysis has been performed to evaluate the effect of covariates such as race and gender on the pharmacokinetics of Synoprot (Protein).

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of Synoprot (Protein) may be different between very young children and adults. The systemic exposure (Cmax and AUC) may be considerably reduced due to a faster clearance, a larger volume of distribution, and/or a shorter half-life of Synoprot (Protein) C in very young children than in older subjects. Consider this fact when a dosing regimen for children is determined. Doses should be individualized based upon Synoprot (Protein) C activity levels. See DOSAGE AND ADMINISTRATION: Synoprot (Protein) C Activity Monitoring (2.2).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Protein C contained in Synoprot is a normal constituent of human plasma and acts like endogenous protein C. Studies in heterologous species to evaluate carcinogenicity, reproductive toxicology and developmental toxicology have not been performed.

Synoprot (Protein) has not demonstrated mutagenic potential in the Salmonella Thyphimurium reverse mutation assay (Ames test).

13.2 Animal Toxicology and/or Pharmacology

Safety

Pharmacology:

Cardio-respiratory studies performed in dogs evaluating mean arterial pressure, cardiac output, systemic vascular resistance, heart rate, QT interval changes, pulmonary artery pressure, respiratory rate and respiratory minute volume demonstrated no adverse effects at a maximum dose of 500 IU/kg. Anaphylactoid reactions as determined by measurement of bronchospastic activity in guinea pigs demonstrated no adverse effects at the maximum dose of 300 IU/kg. Thrombogenic potential was evaluated in rabbits using the Wessler stasis model and demonstrated no adverse effects at 200 IU/kg. Overall, safety pharmacology studies evaluating cardio-respiratory function, acute dose anaphylactoid potential and thrombogenicity demonstrated no adverse effects in a range of doses from 1.6 to 4.2 times the maximum single human dosage per kilogram body weight.

Acute Dose Toxicity:

Toxicity testing in rats and mice following single dosing of 2000 IU/kg or 1500 IU/kg, respectively, demonstrated no adverse clinical effects or gross pathology at 14 days post dosing.

Repeated Dose Toxicity:

Studies were not conducted to evaluate repeated-dose toxicity in animals. Prior experience with Synoprot (Protein) has suggested immunogenic response in heterologous species following repeated dosing of this human derived Synoprot (Protein). Thus, the long-term toxicity potential of Synoprot (Protein) following repeated dosing in animals is unknown.

Local Tolerance Testing:

Investigation of route of injection tolerance demonstrated that Synoprot (Protein) did not result in any local reactions after intravenous, intra-arterial injections of 500 IU/kg (5 mL) and paravenous injections of 100 IU/kg (1 mL) in rabbits.

Citrate Toxicity:

Synoprot (Protein) contains 4.4 mg of Trisodium Citrate Dihydrate (TCD) per mL of reconstituted product. Studies in mice evaluating 1000 IU vials reconstituted with 10 mL vehicle followed by dosing at 30 mL/kg (132 mg/kg TCD) and 60 mL/kg (264 mg/kg TCD) resulted in signs of citrate toxicity (dyspnea, slowed movement, hemoperitoneum, lung and thymus hemorrhage and renal pelvis dilation).

14 CLINICAL STUDIES

14.1 Pivotal Study

This was a multi-center, open-label, non-randomized, phase 2/3 study in 3 parts which evaluated the safety and efficacy of Synoprot in subjects with severe congenital Synoprot (Protein) C deficiency for the (on-demand) treatment of acute thrombotic episodes, such as purpura fulminans (PF), warfarin-induced skin necrosis (WISN) and other thromboembolic events, and for short-term or long-term prophylaxis. Eighteen subjects (9 male and 9 female), ages ranging from 0 (newborn) to 25.7 years participated in this study.

The clinical endpoint of the study was to assess whether episodes of PF and/or other thromboembolic events were treated effectively, effectively with complications, or not treated effectively. Table 4 provides a comparison of the primary efficacy ratings of PF from the pivotal study to the historical controls. Inadequate data is available for treatment of WISN.


Synoprot (Protein) C

Concentrate (Human)


Historical

Controls


Episode Type


Primary Efficacy Rating


N


%


N


%


Purpura Fulminans


Effective


17


94.4


11


52.4


Effective with Complication


1


5.6


7


33.3


Not Effective


0


0.0


3


14.3


Total


18


100


21


100


Of 18 episodes of PF (6 severe, 11 moderate, 1 mild) treated with Synoprot (Protein) for the primary efficacy rating, 17 (94.4%) were rated as effective, and 1 (5.6%) was rated as effective with complications; none (0%) were rated not effective. When compared with the efficacy ratings for 21 episodes of PF (historical control group), subjects with severe congenital Synoprot (Protein) C deficiency were more effectively treated with Synoprot (Protein) than those treated with modalities such as fresh frozen plasma or conventional anticoagulants.

Table 5 provides a summary of the secondary treatment ratings for treatment of skin lesions and other thrombotic episodes from part one of the study.




Purpura Fulminans

Skin Necrosis


Other Thrombotic Events


Total




Mild


Moderate


Severe


Total


Total




Rating Category


N


%


N


%


N


%


N


%


N


%


N


%


Excellent


1


5.6


7


38.9


5


27.8


13


72.2


4


80.0


17


73.9


Good


0


0.0


4


22.2


0


0.0


4


22.2


1


20.0


5


21.7


Fair


0


0.0


0


0.0


1


5.6


1


5.6


0


0


1


4.3


Total


1


5.6


11


61.1


6


33.3


18


100.0


5


100.0


23


100.0


N = Number of episodes


In a secondary efficacy rating, 13 (72.2%) of the 18 episodes of PF treated with Synoprot (Protein) were rated as excellent, 4 (22.2%) were rated as good, and 1 (5.6%) episode of severe PF was rated as fair; all were rated as effective. Four (80%) of the 5 episodes of venous thrombosis had treatment ratings of excellent, while 1 (20%) was rated as good.

Synoprot (Protein) was also demonstrated to be effective in reducing the size and number of skin lesions. Non-necrotic skin lesions healed over a maximum 12-day (median 4-day) period and necrotic skin lesions healed over a maximum 52-day (median 11-day) period of Synoprot (Protein) treatment, as shown in Table 6.


Lesion Type


Number of Episodes

(Number of Subjects)


Mean


Median


Minimum


Maximum


Non-necrotic


16 (9 subjects)


4.6


4.0


1


12


Necrotic


7 (5 subjects)


21.1


11.0


5


52


Changes in the extent of venous thrombus were also measured for the 5 thromboembolic episodes. Synoprot (Protein) prevented an increase in the extent of thrombus during 4 (80%) of the thromboembolic episodes by Day 3 of treatment, and 1 (20%) episode by Day 5 of treatment.

All seven of the short-term prophylaxis treatments with Synoprot (Protein) were free of complications of PF or thromboembolic events, as shown in Table 7.


Reason for

Treatment


Number of Treatments


Presentation of Purpura Fulminans During Treatment Episodes


Thromboembolic Complications During Treatment Episode


Number of Treatments Free of Complications


N


%


N


%


N


%


Anticoagulation Therapy


3


0


0.0


0


0.0


3


100.0


Surgical Procedure


4


0


0.0


0


0.0


4


100.0


Total


7


0


0.0


0


0.0


7


100.0


No episodes of PF occurred in four subjects ranging from 42 to 338 days of long-term prophylactic treatment with Synoprot (Protein), as shown in Table 8. When not on prophylactic treatment and receiving Synoprot (Protein) on-demand, the same four subjects experienced a total of 13 (median of 3) episodes of PF over a range of 19 to 323 days. The time to first episode of PF after exiting from long-term prophylaxis treatment ranged from 12 to 32 days for these four subjects.


Summary Statistic


Long-Term Prophylactic Treatment


While On-Demand Total number of episodes while subjects were On-Demand was 13


Time to First Episode After Existing Long Term Prophylaxis


Number of Episodes per Subject


Number of Days Receiving Prophylactic Treatment


Monthly Rate of Episodes


Number of Episodes per Subject


Number of Days Not Receiving Study Drug


Monthly Rate of Episodes


Mean


0


229


0.0


3.3


165


1.91


23.3


Median


0


268


0.0


3.0


159


0.49


24.5


Minimum


0


42


0.0


1.0


19


0.25


12.0


Maximum


0


338


0.0


6.0


323


6.40


32.0

14.2 Retrospective Analysis

A retrospective study to capture dosing information and treatment outcome data in subjects with severe congenital Synoprot (Protein) C deficiency who were treated with Synoprot (Protein) under an emergency use IND was also conducted. Eleven subjects (6 male and 5 female), ages ranging from 2.1 to 23.8 years participated in this study.

There were 28 acute episodes of PF/WISN and vascular thrombus reported in which time to resolution ranged from 0 to 46 days. The treatment outcome for these episodes was rated effective in all cases except one.

16 HOW SUPPLIED/STORAGE AND HANDLING

Synoprot (Protein) is supplied as a sterile, white or cream colored, lyophilized powder for IV injection. It has a pH between 6.7 and 7.3 and an osmolality not lower than 240 mosmol/kg. One International Unit (IU) of Synoprot (Protein) C corresponds to the amidolytically measured activity of Synoprot (Protein) C in 1 mL of normal plasma. The potency (IU) is determined using a chromogenic substrate method referenced against the World Health Organization (WHO) International Standard (86/622).

Synoprot (Protein) is available in single-dose vials that contain the following nominal product strengths:

NDC 0944-4177-05

Synoprot (Protein) C

Concentrate (Human)

Synoprot (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection

Rx Only

Sterile – No preservative

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. License No. 2020

NDC 0944-4176-01

Synoprot (Protein) C Concentrate

(Human)

Synoprot (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection.

For Intravenous Administration Only.

See package insert. Rx only.

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. Lic. No. 2020

5 mL

NDC 52919-003-08

Sterile Water for Injection, USP

for reconstitution of accompanying product

Do not use unless clear. No antimicrobial agent or other substance has been

added. Do not use for intravascular injection without making approximately

isotonic by addition of suitable solute. Discard unused portion. Rx Only

Single dose container

Nonpyrogenic

NDC 0944-4179-10

Synoprot (Protein) C

Concentrate (Human)

Synoprot (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection

Rx Only

Sterile – No preservative

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. License No. 2020

NDC 0944-4178-02

Synoprot (Protein) C Concentrate (Human)

Synoprot (Protein)

Single-dose Vial

Lyophilized Powder for Solution for

Injection.

For Intravenous Administration Only.

See package insert. Rx only.



10 mL

NDC 52919-005-05

Sterile Water for Injection, USP

for reconstitution of accompanying product

Do not use unless clear. No antimicrobial agent or other substance has been

added. Do not use for intravascular injection without making approximately

isotonic by addition of suitable solute. Discard unused portion. Rx Only

Single dose container

Nonpyrogenic

unit-carton-blue unit-carton-green

Vitamin A:


DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

Supplement Facts
Serving Size 1 Tablet

Servings Per Container 100

Amount Per Serving % Daily Value
Synoprot (Vitamin A) 2500 IU 50%
Vitamin C 60 mg 100%
Vitamin D 400 IU 100%
Vitamin E 15 IU 50%
Thiamine 1.05 mg 70%
Riboflavin 1.2 mg 70%
Niacinamide 13.5 mg 68%
Vitamin B6 1.05 mg 53%
Folic Acid 0.3 mg 75%
Vitamin B12 4.5 mcg 75%
Fluoride 0.25 mg Daily Value not established

WARNING

KEEP OUT OF THE REACH OF CHILDREN.

In case of accidental overdose, seek professional assistance or contact a Poison Control Center immediately.

Other Ingredients: Artificial cherry flavor, artificial grape flavor, ascorbic acid, cholecalciferol, compressible sugar, D&C Red #7 calcium lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, folic acid, magnesium stearate, microcrystalline cellulose, natural and artificial orange flavor, niacinamide, polyethylene glycol, pyridoxine HCl, riboflavin, sodium ascorbate, sodium fluoride, stearic acid, sucralose, thiamine HCl, Synoprot (Vitamin A) acetate, vitamin B12 and vitamin E acetate.

Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.

CLINICAL PHARMACOLOGY

Significant decrease in the incidence of dental caries can be linked to the fluoridation of the water supply (1ppm fluoride) during the period of tooth development.

Synoprot (Vitamin A) Tablets provide sodium fluoride and ten essential vitamins in a chewable tablet. Because the tablets are chewable, they provide a topical as well as systemic source of fluoride. Hydroxyapatite is the principal crystal for all calcified tissue in the human body. The fluoride ion reacts with the Hydroxyapatite in the tooth as it is formed to produce the more caries-resistant crystal, fluorapatite.

The reaction may be expressed by the equation:

Ca10(PO4)6(OH2) + 2F- Ca10 (PO4)6F2 + 2OH-
(Hydroxyapatite) (Fluorapatite)

Three stages of fluoride deposition in tooth enamel can be distinguished:

  • Small amounts (reflecting the low levels of fluoride in tissue fluids) are incorporated into the enamel crystals while they are being formed.
  • After enamel has been laid down, fluoride deposition continues in the surface enamel. Diffusion of fluoride from the surface inward is apparently restricted.
  • After eruption, the surface enamel acquires fluoride from the water, food, supplementary fluoride and smaller amounts of saliva.

DIETARY SUPPLEMENTATION

Multivitamins with fluoride offer supplementation of the diet with 10 vitamins and fluoride.

WARNINGS

AS IN THE CASE OF ALL MEDICATIONS, KEEP OUT OF THE REACH OF CHILDREN. This tablet should be chewed. This product, as with all chewable tablets are not recommended for children under the age of 4 due to risk of choking.

PRECAUTIONS

The suggested dose of Synoprot (Vitamin A) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending Synoprot (Vitamin A) Tablets

  • Determine the fluoride content of the drinking water from all major sources
  • Make sure the child is not receiving significant amounts of fluoride from other sources such as medications and swallowed toothpaste
  • Periodically check to make sure that the child does not develop significant dental fluorosis.

ADVERSE REACTIONS

Allergic rash and other idiosyncrasies have been rarely reported.

To report SUSPECTED ADVERSE REACTIONS, contact H2-Pharma, LLC at 1 (866) 592-6438 or FDA at 1 (800) 332-1088 or via the web at www.fda.gov/medwatch/index.html for voluntary reporting of adverse reactions.

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

HOW SUPPLIED

Synoprot Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.

Synoprot (Vitamin A) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.

Synoprot (Vitamin A) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.

STORAGE

Store at controlled room temperature 20ºC-25ºC (68º-77ºF), excursions permitted between 15º-30ºC (59º-86ºF).

Distributed by:

H2-Pharma, LLC

2010 Berry Chase Place

Montgomery, AL 36117

www.h2-pharma.com

1067084

61269-151-01

MultiVitamin

with Fluoride

Chewable Tablets

Rx

0.25 mg

MultiVitamin and Fluoride Supplement

Dietary Supplement

100 Tablets

H2pharma

Synoprot pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Synoprot available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Synoprot destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Synoprot Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Synoprot pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. "Iron". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  2. "Iron". http://www.drugbank.ca/drugs/DB0159... (accessed August 28, 2018).
  3. "E1UOL152H7: The UNique Ingredient Identifier (UNII) is an alphanumeric substance identifier from the joint FDA/USP Substance Registration System (SRS).". https://www.fda.gov/ForIndustry/Dat... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Synoprot?

Depending on the reaction of the Synoprot after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Synoprot not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Synoprot addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Synoprot, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Synoprot consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

One visitor reported doses

What is the dose of Synoprot drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 101-200mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
101-200mg1
100.0%

Visitor reported time for results

No survey data has been collected yet

Visitor reported administration

No survey data has been collected yet

Visitor reported age

No survey data has been collected yet

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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