Unifer

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Unifer uses

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

1 INDICATIONS AND USAGE

Unifer is indicated for the treatment of Unifer deficiency anemia in patients with chronic kidney disease (CKD).

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

2 DOSAGE AND ADMINISTRATION

Unifer must only be administered intravenously either by slow injection or by infusion. The dosage of Unifer is expressed in mg of elemental Unifer. Each mL contains 20 mg of elemental Unifer.

Population		Dose
Adult patients	Hemodialysis Dependent-Chronic Kidney Disease (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 Unifer 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. Unifer should be administered early during the dialysis session. The usual total treatment course of Unifer is 1000 mg. Unifer treatment may be repeated if Unifer deficiency reoccurs.

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

Administer Unifer 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 Unifer, 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. Unifer treatment may be repeated if Unifer deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Unifer 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 Unifer in a maximum of 250 mL of 0.9% NaCl. Unifer treatment may be repeated if Unifer deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Unifer maintenance treatment

The dosing for Unifer replacement treatment in pediatric patients with HDD-CKD has not been established.

For Unifer maintenance treatment: Administer Unifer 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. Unifer treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Unifer maintenance treatment

The dosing for Unifer replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Unifer maintenance treatment: Administer Unifer 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. Unifer treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Unifer (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Unifer (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Unifer (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Unifer (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Unifer (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Unifer (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Unifer

• Known hypersensitivity to Unifer (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

Unifer may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Unifer. Hypotension following administration of Unifer may be related to the rate of administration and/or total dose administered .

5.3 Unifer Overload

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

6 ADVERSE REACTIONS

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

• The most common adverse reactions (≥2%) following the administration of Unifer 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 Unifer 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 Unifer 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	HDD-CKD	NDD-CKD		PDD-CKD
	Unifer	Unifer	Oral Unifer	Unifer	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 Unifer therapy and were reported to be intolerant (defined as precluding further use of that Unifer product). When these patients were treated with Unifer there were no occurrences of adverse reactions that precluded further use of Unifer .

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

A total of 5 (11%) subjects in the Unifer 0.5 mg/kg group, 10 (21%) patients in the Unifer 1.0 mg/kg group, and 10 (21%) patients in the Unifer 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 Unifer. 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 Unifer 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 Unifer injection. Reactions have occurred following the first dose or subsequent doses of Unifer. 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 Unifer have not been studied. However, Unifer may reduce the absorption of concomitantly administered oral Unifer 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, Unifer sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Unifer and revealed no evidence of harm to the fetus due to Unifer sucrose. Because animal reproductive studies are not always predictive of human response, Unifer should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness of Unifer for Unifer replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

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

Unifer has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

Clinical studies of Unifer 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 Unifer, 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 Unifer in humans. Excessive dosages of Unifer may lead to accumulation of Unifer in storage sites potentially leading to hemosiderosis. Do not administer Unifer to patients with Unifer overload.

Toxicities in single-dose studies in mice and rats, at intravenous Unifer 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

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

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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

Following intravenous administration of Unifer, Unifer sucrose is dissociated into Unifer and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Unifer containing 1,510 mg of sucrose and 100 mg of Unifer in 12 healthy adults, 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Unifer 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 Unifer sucrose containing 500 to 700 mg of Unifer in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Unifer was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Unifer have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

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

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

Unifer sucrose at intravenous doses up to 15 mg/kg/day of elemental Unifer (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 Unifer.

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Unifer treatment and 24 in the historical control group) with Unifer deficiency anemia. Eligibility criteria for Unifer 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.

Unifer 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 Unifer, who were off intravenous Unifer 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 Unifer 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
	Unifer (n=69	Historical Control (n=18)	Unifer (n=73)	Historical Control (n=18)	Unifer (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 Unifer in 23 patients with Unifer deficiency and HDD-CKD who had been discontinued from Unifer 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 Unifer. Exclusion criteria were similar to those in studies A and B. Unifer was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Unifer 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 Unifer versus Unifer 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 Unifer (325 mg ferrous sulfate three times daily for 56 days); or Unifer (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 Unifer 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 Unifer group.

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

Unifer is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Unifer, each 5 mL vial contains 100 mg elemental Unifer, and each 2.5 mL vial contains 50 mg elemental Unifer.

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

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Unifer is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Unifer pharmaceutical active ingredients containing related brand and generic drugs:

• Iron (Ferrous Gluceptate)

Unifer available forms, composition, doses:

• Drops; Oral; Iron (Ferrous Gluceptate) 25 mg / ml
• Syrup; Oral; Iron (Ferrous Gluceptate) 55 mg / 5 ml

Unifer destination | category:

• Human:
• Iron preparations

Unifer Anatomical Therapeutic Chemical codes:

• B03A - Iron preparations

Unifer pharmaceutical companies:

• Rider Laboratorios

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 Unifer?

Depending on the reaction of the Unifer after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Unifer 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 Unifer 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.

Review

sdrugs.com conducted a study on Unifer, 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 Unifer 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.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology