Marpro-Z

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Marpro-Z uses

Marpro-Z consists of Iron (Iron Choline Citrate), Magnesium Chloride, Manganese (Manganese Chloride), Protein Hydrolysate, Vitamin B1, Vitamin B2, Vitamin B3 (Niacinamide), Vitamin B5 (D-Panthenol), Vitamin B6, Zinc.

Iron (Iron Choline Citrate):


1 INDICATIONS AND USAGE

Marpro-Z (Iron (Iron Choline Citrate)) is indicated for the treatment of Marpro-Z (Iron (Iron Choline Citrate)) deficiency anemia in patients with chronic kidney disease (CKD).

Marpro-Z (Iron (Iron Choline Citrate)) is an Marpro-Z (Iron (Iron Choline Citrate)) replacement product indicated for the treatment of Marpro-Z (Iron (Iron Choline Citrate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Marpro-Z ) must only be administered intravenously either by slow injection or by infusion. The dosage of Marpro-Z (Iron (Iron Choline Citrate)) is expressed in mg of elemental Marpro-Z (Iron (Iron Choline Citrate)). Each mL contains 20 mg of elemental Marpro-Z (Iron (Iron Choline 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 Marpro-Z (Iron (Iron Choline 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. Marpro-Z (Iron (Iron Choline Citrate)) should be administered early during the dialysis session. The usual total treatment course of Marpro-Z (Iron (Iron Choline Citrate)) is 1000 mg. Marpro-Z (Iron (Iron Choline Citrate)) treatment may be repeated if Marpro-Z (Iron (Iron Choline Citrate)) deficiency reoccurs.

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

Administer Marpro-Z (Iron (Iron Choline 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 Marpro-Z (Iron (Iron Choline 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. Marpro-Z (Iron (Iron Choline Citrate)) treatment may be repeated if Marpro-Z (Iron (Iron Choline Citrate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Marpro-Z (Iron (Iron Choline 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 Marpro-Z (Iron (Iron Choline Citrate)) in a maximum of 250 mL of 0.9% NaCl. Marpro-Z (Iron (Iron Choline Citrate)) treatment may be repeated if Marpro-Z (Iron (Iron Choline Citrate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Marpro-Z (Iron (Iron Choline Citrate)) maintenance treatment

The dosing for Marpro-Z (Iron (Iron Choline Citrate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Marpro-Z (Iron (Iron Choline Citrate)) maintenance treatment: Administer Marpro-Z (Iron (Iron Choline 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. Marpro-Z (Iron (Iron Choline Citrate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Marpro-Z (Iron (Iron Choline Citrate)) maintenance treatment

The dosing for Marpro-Z (Iron (Iron Choline Citrate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Marpro-Z (Iron (Iron Choline Citrate)) maintenance treatment: Administer Marpro-Z (Iron (Iron Choline 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. Marpro-Z (Iron (Iron Choline Citrate)) treatment may be repeated if necessary.

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3 DOSAGE FORMS AND STRENGTHS

  • 10 mL single-use vial / 200 mg elemental Marpro-Z (Iron (Iron Choline Citrate)) (20 mg/mL)
  • 5 mL single-use vial / 100 mg elemental Marpro-Z (Iron (Iron Choline Citrate)) (20 mg/mL)
  • 2.5 mL single-use vial / 50 mg elemental Marpro-Z (Iron (Iron Choline Citrate)) (20 mg/mL)
  • 10 mL single-use vial / 200 mg elemental Marpro-Z (Iron (Iron Choline Citrate)) (20 mg/mL) (3)
  • 5 mL single-use vial / 100 mg elemental Marpro-Z (Iron (Iron Choline Citrate)) (20 mg/mL) (3)
  • 2.5 mL single-use vial / 50 mg elemental Marpro-Z (Iron (Iron Choline Citrate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

  • Known hypersensitivity to Marpro-Z (Iron (Iron Choline Citrate))
  • Known hypersensitivity to Marpro-Z (Iron (Iron Choline Citrate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

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

5.3 Marpro-Z (Iron (Iron Choline Citrate)) Overload

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

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6 ADVERSE REACTIONS

The following serious adverse reactions associated with Marpro-Z ) are described in other sections .

  • The most common adverse reactions (≥2%) following the administration of Marpro-Z (Iron (Iron Choline 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 Marpro-Z ) 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 Marpro-Z (Iron (Iron Choline 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
Marpro-Z (Iron (Iron Choline Citrate)) Marpro-Z (Iron (Iron Choline Citrate)) Oral Marpro-Z (Iron (Iron Choline Citrate)) Marpro-Z (Iron (Iron Choline 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 Marpro-Z (Iron (Iron Choline Citrate)) therapy and were reported to be intolerant (defined as precluding further use of that Marpro-Z (Iron (Iron Choline Citrate)) product). When these patients were treated with Marpro-Z (Iron (Iron Choline Citrate)) there were no occurrences of adverse reactions that precluded further use of Marpro-Z (Iron (Iron Choline 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 Marpro-Z (Iron (Iron Choline Citrate)) maintenance treatment with Marpro-Z (Iron (Iron Choline 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 Marpro-Z (Iron (Iron Choline Citrate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Marpro-Z (Iron (Iron Choline Citrate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Marpro-Z (Iron (Iron Choline Citrate)) 2.0 mg/kg.

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

Safety and effectiveness of Marpro-Z (Iron (Iron Choline Citrate)) for Marpro-Z (Iron (Iron Choline 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. Marpro-Z (Iron (Iron Choline 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)]

Marpro-Z (Iron (Iron Choline Citrate)) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

Clinical studies of Marpro-Z (Iron (Iron Choline 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 Marpro-Z (Iron (Iron Choline 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 Marpro-Z (Iron (Iron Choline Citrate)) in humans. Excessive dosages of Marpro-Z (Iron (Iron Choline Citrate)) may lead to accumulation of Marpro-Z (Iron (Iron Choline Citrate)) in storage sites potentially leading to hemosiderosis. Do not administer Marpro-Z (Iron (Iron Choline Citrate)) to patients with Marpro-Z (Iron (Iron Choline Citrate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Marpro-Z (Iron (Iron Choline 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

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

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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

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

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

Marpro-Z (Iron (Iron Choline Citrate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Marpro-Z (Iron (Iron Choline 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 Marpro-Z ).

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 Marpro-Z (Iron (Iron Choline Citrate)) treatment and 24 in the historical control group) with Marpro-Z (Iron (Iron Choline Citrate)) deficiency anemia. Eligibility criteria for Marpro-Z (Iron (Iron Choline 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.

Marpro-Z (Iron (Iron Choline 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 Marpro-Z (Iron (Iron Choline Citrate)), who were off intravenous Marpro-Z (Iron (Iron Choline 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 Marpro-Z (Iron (Iron Choline 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
Marpro-Z (Iron (Iron Choline Citrate)) (n=69 Historical Control (n=18) Marpro-Z (Iron (Iron Choline Citrate))

(n=73)

Historical Control

(n=18)

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

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

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

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Marpro-Z (Iron (Iron Choline Citrate)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx®

IN2340

MG #15727

Magnesium Chloride:



Marpro-Z (Magnesium Chloride) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Marpro-Z (Magnesium Chloride) Sulfate Injection, USP is a sterile solution of Marpro-Z (Magnesium Chloride) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Marpro-Z (Magnesium Chloride) Sulfate, USP heptahydrate is chemically designated MgSO4 - 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Marpro-Z (Magnesium Chloride) (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Marpro-Z (Magnesium Chloride) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Marpro-Z (Magnesium Chloride). While there are large stores of Marpro-Z (Magnesium Chloride) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Marpro-Z (Magnesium Chloride) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Marpro-Z (Magnesium Chloride) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Marpro-Z (Magnesium Chloride) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Marpro-Z (Magnesium Chloride) levels range from 1.5 to 2.5 mEq/liter.

As plasma Marpro-Z (Magnesium Chloride) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Marpro-Z (Magnesium Chloride). Serum Marpro-Z (Magnesium Chloride) concentrations in excess of 12 mEq/L may be fatal.

Marpro-Z (Magnesium Chloride) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Marpro-Z (Magnesium Chloride) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Marpro-Z (Magnesium Chloride) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Marpro-Z (Magnesium Chloride) Sulfate Injection, USP is suitable for replacement therapy in Marpro-Z (Magnesium Chloride) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Marpro-Z (Magnesium Chloride) (Mg++) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca++) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Marpro-Z (Magnesium Chloride) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Marpro-Z (Magnesium Chloride) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Marpro-Z (Magnesium Chloride) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Marpro-Z (Magnesium Chloride) sulfate should be used during pregnancy only if clearly needed. If Marpro-Z (Magnesium Chloride) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Marpro-Z (Magnesium Chloride) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Marpro-Z (Magnesium Chloride) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Marpro-Z (Magnesium Chloride), their dosage should be adjusted with caution because of additive CNS depressant effects of Marpro-Z (Magnesium Chloride).

Because Marpro-Z (Magnesium Chloride) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Marpro-Z (Magnesium Chloride) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Marpro-Z (Magnesium Chloride) should be given until they return. Serum Marpro-Z (Magnesium Chloride) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Marpro-Z (Magnesium Chloride) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Marpro-Z (Magnesium Chloride) intoxication in eclampsia.

50% Marpro-Z (Magnesium Chloride) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Marpro-Z (Magnesium Chloride) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Marpro-Z (Magnesium Chloride) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Marpro-Z (Magnesium Chloride), their dosage should be adjusted with caution because of additive CNS depressant effects of Marpro-Z (Magnesium Chloride). CNS depression and peripheral transmission defects produced by Marpro-Z (Magnesium Chloride) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Marpro-Z (Magnesium Chloride) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Marpro-Z (Magnesium Chloride) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Marpro-Z (Magnesium Chloride) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Marpro-Z (Magnesium Chloride) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Marpro-Z (Magnesium Chloride) sulfate for more than 5 to 7 days.1-10 Marpro-Z (Magnesium Chloride) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Marpro-Z (Magnesium Chloride) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Marpro-Z (Magnesium Chloride) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Marpro-Z (Magnesium Chloride) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Marpro-Z (Magnesium Chloride) is distributed into milk during parenteral Marpro-Z (Magnesium Chloride) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Marpro-Z (Magnesium Chloride) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Marpro-Z (Magnesium Chloride) usually are the result of Marpro-Z (Magnesium Chloride) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Marpro-Z (Magnesium Chloride) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Marpro-Z (Magnesium Chloride) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Marpro-Z (Magnesium Chloride) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Marpro-Z (Magnesium Chloride).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Marpro-Z (Magnesium Chloride) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Marpro-Z (Magnesium Chloride) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Marpro-Z (Magnesium Chloride) Deficiency

In the treatment of mild Marpro-Z (Magnesium Chloride) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Marpro-Z (Magnesium Chloride) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Marpro-Z (Magnesium Chloride) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Marpro-Z (Magnesium Chloride) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Marpro-Z (Magnesium Chloride) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Marpro-Z (Magnesium Chloride) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Marpro-Z (Magnesium Chloride) sulfate is 20 grams/48 hours and frequent serum Marpro-Z (Magnesium Chloride) concentrations must be obtained. Continuous use of Marpro-Z (Magnesium Chloride) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Marpro-Z (Magnesium Chloride) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Marpro-Z (Magnesium Chloride) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Marpro-Z (Magnesium Chloride) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Marpro-Z (Magnesium Chloride) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

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

HOW SUPPLIED

Marpro-Z (Magnesium Chloride) Sulfate Injection, USP is supplied in single-dose containers as follows:


NDC No.


Container


Total

Amount


Concentration


mEq

Mg++/mL


0409-1754-10


Ansyr

Plastic Syringe


5 g/10 mL


50%


4 mEq/mL


Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

  • Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Marpro-Z (Magnesium Chloride) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
  • Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Marpro-Z (Magnesium Chloride) toxicity. J. Perinatol. 2006; 26(6):371-4.
  • Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Marpro-Z (Magnesium Chloride) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
  • Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Marpro-Z (Magnesium Chloride) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
  • Matsuda Y, Maeda Y, Ito M, et al. Effect of Marpro-Z (Magnesium Chloride) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
  • Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Marpro-Z (Magnesium Chloride) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
  • Santi MD, Henry GW, Douglas GL. Marpro-Z (Magnesium Chloride) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
  • Holcomb WL, Shackelford GD, Petrie RH. Marpro-Z (Magnesium Chloride) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
  • Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
  • Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Marpro-Z (Magnesium Chloride) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Marpro-Z (Magnesium Chloride) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
  • Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Marpro-Z (Magnesium Chloride) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

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50% Marpro-Z (Magnesium Chloride) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Marpro-Z (Magnesium Chloride) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Manganese (Manganese Chloride):


INDICATIONS AND USAGE

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

Administration helps to maintain Marpro-Z (Manganese (Manganese Chloride)) serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

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

Liver and/or biliary tract dysfunction may require omission or reduction of copper and Marpro-Z (Manganese (Manganese Chloride)) doses because these elements are primarily eliminated in the bile.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

General

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

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

Laboratory Tests

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

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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

Nursing Mothers

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

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Pregnancy Category C.

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

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Marpro-Z (Manganese (Manganese Chloride)) toxicity in TPN patients has not been reported.

DOSAGE AND ADMINISTRATION

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

Periodic monitoring of Marpro-Z (Manganese (Manganese Chloride)) plasma levels is suggested as a guideline for subsequent administration.

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

HOW SUPPLIED

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

Store at 20 to 25°C (68 to 77°F)

Revised: November, 2009

Printed in USA EN-2320

Hospira, Inc., Lake Forest, IL 60045 USA

RL-0104


Protein Hydrolysate:


1 INDICATIONS AND USAGE

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

1.1 Severe Congenital Marpro-Z (Protein Hydrolysate) C Deficiency

Marpro-Z (Protein Hydrolysate) is indicated for pediatric and adult patients with severe congenital Marpro-Z (Protein Hydrolysate) 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 Marpro-Z C activity is feasible. (2.1)


Marpro-Z (Protein Hydrolysate) 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 ProphyaxisMarpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of Marpro-Z (Protein Hydrolysate) C activity is feasible.

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

Table 1 provides the Marpro-Z (Protein Hydrolysate) 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 ProphylaxisMarpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough Marpro-Z (Protein Hydrolysate) C activity level above 25% for the duration of treatment.

In patients receiving prophylactic administration of Marpro-Z (Protein Hydrolysate), higher peak Marpro-Z (Protein Hydrolysate) C activity levels may be warranted in situations of an increased risk of thrombosis (such as infection, trauma, or surgical intervention). Maintenance of trough Marpro-Z (Protein Hydrolysate) 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 Marpro-Z C Activity Monitoring

The measurement of Marpro-Z (Protein Hydrolysate) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of Marpro-Z (Protein Hydrolysate) C before and during treatment with Marpro-Z (Protein Hydrolysate). The half-life of Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the Marpro-Z (Protein Hydrolysate) C levels to maintain the trough Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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 Marpro-Z C, itself a vitamin K-dependent plasma Marpro-Z (Protein Hydrolysate), 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 Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) [Protein C Concentrate (Human)]

Reconstitution: Use Aseptic Technique

  • Bring the Marpro-Z (Protein Hydrolysate) (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
  • Remove caps from the Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) vial; then rapidly insert the free end of the needle through the Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) vial. Gently swirl the vial until all powder is dissolved. Be sure that Marpro-Z (Protein Hydrolysate) is completely dissolved; otherwise, active materials will be removed by the filter needle.

2.5 Administration of Marpro-Z [Protein C Concentrate (Human)]

Administration: Use Aseptic Technique

Visually inspect Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate).
  • Inject air into the vial and then withdraw the reconstituted Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) is administered to a patient.

Administration by Infusion

Administer Marpro-Z (Protein Hydrolysate) 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

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

Marpro-Z (Protein Hydrolysate), 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

Marpro-Z (Protein Hydrolysate) may contain traces of mouse Marpro-Z (Protein Hydrolysate) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse Marpro-Z (Protein Hydrolysate) 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 Marpro-Z 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 Marpro-Z (Protein Hydrolysate) further contributed to these bleeding events.

Simultaneous administration of Marpro-Z (Protein Hydrolysate) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.

5.4 Heparin-induced Thrombocytopenia

Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) C deficiency. Determine the platelet count immediately and consider discontinuation of Marpro-Z (Protein Hydrolysate).

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 Marpro-Z (Protein Hydrolysate) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

The common adverse reactions related to Marpro-Z 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 Marpro-Z (Protein Hydrolysate) was based on 121 patients from clinical studies and compassionate use in severe congenital Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate).

No inhibiting antibodies to Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate):

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 Marpro-Z (Protein Hydrolysate) and tissue plasminogen activator (tPA).

See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate). It is also not known whether Marpro-Z (Protein Hydrolysate) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Marpro-Z (Protein Hydrolysate) should be given to pregnant women only if clearly needed.

8.2 Labor and Delivery

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

8.3 Nursing Mothers

Marpro-Z (Protein Hydrolysate) has not been studied for use in nursing mothers. Use Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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

Marpro-Z (Protein Hydrolysate) [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 Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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

Marpro-Z 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 Marpro-Z (Protein Hydrolysate) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) C is not compatible with life. A severe deficiency of this anticoagulant Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) C concentration following infusion divided by dose


The Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate). 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 Marpro-Z (Protein Hydrolysate).

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) C activity levels. See DOSAGE AND ADMINISTRATION: Marpro-Z (Protein Hydrolysate) C Activity Monitoring (2.2).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Protein C contained in Marpro-Z 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.

Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) has suggested immunogenic response in heterologous species following repeated dosing of this human derived Marpro-Z (Protein Hydrolysate). Thus, the long-term toxicity potential of Marpro-Z (Protein Hydrolysate) following repeated dosing in animals is unknown.

Local Tolerance Testing:

Investigation of route of injection tolerance demonstrated that Marpro-Z (Protein Hydrolysate) 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:

Marpro-Z (Protein Hydrolysate) 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 Marpro-Z in subjects with severe congenital Marpro-Z (Protein Hydrolysate) 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.


Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) C deficiency were more effectively treated with Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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.

Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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. Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate), as shown in Table 8. When not on prophylactic treatment and receiving Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) C deficiency who were treated with Marpro-Z (Protein Hydrolysate) 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

Marpro-Z (Protein Hydrolysate) 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 Marpro-Z (Protein Hydrolysate) C corresponds to the amidolytically measured activity of Marpro-Z (Protein Hydrolysate) 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).

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

NDC 0944-4177-05

Marpro-Z (Protein Hydrolysate) C

Concentrate (Human)

Marpro-Z (Protein Hydrolysate)

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

Marpro-Z (Protein Hydrolysate) C Concentrate

(Human)

Marpro-Z (Protein Hydrolysate)

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

Marpro-Z (Protein Hydrolysate) C

Concentrate (Human)

Marpro-Z (Protein Hydrolysate)

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

Marpro-Z (Protein Hydrolysate) C Concentrate (Human)

Marpro-Z (Protein Hydrolysate)

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

Zinc:


INDICATIONS AND USAGE

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

CONTRAINDICATIONS

None known.

WARNINGS

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

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

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

General

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

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

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

Laboratory Tests

Periodic determinations of serum copper as well as Marpro-Z (Zinc) are suggested as a guideline for subsequent Marpro-Z (Zinc) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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

Nursing Mothers

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

Pediatric Use

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

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

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

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

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

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

Calcium supplements may confer a protective effect against Marpro-Z (Zinc) toxicity.

DOSAGE AND ADMINISTRATION

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

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

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

HOW SUPPLIED

Marpro-Z (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).

Store at 20 to 25°C (68 to 77°F).

Revised: October, 2004


© Hospira 2004 EN-0488 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

10 mL Vial

Marpro-Z (Zinc)

1 mg/mL

Marpro-Z (Zinc) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

Marpro-Z 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.


Marpro-Z 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.


Marpro-Z 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.


Marpro-Z 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.


Marpro-Z 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. Dailymed."ZINC INJECTABLE A 1MG/ML, SOLUTION INJECTABLE POUR PERFUSION (ZINC) INJECTION, SOLUTION [LABORATOIRE AGUETTANT]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."MAGNESIUM CHLORIDE DIETARY SUPPLEMENT (MAGNESIUM CHLORIDE) TABLET, DELAYED RELEASE [LEADING PHARMA]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."MAGNESIUM CHLORIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Marpro-Z?

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

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