Hepp-Tone

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Hepp-Tone uses

Hepp-Tone consists of Calcium Lactate, Folic Acid, Iron (Ferrous Gluconate), Vitamin B12.

Calcium Lactate:


1 INDICATIONS AND USAGE

Hepp-Tone (Calcium Lactate) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

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

2 DOSAGE AND ADMINISTRATION

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

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

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

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Hepp-Tone (Calcium Lactate) acetate capsule.

- Capsule: 667 mg Hepp-Tone (Calcium Lactate) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

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

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

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

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

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

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

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

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

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6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

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

- In clinical studies, patients have occasionally experienced nausea during Hepp-Tone (Calcium Lactate) acetate therapy. (6)

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

6.1 Clinical Trial Experience

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

In clinical studies, Hepp-Tone (Calcium Lactate) acetate has been generally well tolerated.

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


Preferred Term


Total adverse reactions reported for Hepp-Tone (Calcium Lactate) acetate

N=167

N (%)


3 month, open label study of Hepp-Tone (Calcium Lactate) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Hepp-Tone (Calcium Lactate) acetate

N=69


Hepp-Tone (Calcium Lactate) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (12.6)


16 (16.3)


5 (7.2)


0 (0)


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

6.2 Postmarketing Experience

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

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

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7 DRUG INTERACTIONS

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

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

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

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

7.1 Ciprofloxacin

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

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

8.2 Labor and Delivery

The effects of Hepp-Tone (Calcium Lactate) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Hepp-Tone (Calcium Lactate) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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10 OVERDOSAGE

Administration of Hepp-Tone (Calcium Lactate) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

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


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

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

Chemical Structure

12 CLINICAL PHARMACOLOGY

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

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

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13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Hepp-Tone (Calcium Lactate) acetate.

14 CLINICAL STUDIES

Effectiveness of Hepp-Tone (Calcium Lactate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Hepp-Tone (Calcium Lactate) acetate solid oral dosage form.

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

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

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


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Hepp-Tone (Calcium Lactate) (mg/dL)‡


8.9 ± 0.09


9.5 ± 0.10


9.7 ± 0.10


9.7 ± 0.10


≤0.01


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

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

The phosphate binding effect of Hepp-Tone (Calcium Lactate) acetate is shown in the Table 3.


* ANOVA of Hepp-Tone (Calcium Lactate) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Hepp-Tone (Calcium Lactate) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Hepp-Tone (Calcium Lactate) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


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

16 HOW SUPPLIED/STORAGE AND HANDLING

Hepp-Tone (Calcium Lactate) Acetate Capsules

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

NDC 0615-2303-39: Blistercards of 30 Capsules

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

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

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

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

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Folic Acid:


INDICATIONS AND USAGE

Hepp-Tone (Folic Acid)® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.

CONTRAINDICATIONS

This product is contraindicated in patients with a known hypersensitivity to any of the ingredients. Hemochromatosis and hemosiderosis are contraindications to iron therapy.

WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately.

PRECAUTIONS

Hepp-Tone (Folic Acid) acid when administered as a single agent in doses above 0.1 mg daily may obscure pernicious anemia in that hematological remission can occur while neurological manifestations remain progressive. While prescribing this nutritional supplement for pregnant women, nursing mothers, or for women prior to conception, their medical condition and other drugs, herbs, and/or supplements consumption should be considered.

ADVERSE REACTIONS

Allergic sensitization has been reported following both oral and parenteral administration of Hepp-Tone (Folic Acid) acid.

DOSAGE AND ADMINISTRATION

One tablet daily with or without food or as prescribed by a licensed healthcare provider with prescribing authority.

HOW SUPPLIED

Hepp-Tone (Folic Acid)® tablets are supplied in child-resistant bottles of 90 tablets (NDC 0037-6885-90)

KEEP OUT OF REACH OF CHILDREN.

STORAGE

Store at controlled room temperature 20°-25°C (68°-77°F). Excursions permitted to 15°-30°C (59°-86°F).

Dispense in a tight, light-resistant container to protect from light and moisture.

To report SUSPECTED ADVERSE REACTIONS contact Meda Pharmaceuticals Inc. at 1-888-349-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch

Distributed by:

Meda Pharmaceuticals Inc.

Somerset New Jersey 08873-4120

© 2014 Meda Pharmaceuticals Inc.

U.S. Patent Nos. 7,585,527 and 8,080,520

Proferrin® is a registered trademark of Colorado BioLabs, Inc., Cozad, NE.

Hepp-Tone (Folic Acid) and the BIFERA logo are registered trademarks and the Hepp-Tone (Folic Acid) logo is a trademark of Alaven Pharmaceutical LLC, used under license by Meda Pharmaceuticals Inc.

MEDA PHARMACEUTICALS mark and logo are trademarks of Meda AB.

IN-6885-02 Rev 6/2014

Iron (Ferrous Gluconate):


1 INDICATIONS AND USAGE

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

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

2 DOSAGE AND ADMINISTRATION

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

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

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

Administer Hepp-Tone (Iron (Ferrous Gluconate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Hepp-Tone (Iron (Ferrous Gluconate)) should be administered early during the dialysis session. The usual total treatment course of Hepp-Tone (Iron (Ferrous Gluconate)) is 1000 mg. Hepp-Tone (Iron (Ferrous Gluconate)) treatment may be repeated if Hepp-Tone (Iron (Ferrous Gluconate)) deficiency reoccurs.

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

Administer Hepp-Tone (Iron (Ferrous Gluconate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Hepp-Tone (Iron (Ferrous Gluconate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Hepp-Tone (Iron (Ferrous Gluconate)) treatment may be repeated if Hepp-Tone (Iron (Ferrous Gluconate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Hepp-Tone (Iron (Ferrous Gluconate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Hepp-Tone (Iron (Ferrous Gluconate)) in a maximum of 250 mL of 0.9% NaCl. Hepp-Tone (Iron (Ferrous Gluconate)) treatment may be repeated if Hepp-Tone (Iron (Ferrous Gluconate)) deficiency reoccurs.

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

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

For Hepp-Tone (Iron (Ferrous Gluconate)) maintenance treatment: Administer Hepp-Tone (Iron (Ferrous Gluconate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Hepp-Tone (Iron (Ferrous Gluconate)) treatment may be repeated if necessary.

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

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

For Hepp-Tone (Iron (Ferrous Gluconate)) maintenance treatment: Administer Hepp-Tone (Iron (Ferrous Gluconate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Hepp-Tone (Iron (Ferrous Gluconate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

  • Known hypersensitivity to Hepp-Tone (Iron (Ferrous Gluconate))
  • Known hypersensitivity to Hepp-Tone (Iron (Ferrous Gluconate)) (4)

5 WARNINGS AND PRECAUTIONS

  • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Hepp-Tone ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Hepp-Tone (Iron (Ferrous Gluconate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
  • Hypotension: Hepp-Tone (Iron (Ferrous Gluconate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Hepp-Tone (Iron (Ferrous Gluconate)). (5.2)
  • Hepp-Tone (Iron (Ferrous Gluconate)) Overload: Regularly monitor hematologic responses during Hepp-Tone (Iron (Ferrous Gluconate)) therapy. Do not administer Hepp-Tone (Iron (Ferrous Gluconate)) to patients with Hepp-Tone (Iron (Ferrous Gluconate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Hepp-Tone (Iron (Ferrous Gluconate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Hepp-Tone (Iron (Ferrous Gluconate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Hepp-Tone (Iron (Ferrous Gluconate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Hepp-Tone (Iron (Ferrous Gluconate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Hepp-Tone (Iron (Ferrous Gluconate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

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

5.3 Hepp-Tone (Iron (Ferrous Gluconate)) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Hepp-Tone ) are described in other sections .

  • The most common adverse reactions (≥2%) following the administration of Hepp-Tone (Iron (Ferrous Gluconate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Hepp-Tone ) 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 Hepp-Tone (Iron (Ferrous Gluconate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.


* EPO=Erythropoietin

Adverse Reactions

(Preferred Term)

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

respiratory tract infections, Pharyngitis

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

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Hepp-Tone (Iron (Ferrous Gluconate)) therapy and were reported to be intolerant (defined as precluding further use of that Hepp-Tone (Iron (Ferrous Gluconate)) product). When these patients were treated with Hepp-Tone (Iron (Ferrous Gluconate)) there were no occurrences of adverse reactions that precluded further use of Hepp-Tone (Iron (Ferrous Gluconate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Hepp-Tone (Iron (Ferrous Gluconate)) maintenance treatment with Hepp-Tone (Iron (Ferrous Gluconate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Hepp-Tone (Iron (Ferrous Gluconate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Hepp-Tone (Iron (Ferrous Gluconate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Hepp-Tone (Iron (Ferrous Gluconate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Hepp-Tone (Iron (Ferrous Gluconate)) 0.5 mg/kg group, 10 (21%) patients in the Hepp-Tone (Iron (Ferrous Gluconate)) 1.0 mg/kg group, and 10 (21%) patients in the Hepp-Tone (Iron (Ferrous Gluconate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

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

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Hepp-Tone (Iron (Ferrous Gluconate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Hepp-Tone (Iron (Ferrous Gluconate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Hepp-Tone (Iron (Ferrous Gluconate)) injection. Reactions have occurred following the first dose or subsequent doses of Hepp-Tone (Iron (Ferrous Gluconate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Hepp-Tone (Iron (Ferrous Gluconate)) have not been studied. However, Hepp-Tone (Iron (Ferrous Gluconate)) may reduce the absorption of concomitantly administered oral Hepp-Tone (Iron (Ferrous Gluconate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Hepp-Tone ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Hepp-Tone (Iron (Ferrous Gluconate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Hepp-Tone (Iron (Ferrous Gluconate)) sucrose. Because animal reproductive studies are not always predictive of human response, Hepp-Tone (Iron (Ferrous Gluconate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

Safety and effectiveness of Hepp-Tone (Iron (Ferrous Gluconate)) for Hepp-Tone (Iron (Ferrous Gluconate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Hepp-Tone (Iron (Ferrous Gluconate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

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

In a country where Hepp-Tone (Iron (Ferrous Gluconate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Hepp-Tone (Iron (Ferrous Gluconate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Hepp-Tone (Iron (Ferrous Gluconate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Hepp-Tone (Iron (Ferrous Gluconate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Hepp-Tone (Iron (Ferrous Gluconate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Hepp-Tone (Iron (Ferrous Gluconate)) in humans. Excessive dosages of Hepp-Tone (Iron (Ferrous Gluconate)) may lead to accumulation of Hepp-Tone (Iron (Ferrous Gluconate)) in storage sites potentially leading to hemosiderosis. Do not administer Hepp-Tone (Iron (Ferrous Gluconate)) to patients with Hepp-Tone (Iron (Ferrous Gluconate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Hepp-Tone (Iron (Ferrous Gluconate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Hepp-Tone (Iron (Ferrous Gluconate)) (iron sucrose injection, USP), an Hepp-Tone (Iron (Ferrous Gluconate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Hepp-Tone (Iron (Ferrous Gluconate)) (III)-hydroxide in sucrose for intravenous use. Hepp-Tone (Iron (Ferrous Gluconate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na2Fe5O8(OH) ·3(H2O)]n ·m(C12H22O11)

where: n is the degree of Hepp-Tone (Iron (Ferrous Gluconate)) polymerization and m is the number of sucrose molecules associated with the Hepp-Tone (Iron (Ferrous Gluconate)) (III)-hydroxide.

Each mL contains 20 mg elemental Hepp-Tone (Iron (Ferrous Gluconate)) as Hepp-Tone (Iron (Ferrous Gluconate)) sucrose in water for injection. Hepp-Tone (Iron (Ferrous Gluconate)) is available in 10 mL single-use vials (200 mg elemental Hepp-Tone (Iron (Ferrous Gluconate)) per 10 mL), 5 mL single-use vials (100 mg elemental Hepp-Tone (Iron (Ferrous Gluconate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Hepp-Tone (Iron (Ferrous Gluconate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Hepp-Tone ), its Hepp-Tone (Iron (Ferrous Gluconate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Hepp-Tone (Iron (Ferrous Gluconate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Hepp-Tone (Iron (Ferrous Gluconate)) containing 100 mg of Hepp-Tone (Iron (Ferrous Gluconate)) labeled with 52Fe/59Fe in patients with Hepp-Tone (Iron (Ferrous Gluconate)) deficiency showed that a significant amount of the administered Hepp-Tone (Iron (Ferrous Gluconate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Hepp-Tone (Iron (Ferrous Gluconate)) trapping compartment.

Following intravenous administration of Hepp-Tone (Iron (Ferrous Gluconate)), Hepp-Tone (Iron (Ferrous Gluconate)) sucrose is dissociated into Hepp-Tone (Iron (Ferrous Gluconate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Hepp-Tone (Iron (Ferrous Gluconate)) containing 1,510 mg of sucrose and 100 mg of Hepp-Tone (Iron (Ferrous Gluconate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Hepp-Tone (Iron (Ferrous Gluconate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Hepp-Tone (Iron (Ferrous Gluconate)) sucrose containing 500 to 700 mg of Hepp-Tone (Iron (Ferrous Gluconate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Hepp-Tone (Iron (Ferrous Gluconate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Hepp-Tone (Iron (Ferrous Gluconate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Hepp-Tone (Iron (Ferrous Gluconate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Hepp-Tone (Iron (Ferrous Gluconate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Hepp-Tone (Iron (Ferrous Gluconate)), the half-life of total serum Hepp-Tone (Iron (Ferrous Gluconate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Hepp-Tone (Iron (Ferrous Gluconate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Hepp-Tone (Iron (Ferrous Gluconate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Hepp-Tone (Iron (Ferrous Gluconate)) sucrose.

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

Hepp-Tone (Iron (Ferrous Gluconate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Hepp-Tone (Iron (Ferrous Gluconate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Hepp-Tone ).

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 Hepp-Tone (Iron (Ferrous Gluconate)) treatment and 24 in the historical control group) with Hepp-Tone (Iron (Ferrous Gluconate)) deficiency anemia. Eligibility criteria for Hepp-Tone (Iron (Ferrous Gluconate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Hepp-Tone (Iron (Ferrous Gluconate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Hepp-Tone (Iron (Ferrous Gluconate)), who were off intravenous Hepp-Tone (Iron (Ferrous Gluconate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Hepp-Tone (Iron (Ferrous Gluconate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.


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


Efficacy

parameters

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

(n=73)

Historical Control

(n=18)

Hepp-Tone (Iron (Ferrous Gluconate))

(n=71)

Historical

Control

(n=15)

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

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Hepp-Tone (Iron (Ferrous Gluconate)) in 23 patients with Hepp-Tone (Iron (Ferrous Gluconate)) deficiency and HDD-CKD who had been discontinued from Hepp-Tone (Iron (Ferrous Gluconate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Hepp-Tone (Iron (Ferrous Gluconate)). Exclusion criteria were similar to those in studies A and B. Hepp-Tone (Iron (Ferrous Gluconate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Hepp-Tone (Iron (Ferrous Gluconate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Hepp-Tone (Iron (Ferrous Gluconate)) versus Hepp-Tone (Iron (Ferrous Gluconate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Hepp-Tone (Iron (Ferrous Gluconate)) (325 mg ferrous sulfate three times daily for 56 days); or Hepp-Tone (Iron (Ferrous Gluconate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Hepp-Tone (Iron (Ferrous Gluconate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Hepp-Tone (Iron (Ferrous Gluconate)) group.

A statistically significantly greater proportion of Hepp-Tone (Iron (Ferrous Gluconate)) subjects (35/79; 44.3%) compared to oral Hepp-Tone (Iron (Ferrous Gluconate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Hepp-Tone (Iron (Ferrous Gluconate)) to patients with PDD-CKD receiving an erythropoietin alone without Hepp-Tone (Iron (Ferrous Gluconate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Hepp-Tone (Iron (Ferrous Gluconate)) or Hepp-Tone (Iron (Ferrous Gluconate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Hepp-Tone (Iron (Ferrous Gluconate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Hepp-Tone (Iron (Ferrous Gluconate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Hepp-Tone (Iron (Ferrous Gluconate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Hepp-Tone ) 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 Hepp-Tone (Iron (Ferrous Gluconate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Hepp-Tone (Iron (Ferrous Gluconate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Hepp-Tone (Iron (Ferrous Gluconate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Hepp-Tone (Iron (Ferrous Gluconate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Hepp-Tone (Iron (Ferrous Gluconate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

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

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

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Hepp-Tone (Iron (Ferrous Gluconate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Hepp-Tone (Iron (Ferrous Gluconate)) per mL, or undiluted (20 mg elemental Hepp-Tone (Iron (Ferrous Gluconate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Hepp-Tone (Iron (Ferrous Gluconate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Hepp-Tone (Iron (Ferrous Gluconate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Hepp-Tone (Iron (Ferrous Gluconate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Hepp-Tone (Iron (Ferrous Gluconate)) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

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

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

PREMIERProRx®

IN2340

MG #15727

Vitamin B12:


Pharmacological action

Hepp-Tone refers to a group of water-soluble vitamins. It has high biological activity. Hepp-Tone (Vitamin B12) is necessary for normal hematopoiesis (promotes maturation of erythrocytes). Involved in the processes of transmethylation, hydrogen transport, synthesis of methionine, nucleic acids, choline, creatine. Contributes to the accumulation in erythrocytes of compounds containing sulfhydryl groups. Has a beneficial effect on liver function and the nervous system. Activates the coagulation of blood in high doses causes an increase in the activity of thromboplastin and prothrombin.

Pharmacokinetics

After oral administration Hepp-Tone (Vitamin B12) absorbed from the gastrointestinal tract. Metabolized in the tissues, becoming a co-enzyme form - adenosylcobalamin which is the active form of cyanocobalamin. Excreted in bile and urine.

Why is Hepp-Tone prescribed?

Anemia due to B12-deficiency conditions; in the complex therapy for iron and posthemorrhagic anemia; aplastic anemia caused by toxic substances and drugs; liver disease (hepatitis, cirrhosis); funicular myelosis; polyneuritis, radiculitis, neuralgia, amyotrophic lateral sclerosis; children cerebral palsy, Down syndrome, peripheral nerve injury; skin diseases (psoriasis, photodermatosis, herpetiformis dermatitis, neurodermatitis); to prevent and treat symptoms of deficiency of Hepp-Tone (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.

Dosage and administration

Hepp-Tone is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Hepp-Tone (Vitamin B12) deficiency is introduced on 100-200 mcg in 2 days. In anemia with symptoms of funicular myelosis and megalocytic anemia with diseases of the nervous system - 400-500 micrograms in the first 7 days daily, then 1 time every 5-7 days. In the period of remission in the absence of events funicular myelosis maintenance dose - 100 mcg 2 times a month, in the presence of neurological symptoms - at 200-400 mcg 2-4 times a month. In acute post-hemorrhagic anemia and iron anemia by 30-100 mcg 2-3 times a week. When aplastic anemia (especially in children) - 100 micrograms before clinical improvement. When nutritional anemia in infants and preterm - 30 mcg / day during 15 days.

In diseases of the central and peripheral nervous system and neurological diseases with a pain syndrome is administered in increasing doses - 200-500 mcg, with the improvement in the state - 100 mcg / day. The course of treatment with Hepp-Tone (Vitamin B12) is 2 weeks. In traumatic lesions of peripheral nervous system - at 200-400 mcg every other day for 40-45 days.

When hepatitis and cirrhosis - 30-60 mcg / day or 100 mg every other day for 25-40 days.

Dystrophy in young children, Down syndrome and cerebral palsy - by 15-30 mcg every other day.

When funicular myelosis, amyotrophic lateral sclerosis can be introduced into the spinal canal at 15-30 mcg, gradually increasing the dose of 200-250 micrograms.

In radiation sickness, diabetic neuropathy, sprue - by 60-100 mcg daily for 20-30 days.

When deficiency of Hepp-Tone (Vitamin B12) to prevent - IV or IM for 1 mg 1 time a month; for treatment - IV or IM for 1 mg daily for 1-2 weeks, the maintenance dose is 1-2 mg IV or IM from 1 per week, up to 1 per month. Duration of treatment is determined individually.

Hepp-Tone (Vitamin B12) side effects, adverse reactions

CNS: rarely - a state of arousal.

Cardiovascular system: rarely - pain in the heart, tachycardia.

Allergic reactions: rarely - urticaria.

Hepp-Tone contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

Hepp-Tone using during pregnancy and breastfeeding

Cyanocobalamin can be used in pregnancy according to prescriptions.

Special instructions

When stenocardia should be used with caution in a single dose of Hepp-Tone 100 mcg. During treatment should regularly monitor the blood picture and coagulation. It is unacceptable to enter in the same syringe with cyanocobalamin solutions of thiamine and pyridoxine.

Hepp-Tone (Vitamin B12) drug interactions

In an application of Hepp-Tone (Vitamin B12) with hormonal contraceptives for oral administration may decrease the concentration of cyanocobalamin in plasma.

In an application with anticonvulsant drugs decreased cyanocobalamin absorption from the gut.

In an Hepp-Tone (Vitamin B12) application with neomycin, aminosalicylic acid, colchicine, cimetidine, ranitidine, drugs potassium decreased cyanocobalamin absorption from the gut.

Cyanocobalamin may exacerbate allergic reactions caused by thiamine.

When parenteral application of chloramphenicol may decrease the hematopoietic effects of cyanocobalamin with anemia.

Pharmaceutical incompatibility

Contained in the molecule of cyanocobalamin cobalt ion contributes to the destruction of ascorbic acid, thiamine bromide, riboflavin in one solution.

Hepp-Tone 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.


Hepp-Tone 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.


Hepp-Tone 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.


Hepp-Tone 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.


Hepp-Tone 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."FOLIC ACID INJECTION, SOLUTION [FRESENIUS KABI USA, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."ASCORBIC ACID; BIOTIN; CYANOCOBALAMIN; DEXPANTHENOL; ERGOCALCIFEROL; FOLIC ACID; NIACINAMIDE; PHYTONADIONE; PYRIDOXINE HYDROCHLORIDE; RIBOFLAVIN 5'-PHOSPHATE SODIUM; THIAMINE HYDROCHLORIDE; VITAMIN A; VITAMIN E: 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).
  3. Dailymed."CALCIUM: 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 Hepp-Tone?

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