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DRUGS & SUPPLEMENTS
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How old is patient? |
Folic Acid:
Tonoferon Drops (Folic Acid)® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.
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. |
Tonoferon Drops (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.
Allergic sensitization has been reported following both oral and parenteral administration of Tonoferon Drops (Folic Acid) acid.
One tablet daily with or without food or as prescribed by a licensed healthcare provider with prescribing authority.
Tonoferon Drops (Folic Acid)® tablets are supplied in child-resistant bottles of 90 tablets (NDC 0037-6885-90)
KEEP OUT OF REACH OF CHILDREN.
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.
Tonoferon Drops (Folic Acid) and the BIFERA logo are registered trademarks and the Tonoferon Drops (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 (Iron Hydroxide Colloidal):
Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) is indicated for the treatment of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) deficiency anemia in patients with chronic kidney disease (CKD).
Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) is an Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) replacement product indicated for the treatment of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) deficiency anemia in patients with chronic kidney disease (CKD). (1)
Tonoferon Drops ) must only be administered intravenously either by slow injection or by infusion. The dosage of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) is expressed in mg of elemental Tonoferon Drops (Iron (Iron Hydroxide Colloidal)). Each mL contains 20 mg of elemental Tonoferon Drops (Iron (Iron Hydroxide Colloidal)).
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 |
Administer Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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. Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) should be administered early during the dialysis session. The usual total treatment course of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) is 1000 mg. Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) treatment may be repeated if Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) deficiency reoccurs.
Administer Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)), 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. Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) treatment may be repeated if Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) deficiency reoccurs.
Administer Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) in a maximum of 250 mL of 0.9% NaCl. Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) treatment may be repeated if Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) deficiency reoccurs.
The dosing for Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) replacement treatment in pediatric patients with HDD-CKD has not been established.
For Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) maintenance treatment: Administer Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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. Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) treatment may be repeated if necessary.
The dosing for Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.
For Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) maintenance treatment: Administer Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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. Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) treatment may be repeated if necessary.
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Tonoferon Drops (Iron (Iron Hydroxide Colloidal)). 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) preparations occur within 30 minutes of the completion of the infusion .
Tonoferon Drops ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)). Hypotension following administration of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) may be related to the rate of administration and/or total dose administered .
Excessive therapy with parenteral Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) can lead to excess storage of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) require periodic monitoring of hematologic and Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) to patients with evidence of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose; do not perform serum Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) measurements for at least 48 hours after intravenous dosing .
The following serious adverse reactions associated with Tonoferon Drops ) are described in other sections .
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 .
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 Adult Patients with CKD
The frequency of adverse reactions associated with the use of Tonoferon Drops ) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 | ||
Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) | Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) | Oral Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) | Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) | 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) therapy and were reported to be intolerant (defined as precluding further use of that Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) product). When these patients were treated with Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) there were no occurrences of adverse reactions that precluded further use of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) .
Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)
In a randomized, open-label, dose-ranging trial for Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) maintenance treatment with Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 0.5 mg/kg, 53% (25/47) of the patients receiving Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 2.0 mg/kg.
A total of 5 (11%) subjects in the Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 0.5 mg/kg group, 10 (21%) patients in the Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 1.0 mg/kg group, and 10 (21%) patients in the Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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%).
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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)). 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) injection. Reactions have occurred following the first dose or subsequent doses of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)). 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.
Drug interactions involving Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) have not been studied. However, Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) may reduce the absorption of concomitantly administered oral Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) preparations.
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Tonoferon Drops ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose. Because animal reproductive studies are not always predictive of human response, Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) should be used during pregnancy only if clearly needed.
It is not known whether Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose is excreted in human milk. Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) is administered to a nursing woman.
Safety and effectiveness of Tonoferon Drops ) for Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.
Safety and effectiveness of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) for Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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)]
Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) has not been studied in patients younger than 2 years of age.
In a country where Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) or any other drugs could be established.
Clinical studies of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)), 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.
No data are available regarding overdosage of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) in humans. Excessive dosages of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) may lead to accumulation of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) in storage sites potentially leading to hemosiderosis. Do not administer Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) to patients with Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) overload.
Toxicities in single-dose studies in mice and rats, at intravenous Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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.
Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (iron sucrose injection, USP), an Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (III)-hydroxide in sucrose for intravenous use. Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) polymerization and m is the number of sucrose molecules associated with the Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (III)-hydroxide.
Each mL contains 20 mg elemental Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) as Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose in water for injection. Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) is available in 10 mL single-use vials (200 mg elemental Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) per 10 mL), 5 mL single-use vials (100 mg elemental Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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.
Tonoferon Drops ) is an aqueous complex of poly-nuclear Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (III)-hydroxide in sucrose. Following intravenous administration, Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) is dissociated into Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) and sucrose and the Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.
Following intravenous administration, Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) is dissociated into Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose containing 100 mg of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)), three times weekly for three weeks, significant increases in serum Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) and serum ferritin and significant decreases in total Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) binding capacity occurred four weeks from the initiation of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose treatment.
In healthy adults administered intravenous doses of Tonoferon Drops ), its Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) containing 100 mg of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) labeled with 52Fe/59Fe in patients with Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) deficiency showed that a significant amount of the administered Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) trapping compartment.
Following intravenous administration of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)), Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose is dissociated into Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) containing 1,510 mg of sucrose and 100 mg of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose containing 500 to 700 mg of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) have not been studied.
Pharmacokinetics in Pediatric Patients
In a single-dose PK study of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Tonoferon Drops (Iron (Iron Hydroxide Colloidal)), the half-life of total serum Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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.
Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).
Carcinogenicity studies have not been performed with Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose.
Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.
Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (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.
Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Tonoferon Drops ).
Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) treatment and 24 in the historical control group) with Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) deficiency anemia. Eligibility criteria for Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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.
Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)), who were off intravenous Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 | |||
Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (n=69 | Historical Control (n=18) | Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (n=73) | Historical Control (n=18) | Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (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%).
Study B was a multicenter, open label study of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) in 23 patients with Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) deficiency and HDD-CKD who had been discontinued from Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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.
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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)). Exclusion criteria were similar to those in studies A and B. Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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.
Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) versus Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (325 mg ferrous sulfate three times daily for 56 days); or Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) group.
A statistically significantly greater proportion of Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) subjects (35/79; 44.3%) compared to oral Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).
Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) to patients with PDD-CKD receiving an erythropoietin alone without Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) or Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) / 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) / 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) / 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%).
Study F was a randomized, open-label, dose-ranging study for Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.
Tonoferon Drops ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Tonoferon Drops (Iron (Iron Hydroxide Colloidal)), each 5 mL vial contains 100 mg elemental Tonoferon Drops (Iron (Iron Hydroxide Colloidal)), and each 2.5 mL vial contains 50 mg elemental Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) (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 |
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: Tonoferon Drops (Iron (Iron Hydroxide Colloidal)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) per mL, or undiluted (20 mg elemental Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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: Tonoferon Drops (Iron (Iron Hydroxide Colloidal)), 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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 Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) 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.
Prior to Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) administration:
AMERICAN
REGENT, INC.
SHIRLEY, NY 11967
Tonoferon Drops (Iron (Iron Hydroxide Colloidal)) is manufactured under license from Vifor (International) Inc., Switzerland.
PremierProRx® is a trademark of Premier, Inc., used under license.
PREMIERProRx®
IN2340
MG #15727
Lysine Hydrochloride:
Pharmacy Bulk Package
Not For Direct Infusion
Tonoferon Drops (Lysine Hydrochloride)® 15% Amino Acids Injection in a Pharmacy Bulk Package is a sterile, clear, nonpyrogenic solution of essential and nonessential amino acids for intravenous infusion in parenteral nutrition following appropriate dilution.
Tonoferon Drops (Lysine Hydrochloride)® 15% in a Pharmacy Bulk Package is not for direct infusion. It is a sterile dosage from which contains several single doses for use in a pharmacy admixture program in the preparation of intravenous parenteral fluids.
Each 100 mL contains:
Essential Amino Acids | ||
Tonoferon Drops (Lysine Hydrochloride) (from Tonoferon Drops (Lysine Hydrochloride) Acetate, USP)……………………………………...1.18 | g | |
Leucine, USP……………………………………………………………...1.04 | g | |
Phenylalanine, USP……………………………………...1.04 | g | |
Valine, USP……………………………………………………………...960 | mg | |
Isoleucine, USP………………………………………...749 | mg | |
Methionine, USP………………………………………...749 | mg | |
Threonine, USP………………………………………...749 | mg | |
Tryptophan, USP………………………………………...250 | mg | |
Nonessential Amino Acids | ||
Alanine, USP…………………………………………...2.17 | g | |
Arginine, USP…………………………………………...1.47 | g | |
Glycine, USP…………………………………………...1.04 | g | |
Histidine, USP…………………………………………...894 | mg | |
Proline, USP……………………………………………………………...894 | mg | |
Glutamic Acid…………………………………………...749 | mg | |
Serine, USP……………………………………………...592 | mg | |
Aspartic Acid, USP……………………………………...434 | mg | |
Tyrosine, USP…………………………………………...39 | mg | |
Sodium Metabisulfite, NF added……………………………………………...30 | mg | |
Water for Injection, USP……………………………………………………... | qs | |
Essential Amino Acids………………………………………………………...6.7 | g | |
Nonessential Amino Acids…………………………………………………...8.3 | g | |
Total Amino Acids…………………………………………………………...15.0 | g | |
Total Nitrogen………………………………………………………………...2.37 | g | |
Acetate*……………………………………………………...151 | mEq/L | |
Osmolarity (calculated)……………………………………...1388 | mOsmol/L | |
pH……………………………………………………………………………...5.6(5.2-6.0) | ||
*Acetate from Tonoferon Drops (Lysine Hydrochloride) Acetate, USP and acetic acid used for pH adjustment. |
The formulas for the individual amino acids are as follows:
Formulas for individual amino acids
Tonoferon Drops (Lysine Hydrochloride)® 15% Amino Acids Injection providesseventeen crystalline amino acids. This completely utilizable substrate promotesprotein synthesis and wound healing and reduces the rate of protein catabolism.
A.Total Parenteral Nutrition (Central Infusion)
When enteralfeeding is inadvisable, Tonoferon Drops (Lysine Hydrochloride)® 15% given by central venousinfusion in combination with energy sources, vitamins, trace elements andelectrolytes, will completely satisfy the requirements for weight maintenanceor weight gain, depending upon the dose selected. The energy component inparenteral nutrition by central infusion may be derived solely from dextroseor may be provided by a combination of dextrose and intravenous fat emulsion. The addition of intravenous fat emulsion provides essential fatty acids andpermits a dietary balance of fat and carbohydrate, at the same time offeringthe option of reducing the dextrose load and/or increasing the total caloricinput. An adequate energy supply is essential for optimal utilization of aminoacids.
B. Total Parenteral Nutrition (Peripheral Infusion)
Tonoferon Drops (Lysine Hydrochloride)® 15%can also be administered as part of a total parenteral nutrition program byperipheral vein when the enteral route is inadvisable and use of the centralvenous catheter is contraindicated.
Reduction of proteinloss can be achieved by use of diluted Tonoferon Drops (Lysine Hydrochloride)® 15% in combinationwith dextrose or with dextrose and intravenous fat emulsion by peripheralinfusion. Complete peripheral intravenous nutrition can be achieved in patientswith low caloric requirements by a Tonoferon Drops (Lysine Hydrochloride)®15%-dextrose-fatregimen.
Tonoferon Drops (Lysine Hydrochloride)® 15% is indicated as an amino acid(nitrogen) source in parenteral nutrition regimens. This use is appropriatewhen the enteral route is inadvisable, inadequate or not possible, as when:
-Gastrointestinal absorption is impaired by obstruction, inflammatory diseaseor its complications, or antineoplastic therapy;
-Bowel rest is needed because of gastrointestinal surgery or its complicationssuch as ileus, fistulae or anastomotic leaks;
-Tube feeding methods alone cannot provide adequate nutrition.
This solution should not be used in patients in hepatic coma,severe renal failure, metabolic disorders involving impaired nitrogen utilizationor hypersensitivity to one or more amino acids.
Administration of amino acids solutions at excessive ratesor to patients with hepatic insufficiency may result in plasma amino acidimbalances, hyperammonemia, prerenal azotemia, stupor and coma. Conservativedoses of amino acids should be given to these patients, dictated by the nutritionalstatus of the patient. Should symptoms of hyperammonemia develop, amino acidadministration should be discontinued and the patient’s clinical statusre-evaluated.
Contains sodium metabisulfite, a sulfitethat may cause allergic-type reactions including anaphylactic symptoms andlife-threatening or less severe asthmatic episodes in certain susceptiblepeople. The overall prevalence of sulfite sensitivity in the general populationis unknown and probably low.
Sulfite sensitivity isseen more frequently in asthmatic than in nonasthmatic people.
WARNING: This product contains aluminum that maybe toxic. Aluminum may reach toxic levels with prolonged parenteral administrationif kidney function is impaired. Premature neonates are particularly at riskbecause their kidneys are immature, and they require large amounts of calciumand phosphate solutions, which contain aluminum.
Researchindicates that patients with impaired kidney function, including prematureneonates, who receive parenteral levels of aluminum at greater than 4 to 5mcg/kg/day accumulate aluminum at levels associated with central nervous systemand bone toxicity. Tissue loading may occur at even lower rates of administration.
A. GENERAL
It is essential to provide adequate calories concurrently if parenterally administered amino acids are to be retained by the body and utilized for protein synthesis.
The administration of Tonoferon Drops (Lysine Hydrochloride)® 15% Amino Acids Injection as part of total parenteral nutrition (TPN) with large volumes of hyperosmotic fluids requires periodic monitoring of the patient for signs of hyperosmolarity, hyperglycemia, glycosuria and hypertriglyceridemia.
During parenteral nutrition with concentrated dextrose and amino acids solutions, essential fatty acid deficiency syndrome may develop but may not be clinically apparent. Early demonstration of this condition can only be accomplished by gas liquid chromatographic analysis of plasma lipids. The syndrome may be prevented or corrected by appropriate treatment with intravenous fat emulsions.
For complete nutritional support, TPN regimens must also include multiple vitamins and trace elements. Potentially incompatible ions such as calcium and phosphate may be added to alternate infusate bottles to avoid precipitation. Although the metabolizable acetate ion in Tonoferon Drops (Lysine Hydrochloride)® 15% diminishes the risk of acidosis, the physician must be alert to the potential appearance of this disorder.
Initiation and termination of infusions of TPN fluids must be gradual to permit adjustment of endogenous insulin release.
Undiluted Tonoferon Drops (Lysine Hydrochloride)® 15% should not be administered peripherally. When administered centrally, it should be diluted with appropriate diluents, e.g., dextrose, electrolytes and other nutrient components, to at least half strength. See DOSAGE AND ADMINISTRATION.
Caution against volume overload should be exercised.
Drug product contains no more than 25 mcg/L of aluminum.
B. Laboratory Tests
Infusion of Tonoferon Drops (Lysine Hydrochloride)® 15% without concomitant infusion of an adequate number of non-protein calories may result in elevated BUN. Monitoring of BUN is required and the balance between Tonoferon Drops (Lysine Hydrochloride)® 15% and the calorie source may require adjustment. Frequent clinical evaluations and laboratory determinations are required to prevent the complications which may occur during the administration of solutions used in TPN. Laboratory tests should include blood glucose, serum electrolytes, liver and kidney function, serum osmolarity, blood ammonia, serum protein, pH, hematocrit, WBC and urinary glucose. When Tonoferon Drops (Lysine Hydrochloride)® 15% is combined with electrolytes, care should be used in administering this solution to patients with congestive heart failure, renal failure, edema, adrenal hyperactivity, acid-base imbalance and those receiving diuretics or antihypertensive therapy. Total volume infused should be closely monitored. Serum electrolytes should be monitored daily in these patients.
C. Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with Tonoferon Drops (Lysine Hydrochloride)® 15% have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
D. Pregnancy Category C
Animal reproduction studies have not been conducted with Tonoferon Drops (Lysine Hydrochloride)® 15%. It is also not known whether Tonoferon Drops (Lysine Hydrochloride)® 15% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Tonoferon Drops (Lysine Hydrochloride)® 15% should be given to a pregnant woman only if clearly needed.
E. Nursing Mothers
Caution should be exercised when Tonoferon Drops (Lysine Hydrochloride)® 15% is administered to a nursing woman.
F. Pediatric Use
Safety and effectiveness of Tonoferon Drops (Lysine Hydrochloride)® 15% Amino Acids Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of amino acids injections in pediatric patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen balance is referenced in the medical literature.
G. Special Precautions for Central Infusion
TPN delivered by indwelling catheter through a central or large peripheral vein is a special technique requiring a team effort by physician, nurse and pharmacist. The responsibility for administering this therapy should be confined to those trained in the procedures and alert to signs of complications. Complications known to occur from the placement of central venous catheter are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis, and air/catheter emboli. The risk of sepsis is present during intravenous therapy, especially when using central venous catheters for prolonged periods. It is imperative that the preparation of admixtures and the placement and care of the catheters be accomplished under controlled aseptic conditions.
H. Admixtures
Admixtures should be prepared under a laminar flow hood using aseptic technique.
Admixtures should be stored under refrigeration and must be administered within 24 hours after removal from refrigerator.
Filters of less than 1.2 micron pore size must not be used with admixtures containing fat emulsion.
I. Do not administer unless solution is clear and the seal is intact.
IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.
In the event of overhydration or solute overload, re-evaluatethe patient and institute appropriate corrective measures. See WARNINGS andPRECAUTIONS.
The appropriate daily dose of amino acids to be used withdextrose or with dextrose and intravenous fat emulsion will depend upon themetabolic status and clinical response of the patient as therapy proceeds. Doses which achieve nitrogen equilibrium or positive balance are the mostdesirable. The dosage on the first day should be approximately half the anticipatedoptimal dosage and should be increased gradually to minimize glycosuria; similarly,withdrawal should be accomplished gradually to avoid rebound hypoglycemia.
Fatemulsion coadministration should be considered when prolonged (more than 5days) parenteral nutrition is required in order to prevent essential fattyacid deficiency (EFAD). Serum lipids should be monitored for evidence of EFADin patients maintained on fat free TPN.
The amount administeredis dosed on the basis of amino acids/kg of body weight/day. In general, twoto three g/kg of body weight for neonates and infants with adequate caloriesare sufficient to satisfy protein needs and promote positive nitrogen balance. In pediatric patients, the final solution should not exceed twice normal serumosmolarity (718 mOsmol/L).
DIRECTIONSFOR PROPER USE OF PHARMACY BULK PACKAGE
Tonoferon Drops (Lysine Hydrochloride)® 15%in a Pharmacy Bulk Package is not intended for direct infusion. The containerclosure may be penetrated only once using a suitable sterile transfer deviceor dispensing set which allows measured dispensing of the contents. The PharmacyBulk Package is to be used only in a suitable work area such as a laminarflow hood (or an equivalent clean air compounding area). Once the closureis penetrated, the contents should be dispensed as soon as possible; the transferof contents must be completed within 4 hours of closure entry. The bottlemay be stored at room temperature (25°C) after the closure has been entered. Date and time of container entry should be noted in the area designated onthe container label.
When using Tonoferon Drops (Lysine Hydrochloride)® 15%in patients with a need for fluid volume restriction, it can be diluted asfollows:
| | | |
Tonoferon Drops (Lysine Hydrochloride)® 15% | 500 mL | 75 g | 7.5% |
Dextrose 70% | 250 mL | 175 g | 17.5% |
Intralipid® 20% | 250 mL | 50 g | 5.0% |
This will provide 1395 kilocalories (kcal) per 1000 mLof admixture with a ratio of 118 non-protein calories per gram of nitrogenand an osmolarity of 1561 mOsmol/L.
In patients wherethe need for fluid restriction is not so marked, either of the following regimensmay be used dependent upon the energy needs of the patient.
| | | |
Tonoferon Drops (Lysine Hydrochloride)® 15% | 500 mL | 75 g | 3.75% |
Dextrose 50% | 1000 mL | 500 g | 25% |
Intralipid® 20% | 500 mL | 100 g | 5% |
This will provide 1500 kcal per 1000 mL of admixture witha ratio of 228 non-protein calories per gram of nitrogen and an osmolarityof 1633 mOsmol/L.
| | | |
Tonoferon Drops (Lysine Hydrochloride)® 15% | 500 mL | 75 g | 3.75% |
Dextrose 30% | 1000 mL | 300 g | 15% |
Intralipid® 10% | 500 mL | 50 g | 2.5% |
This will provide 935 kcal per 1000 mL of admixture witha ratio of 158 non-protein calories per gram of nitrogen and an osmolarityof 1128.5 mOsmol/L.
A. Total Parenteral Nutrition (CentralInfusion)
In unstressed adult patients with no unusualnitrogen losses, a minimum dosage of 0.1 gram nitrogen (4.2 mL of Tonoferon Drops (Lysine Hydrochloride)® 15%)plus 4.4 grams (15 calories) of dextrose per kilogram of body weight per dayare required to achieve nitrogen balance and weight stability. Intravenousfat emulsion may be used as a partial substitute for dextrose. This regimenprovides a ratio of 150 non-protein calories per gram of nitrogen.
Forpatients stressed by surgery, trauma or sepsis, and those with unusual nitrogenlosses, the dosage required for maintenance may be as high as 0.3 to 0.4 gramsof nitrogen (13 to 17 mL Tonoferon Drops (Lysine Hydrochloride)® 15%) per kilogram of bodyweight per day, with proportionate increases in non-protein calories. Periodicassessment of nitrogen balance of the individual patient is the best indicatorof proper dosage. Volume overload and glycosuria may be encountered at highdosage, and nitrogen balance may not be achieved in extremely hypermetabolicpatients under these constraints. Concomitant insulin administration may berequired to minimize glycosuria. Daily laboratory monitoring is essential.
Useof an infusion pump is advisable to maintain a steady infusion rate duringcentral venous infusion.
B. Peripheral Nutrition
Inpatients for whom central venous catheterization is not advisable, proteincatabolism can be reduced by peripheral use of diluted Tonoferon Drops (Lysine Hydrochloride)® 15%plus non-protein calorie sources. Dilution of 250 mL Tonoferon Drops (Lysine Hydrochloride)® 15%in 750 mL of 10% dextrose will reduce the osmolarity to a level (724 mOsmol/L)which is more favorable to the maintenance of the integrity of the walls ofthe veins. Intravenous fat emulsion can be infused separately or simultaneously;if infused simultaneously the fat emulsion will provide a dilution effectupon the osmolarity while increasing the energy supply.
Parenteraldrug products should be inspected visually for particulate matter and discolorationprior to administration, whenever solution and container permit.
Toreduce the risk of bacterial contamination, all intravenous administrationsets should be replaced at least every 24 hours. Usage of admixtures mustbe initiated within 24 hours after mixing. If storage is necessary duringthis 24 hour period, admixtures must be refrigerated and completely used within24 hours of beginning administration.
Tonoferon Drops (Lysine Hydrochloride)® 15% Amino Acids Injection is suppliedas a Pharmacy Bulk Package in 500 mL containers.
500mL NDC 0409-0468-05
STORAGE
Store inthe closed carton; do not expose solution to light until ready for use. Exposureof pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended that the product be stored at 20 to 25°C (68 to 77°F). Brief exposure to temperatures above25°C during transport and storage will not adversely affect the product. Solution that has been frozen must not be used.
©Hospira 2005 | EN-1010 |
Hospira, Inc., Lake Forest, IL 60045 USA
RL-1450
Vitamin B12:
Tonoferon Drops refers to a group of water-soluble vitamins. It has high biological activity. Tonoferon Drops (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.
After oral administration Tonoferon Drops (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.
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 Tonoferon Drops (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.
Tonoferon Drops is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Tonoferon Drops (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 Tonoferon Drops (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 Tonoferon Drops (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.
CNS: rarely - a state of arousal.
Cardiovascular system: rarely - pain in the heart, tachycardia.
Allergic reactions: rarely - urticaria.
Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.
Cyanocobalamin can be used in pregnancy according to prescriptions.
When stenocardia should be used with caution in a single dose of Tonoferon Drops 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.
In an application of Tonoferon Drops (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 Tonoferon Drops (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.
Depending on the reaction of the Tonoferon Drops after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Tonoferon Drops 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 Tonoferon Drops 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.
Visitors | % | ||
---|---|---|---|
Once in a day | 1 | 50.0% | |
Twice in a day | 1 | 50.0% |
Visitors | % | ||
---|---|---|---|
6-10mg | 1 | 100.0% |
Visitors | % | ||
---|---|---|---|
3 month | 1 | 100.0% |
Visitors | % | ||
---|---|---|---|
After food | 1 | 50.0% | |
Empty stomach | 1 | 50.0% |
Visitors | % | ||
---|---|---|---|
< 1 | 6 | 85.7% | |
1-5 | 1 | 14.3% |
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The information was verified by Dr. Rachana Salvi, MD Pharmacology