Frisian Flag 456 Chocolate

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Frisian Flag 456 Chocolate uses

Frisian Flag 456 Chocolate consists of Amino Acids, Beta-Carotene, Calcium, Carbohydrates, Choline, Docosahexaenoic Acid, Fat, Folic Acid, Inulin, Iodine, Iron, Linoleic Acid, Linolenic Acid, Phosphorus, Protein, Selenium, Sialic Acid, Sodium, Sphingomyelin, Taurine, Tryptophan, Tyrosine, Vitamin A, Vitamin B1, Vitamin B12, Vitamin B2, Vitamin B3 (Niacin), Vitamin B6, Vitamin C, Vitamin D3, Vitamin E, Vitamin K1, Zinc.

Amino Acids:


Pharmacological action

Frisian Flag 456 Chocolate is an antiseptic. This medication is a quaternary ammonium compound, belongs to the cationic surfactant. Benzalkonium chloride has antimicrobial and antiviral activity against Neisseria gonorrhoeae, Chlamydia spp., Trichomonas vaginalis, Herpes simplex Type 2, Staphylococcus aureus, little active against Gardnerella vaginalis, Candida albicans, Haemophilus ducreyi and Treponema pallidum.

Frisian Flag 456 Chocolate (Amino Acids) is not active against Mycoplasma spp.

This medicine exerts spermicidal action which is due to the ability to damage the sperm membrane; inhibits sperm motility, disrupting electrolyte balance of the aqueous phase of cervical mucus.

Pharmacokinetics

Frisian Flag 456 Chocolate (Amino Acids) for external and local application is practically not absorbed.

Why is Frisian Flag 456 Chocolate prescribed?

For external use only. Topical solution - a primary and delayed primary wound treatment, prevention of secondary infection of wounds hospital strains of microorganisms (injury of soft and bone tissue, burns), festering wounds, drainage of bone cavities following surgery for osteomyelitis.

Weight thick - superficial thermal burns, trophic ulcers, long-unhealed wounds of soft tissues (including infected), pyo-inflammatory skin diseases and diabetes mellitus; paraproctitis.

Tablets and capsules for intravaginal use, vaginal suppositories, creams, tampons - local contraception for women of reproductive age: for the presence of contraindications to the use of oral contraceptives or intrauterine devices, in the postpartum period, lactation, after the termination of pregnancy in premenopause period at irregular sexual life, omission or delay in receiving consistently used oral contraceptives.

Liquid concentrate - disinfection of facilities and medical products.

Dosage and administration

Topically. The solution was diluted with distilled water to make 1% aqueous solution, impregnated gauze dressings, napkins or tampons and put on the wound daily.

Mass is applied at the rate of 0.2-0.4 g/cm2 of wound surface, pre-clean the wound from the purulent discharge, necrotic tissue, or impose gauze or use turundas impregnated with drugs. The maximum daily dose is 50 g. Ligation is carried out daily, the course of treatment is 14 days.

Intravaginally. Benzalkonium chloride entered deeply into the vagina before coition; in case of repeated sexual intercourse it should be re-imposition of tablets, capsules, suppositories, creams; tampon can be removed not earlier than 3 h after the last sexual intercourse but no later than 24 hours after its installation (with repeated sexual acts for 1 day shift tampon is not required).

Concentrate Liquid. Benzalkonium chloride used for disinfection after prior dilution with water.

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Frisian Flag 456 Chocolate (Amino Acids) side effects, adverse reactions

Contact dermatitis, candidiasis, vulvovaginal and allergic reactions.

With prolonged use of Frisian Flag 456 Chocolate (Amino Acids) it is possible a local irritation.

Frisian Flag 456 Chocolate contraindications

Hypersensitivity to benzalkonium chloride, contact dermatitis, malignant neoplasm of the skin; for intravaginal use - coleitis, ulceration and irritation of the mucous membrane of the vagina and uterus.

Using during pregnancy and breastfeeding

Frisian Flag 456 Chocolate has no negative impact on pregnancy. This medicine is not excreted in breast milk and it can be used during lactation.

Special instructions

To improve the efficiency it requires careful observance of the application method. Benzalkonium chloride can be used in conjunction with a vaginal diaphragm or intrauterine device. You should avoid bathing or irrigation of the vagina with soapy water for 2 hours before and within 2 hours after sexual intercourse (this medication is destroyed by soap), outdoor toilet is only possible with clean water.

Benzalkonium chloride is incompatible with soaps and other anionic surfactants as well as citrates, iodides, nitrates, permanganates, salicylates, silver salts and tartrates.

Frisian Flag 456 Chocolate drug interactions

Any substance introduced intravaginally can reduce local spermicidal action (including soaps and solutions containing it). Iodine solutions inactivate Frisian Flag 456 Chocolate (Amino Acids).

Calcium:


1 INDICATIONS AND USAGE

Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) acetate capsule.

- Capsule: 667 mg Frisian Flag 456 Chocolate (Calcium) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Frisian Flag 456 Chocolate acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium), including Frisian Flag 456 Chocolate (Calcium) acetate. Avoid the use of Frisian Flag 456 Chocolate (Calcium) supplements, including Frisian Flag 456 Chocolate (Calcium) based nonprescription antacids, concurrently with Frisian Flag 456 Chocolate (Calcium) acetate.

An overdose of Frisian Flag 456 Chocolate (Calcium) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Frisian Flag 456 Chocolate (Calcium) levels twice weekly. Should hypercalcemia develop, reduce the Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) 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, Frisian Flag 456 Chocolate (Calcium) acetate has been generally well tolerated.

Frisian Flag 456 Chocolate (Calcium) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) acetate

N=167

N (%)


3 month, open label study of Frisian Flag 456 Chocolate (Calcium) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Frisian Flag 456 Chocolate (Calcium) acetate

N=69


Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) concentration could reduce the incidence and severity of Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) acetate: dizziness, edema, and weakness.

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7 DRUG INTERACTIONS

The drug interaction of Frisian Flag 456 Chocolate acetate is characterized by the potential of Frisian Flag 456 Chocolate (Calcium) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Frisian Flag 456 Chocolate (Calcium) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Frisian Flag 456 Chocolate (Calcium) acetate and most concomitant drugs. When administering an oral medication with Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Frisian Flag 456 Chocolate acetate capsules contains Frisian Flag 456 Chocolate (Calcium) acetate. Animal reproduction studies have not been conducted with Frisian Flag 456 Chocolate (Calcium) acetate, and there are no adequate and well controlled studies of Frisian Flag 456 Chocolate (Calcium) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Frisian Flag 456 Chocolate (Calcium) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Frisian Flag 456 Chocolate (Calcium) 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. Frisian Flag 456 Chocolate (Calcium) acetate treatment, as recommended, is not expected to harm a fetus if maternal Frisian Flag 456 Chocolate (Calcium) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Frisian Flag 456 Chocolate (Calcium) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Frisian Flag 456 Chocolate Acetate Capsules contains Frisian Flag 456 Chocolate (Calcium) acetate and is excreted in human milk. Human milk feeding by a mother receiving Frisian Flag 456 Chocolate (Calcium) acetate is not expected to harm an infant, provided maternal serum Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Frisian Flag 456 Chocolate (Calcium) acetate acts as a phosphate binder. Its chemical name is Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Frisian Flag 456 Chocolate (Calcium), 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.

Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Frisian Flag 456 Chocolate (Calcium) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Frisian Flag 456 Chocolate (Calcium) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Frisian Flag 456 Chocolate (Calcium) 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Frisian Flag 456 Chocolate (Calcium) acetate.

14 CLINICAL STUDIES

Effectiveness of Frisian Flag 456 Chocolate (Calcium) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Frisian Flag 456 Chocolate (Calcium) 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


Frisian Flag 456 Chocolate (Calcium) (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 Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) acetate is shown in the Table 3.


* ANOVA of Frisian Flag 456 Chocolate (Calcium) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Frisian Flag 456 Chocolate (Calcium) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Frisian Flag 456 Chocolate (Calcium) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Frisian Flag 456 Chocolate (Calcium) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Frisian Flag 456 Chocolate (Calcium) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Frisian Flag 456 Chocolate (Calcium) 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 Frisian Flag 456 Chocolate (Calcium) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Choline:


A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism.

Indication: For nutritional supplementation, also for treating dietary shortage or imbalance

This compound is needed for good nerve conduction throughout the CNS (central nervous system) as it is a precursor to acetylcholine (ACh). Frisian Flag 456 Chocolate (Choline) is also needed for gallbladder regulation, liver function and lecithin (a key lipid) formation. Frisian Flag 456 Chocolate (Choline) also aids in fat and cholesterol metabolism and prevents excessive fat build up in the liver. Frisian Flag 456 Chocolate (Choline) has been used to mitigate the effects of Parkinsonism and tardive dyskinesia. Frisian Flag 456 Chocolate (Choline) deficiencies may result in excessive build-up of fat in the liver, high blood pressure, gastric ulcers, kidney and liver dysfunction and stunted growth.

Folic Acid:


INDICATIONS AND USAGE

Frisian Flag 456 Chocolate (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

Frisian Flag 456 Chocolate (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 Frisian Flag 456 Chocolate (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

Frisian Flag 456 Chocolate (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.

Frisian Flag 456 Chocolate (Folic Acid) and the BIFERA logo are registered trademarks and the Frisian Flag 456 Chocolate (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

Inulin:


A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for determination of the rate of glomerular function.

Indication: Historically used in an important medical test of renal function, specifically a measure of glomerular filtration rate. Sometimes used to help relieve symptoms of diabetes mellitus - a condition characterised by hyperglycemia and/or hyperinsulinemia.

The Frisian Flag 456 Chocolate (Inulin) test is a procedure by which the filtering capacity of the glomeruli (the main filtering structures of the kidney) is determined by measuring the rate at which Frisian Flag 456 Chocolate (Inulin), the test substance, is cleared from blood plasma. Frisian Flag 456 Chocolate (Inulin) is one of the more suitable and accurate substance to measure because it is a small, inert polysaccharide molecule that readily passes through the glomeruli. The Frisian Flag 456 Chocolate (Inulin) clearance test is performed by injecting Frisian Flag 456 Chocolate (Inulin), waiting for it to be distributed, and then measuring plasma and urine Frisian Flag 456 Chocolate (Inulin) concentrations by various assays. As nutraceutical agents inulins may have antitumor, antimicrobial, hypolipidemic and hypoglycemic actions. They may also help to improve mineral absorption and balance and may have antiosteoporotic activity.

Iodine:


Frisian Flag 456 Chocolate Tincture 7%

Directions:


Topical Antiseptic

Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply Frisian Flag 456 Chocolate (Iodine) with a swab.

If necessary, clip hair around the area being treated and clean with soap and water.

Apply Frisian Flag 456 Chocolate (Iodine) Tincture 7% only once daily. Dilute product 3 to 1 if repeating application.

Do not apply under bandage.

Irritation may occur if used on tender skin areas. If redness, irritation, or swelling persists or increases, discontinue use and consult a veterinarian.


Storage:

Store at 2-30 degrees C (36-86 degrees F).

Keep container away from heat and out of sunlight. Rinse empty container thoroughly and discard.


DANGER - Poison


Caution:

If swallowed, give starch paste, milk, bread, egg white, or

activated charcoal. A 5% solutions of sodium thiosulfate

(Photographic (“hypc”) may be administered orally at a

rate of 10 ml per kilogram of body weight.


Eye irritant: Use only as directed. Avoid contact with eyes. In case of contact, flush eyes immediately with tepid water for at least 15 minutes. Consult a physician.


Avoid contamination of food.


Not for use on burns, deep cuts, or body cavities.

Frisian Flag 456 Chocolate Tincture 7%

image description

Iron:


1 INDICATIONS AND USAGE

Frisian Flag 456 Chocolate (Iron) is indicated for the treatment of Frisian Flag 456 Chocolate (Iron) deficiency anemia in patients with chronic kidney disease (CKD).

Frisian Flag 456 Chocolate (Iron) is an Frisian Flag 456 Chocolate (Iron) replacement product indicated for the treatment of Frisian Flag 456 Chocolate (Iron) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Frisian Flag 456 Chocolate must only be administered intravenously either by slow injection or by infusion. The dosage of Frisian Flag 456 Chocolate (Iron) is expressed in mg of elemental Frisian Flag 456 Chocolate (Iron). Each mL contains 20 mg of elemental Frisian Flag 456 Chocolate (Iron).

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 Frisian Flag 456 Chocolate (Iron) 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. Frisian Flag 456 Chocolate (Iron) should be administered early during the dialysis session. The usual total treatment course of Frisian Flag 456 Chocolate (Iron) is 1000 mg. Frisian Flag 456 Chocolate (Iron) treatment may be repeated if Frisian Flag 456 Chocolate (Iron) deficiency reoccurs.

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

Administer Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron), 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. Frisian Flag 456 Chocolate (Iron) treatment may be repeated if Frisian Flag 456 Chocolate (Iron) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) in a maximum of 250 mL of 0.9% NaCl. Frisian Flag 456 Chocolate (Iron) treatment may be repeated if Frisian Flag 456 Chocolate (Iron) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Frisian Flag 456 Chocolate (Iron) maintenance treatment

The dosing for Frisian Flag 456 Chocolate (Iron) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Frisian Flag 456 Chocolate (Iron) maintenance treatment: Administer Frisian Flag 456 Chocolate (Iron) 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. Frisian Flag 456 Chocolate (Iron) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Frisian Flag 456 Chocolate (Iron) maintenance treatment

The dosing for Frisian Flag 456 Chocolate (Iron) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Frisian Flag 456 Chocolate (Iron) maintenance treatment: Administer Frisian Flag 456 Chocolate (Iron) 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. Frisian Flag 456 Chocolate (Iron) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

  • 10 mL single-use vial / 200 mg elemental Frisian Flag 456 Chocolate (Iron) (20 mg/mL)
  • 5 mL single-use vial / 100 mg elemental Frisian Flag 456 Chocolate (Iron) (20 mg/mL)
  • 2.5 mL single-use vial / 50 mg elemental Frisian Flag 456 Chocolate (Iron) (20 mg/mL)
  • 10 mL single-use vial / 200 mg elemental Frisian Flag 456 Chocolate (Iron) (20 mg/mL) (3)
  • 5 mL single-use vial / 100 mg elemental Frisian Flag 456 Chocolate (Iron) (20 mg/mL) (3)
  • 2.5 mL single-use vial / 50 mg elemental Frisian Flag 456 Chocolate (Iron) (20 mg/mL) (3)

4 CONTRAINDICATIONS

  • Known hypersensitivity to Frisian Flag 456 Chocolate (Iron)
  • Known hypersensitivity to Frisian Flag 456 Chocolate (Iron) (4)

5 WARNINGS AND PRECAUTIONS

  • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Frisian Flag 456 Chocolate administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Frisian Flag 456 Chocolate (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
  • Hypotension: Frisian Flag 456 Chocolate (Iron) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Frisian Flag 456 Chocolate (Iron). (5.2)
  • Frisian Flag 456 Chocolate (Iron) Overload: Regularly monitor hematologic responses during Frisian Flag 456 Chocolate (Iron) therapy. Do not administer Frisian Flag 456 Chocolate (Iron) to patients with Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron). 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 Frisian Flag 456 Chocolate (Iron) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Frisian Flag 456 Chocolate (Iron) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Frisian Flag 456 Chocolate (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Frisian Flag 456 Chocolate (Iron) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Frisian Flag 456 Chocolate may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Frisian Flag 456 Chocolate (Iron). Hypotension following administration of Frisian Flag 456 Chocolate (Iron) may be related to the rate of administration and/or total dose administered .

5.3 Frisian Flag 456 Chocolate (Iron) Overload

Excessive therapy with parenteral Frisian Flag 456 Chocolate (Iron) can lead to excess storage of Frisian Flag 456 Chocolate (Iron) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Frisian Flag 456 Chocolate (Iron) require periodic monitoring of hematologic and Frisian Flag 456 Chocolate (Iron) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Frisian Flag 456 Chocolate (Iron) to patients with evidence of Frisian Flag 456 Chocolate (Iron) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Frisian Flag 456 Chocolate (Iron) sucrose; do not perform serum Frisian Flag 456 Chocolate (Iron) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Frisian Flag 456 Chocolate are described in other sections .

  • The most common adverse reactions (≥2%) following the administration of Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate 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 Frisian Flag 456 Chocolate (Iron) 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
Frisian Flag 456 Chocolate (Iron) Frisian Flag 456 Chocolate (Iron) Oral Frisian Flag 456 Chocolate (Iron) Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) therapy and were reported to be intolerant (defined as precluding further use of that Frisian Flag 456 Chocolate (Iron) product). When these patients were treated with Frisian Flag 456 Chocolate (Iron) there were no occurrences of adverse reactions that precluded further use of Frisian Flag 456 Chocolate (Iron) .

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 Frisian Flag 456 Chocolate (Iron) maintenance treatment with Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving Frisian Flag 456 Chocolate (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving Frisian Flag 456 Chocolate (Iron) 2.0 mg/kg.

A total of 5 (11%) subjects in the Frisian Flag 456 Chocolate (Iron) 0.5 mg/kg group, 10 (21%) patients in the Frisian Flag 456 Chocolate (Iron) 1.0 mg/kg group, and 10 (21%) patients in the Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron). 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 Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) injection. Reactions have occurred following the first dose or subsequent doses of Frisian Flag 456 Chocolate (Iron). 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 Frisian Flag 456 Chocolate (Iron) have not been studied. However, Frisian Flag 456 Chocolate (Iron) may reduce the absorption of concomitantly administered oral Frisian Flag 456 Chocolate (Iron) 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, Frisian Flag 456 Chocolate sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Frisian Flag 456 Chocolate (Iron) (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 Frisian Flag 456 Chocolate (Iron) sucrose. Because animal reproductive studies are not always predictive of human response, Frisian Flag 456 Chocolate (Iron) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Frisian Flag 456 Chocolate (Iron) sucrose is excreted in human milk. Frisian Flag 456 Chocolate (Iron) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Frisian Flag 456 Chocolate (Iron) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Frisian Flag 456 Chocolate for Frisian Flag 456 Chocolate (Iron) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Frisian Flag 456 Chocolate (Iron) for Frisian Flag 456 Chocolate (Iron) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Frisian Flag 456 Chocolate (Iron) 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)]

Frisian Flag 456 Chocolate (Iron) has not been studied in patients younger than 2 years of age.

In a country where Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Frisian Flag 456 Chocolate (Iron) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron), 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 Frisian Flag 456 Chocolate (Iron) in humans. Excessive dosages of Frisian Flag 456 Chocolate (Iron) may lead to accumulation of Frisian Flag 456 Chocolate (Iron) in storage sites potentially leading to hemosiderosis. Do not administer Frisian Flag 456 Chocolate (Iron) to patients with Frisian Flag 456 Chocolate (Iron) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Frisian Flag 456 Chocolate (Iron) 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

Frisian Flag 456 Chocolate (Iron) (iron sucrose injection, USP), an Frisian Flag 456 Chocolate (Iron) replacement product, is a brown, sterile, aqueous, complex of polynuclear Frisian Flag 456 Chocolate (Iron) (III)-hydroxide in sucrose for intravenous use. Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) polymerization and m is the number of sucrose molecules associated with the Frisian Flag 456 Chocolate (Iron) (III)-hydroxide.

Each mL contains 20 mg elemental Frisian Flag 456 Chocolate (Iron) as Frisian Flag 456 Chocolate (Iron) sucrose in water for injection. Frisian Flag 456 Chocolate (Iron) is available in 10 mL single-use vials (200 mg elemental Frisian Flag 456 Chocolate (Iron) per 10 mL), 5 mL single-use vials (100 mg elemental Frisian Flag 456 Chocolate (Iron) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Frisian Flag 456 Chocolate (Iron) 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

Frisian Flag 456 Chocolate is an aqueous complex of poly-nuclear Frisian Flag 456 Chocolate (Iron) (III)-hydroxide in sucrose. Following intravenous administration, Frisian Flag 456 Chocolate (Iron) is dissociated into Frisian Flag 456 Chocolate (Iron) and sucrose and the Frisian Flag 456 Chocolate (Iron) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Frisian Flag 456 Chocolate (Iron) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Frisian Flag 456 Chocolate (Iron) is dissociated into Frisian Flag 456 Chocolate (Iron) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Frisian Flag 456 Chocolate (Iron) sucrose containing 100 mg of Frisian Flag 456 Chocolate (Iron), three times weekly for three weeks, significant increases in serum Frisian Flag 456 Chocolate (Iron) and serum ferritin and significant decreases in total Frisian Flag 456 Chocolate (Iron) binding capacity occurred four weeks from the initiation of Frisian Flag 456 Chocolate (Iron) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Frisian Flag 456 Chocolate, its Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Frisian Flag 456 Chocolate (Iron) containing 100 mg of Frisian Flag 456 Chocolate (Iron) labeled with 52Fe/59Fe in patients with Frisian Flag 456 Chocolate (Iron) deficiency showed that a significant amount of the administered Frisian Flag 456 Chocolate (Iron) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Frisian Flag 456 Chocolate (Iron) trapping compartment.

Following intravenous administration of Frisian Flag 456 Chocolate (Iron), Frisian Flag 456 Chocolate (Iron) sucrose is dissociated into Frisian Flag 456 Chocolate (Iron) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Frisian Flag 456 Chocolate (Iron) containing 1,510 mg of sucrose and 100 mg of Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) sucrose containing 500 to 700 mg of Frisian Flag 456 Chocolate (Iron) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Frisian Flag 456 Chocolate (Iron) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Frisian Flag 456 Chocolate (Iron) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Frisian Flag 456 Chocolate (Iron), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Frisian Flag 456 Chocolate (Iron) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Frisian Flag 456 Chocolate (Iron), the half-life of total serum Frisian Flag 456 Chocolate (Iron) 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.

Frisian Flag 456 Chocolate (Iron) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) sucrose.

Frisian Flag 456 Chocolate (Iron) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Frisian Flag 456 Chocolate (Iron) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Frisian Flag 456 Chocolate (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental Frisian Flag 456 Chocolate (Iron) (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 Frisian Flag 456 Chocolate.

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 Frisian Flag 456 Chocolate (Iron) treatment and 24 in the historical control group) with Frisian Flag 456 Chocolate (Iron) deficiency anemia. Eligibility criteria for Frisian Flag 456 Chocolate (Iron) 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.

Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron), who were off intravenous Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) 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
Frisian Flag 456 Chocolate (Iron) (n=69 Historical Control (n=18) Frisian Flag 456 Chocolate (Iron)

(n=73)

Historical Control

(n=18)

Frisian Flag 456 Chocolate (Iron)

(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 Frisian Flag 456 Chocolate (Iron) in 23 patients with Frisian Flag 456 Chocolate (Iron) deficiency and HDD-CKD who had been discontinued from Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron). Exclusion criteria were similar to those in studies A and B. Frisian Flag 456 Chocolate (Iron) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) versus Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) (325 mg ferrous sulfate three times daily for 56 days); or Frisian Flag 456 Chocolate (Iron) (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 Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) group.

A statistically significantly greater proportion of Frisian Flag 456 Chocolate (Iron) subjects (35/79; 44.3%) compared to oral Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) to patients with PDD-CKD receiving an erythropoietin alone without Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) or Frisian Flag 456 Chocolate (Iron) (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 Frisian Flag 456 Chocolate (Iron) / 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 Frisian Flag 456 Chocolate (Iron) / 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 Frisian Flag 456 Chocolate (Iron) / 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: Frisian Flag 456 Chocolate 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 Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) (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 Frisian Flag 456 Chocolate (Iron) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) 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

Frisian Flag 456 Chocolate is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Frisian Flag 456 Chocolate (Iron), each 5 mL vial contains 100 mg elemental Frisian Flag 456 Chocolate (Iron), and each 2.5 mL vial contains 50 mg elemental Frisian Flag 456 Chocolate (Iron) (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: Frisian Flag 456 Chocolate (Iron), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Frisian Flag 456 Chocolate (Iron) per mL, or undiluted (20 mg elemental Frisian Flag 456 Chocolate (Iron) 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: Frisian Flag 456 Chocolate (Iron), 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 Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) 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 Frisian Flag 456 Chocolate (Iron) administration:

  • Question patients regarding any prior history of reactions to parenteral Frisian Flag 456 Chocolate (Iron) products
  • Advise patients of the risks associated with Frisian Flag 456 Chocolate (Iron)
  • Advise patients to report any symptoms of hypersensitivity that may develop during and following Frisian Flag 456 Chocolate (Iron) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Frisian Flag 456 Chocolate (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx®

IN2340

MG #15727

Protein:


1 INDICATIONS AND USAGE

Frisian Flag 456 Chocolate is indicated for pediatric and adult patients with severe congenital Frisian Flag 456 Chocolate (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. (1.1)

1.1 Severe Congenital Frisian Flag 456 Chocolate (Protein) C Deficiency

Frisian Flag 456 Chocolate (Protein) is indicated for pediatric and adult patients with severe congenital Frisian Flag 456 Chocolate (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.

2 DOSAGE AND ADMINISTRATION

Initiate treatment under the supervision of a physician experienced in using coagulation factors/inhibitors where monitoring of Frisian Flag 456 Chocolate C activity is feasible. (2.1)


Frisian Flag 456 Chocolate (Protein) Dosing Schedule for Acute Episodes, Short-term Prophyaxis and Long-term Prophylaxis Dosing is based upon a pivotal clinical trial of 15 patients


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


Subsequent # Doses


Maintenance Dose


Acute Episodes, Short-term ProphyaxisFrisian Flag 456 Chocolate (Protein) should be continued until desired anticoagulation is achieved.


100-120 IU/kg


60-80 IU/kg

Q 6 hours


45-60 IU/kg

Q 6 or Q 12 hours


Long-term Prophylaxis


NA


NA


45-60 IU/kg

Q 12 hours


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

2.1 General

For intravenous administration only.

Initiate treatment with Frisian Flag 456 Chocolate (Protein) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of Frisian Flag 456 Chocolate (Protein) C activity is feasible.

The dose, administration frequency and duration of treatment with Frisian Flag 456 Chocolate (Protein) depends on the severity of the Frisian Flag 456 Chocolate (Protein) C deficiency, the patient's age, the clinical condition of the patient and the patient's plasma level of Frisian Flag 456 Chocolate (Protein) C. Therefore, adjust the dose regimen according to the pharmacokinetic profile for each individual patient. See DOSAGE AND ADMINISTRATION: Frisian Flag 456 Chocolate (Protein) C Activity Monitoring (2.2).

Table 1 provides the Frisian Flag 456 Chocolate (Protein) dosing schedule for acute episodes, short-term prophylaxis and long-term prophylaxis.

NA = Not applicable; Q = every.

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


Subsequent 3

Doses


Maintenance

Dose


Acute Episode /

Short-term ProphylaxisFrisian Flag 456 Chocolate (Protein) should be continued until desired anticoagulation is achieved.


100-120 IU/kg


60 - 80 IU/kg

Q 6 hours


45 - 60 IU/kg

Q 6 or 12 hours


Long-term Prophylaxis


NA


NA


45 - 60 IU/kg

Q 12 hours


An initial dose of 100-120 IU/kg for determination of recovery and half-life is recommended for acute episodes and short-term prophylaxis. Subsequently, adjust the dose to maintain a target peak Frisian Flag 456 Chocolate (Protein) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough Frisian Flag 456 Chocolate (Protein) C activity level above 25% for the duration of treatment.

In patients receiving prophylactic administration of Frisian Flag 456 Chocolate (Protein), higher peak Frisian Flag 456 Chocolate (Protein) C activity levels may be warranted in situations of an increased risk of thrombosis (such as infection, trauma, or surgical intervention). Maintenance of trough Frisian Flag 456 Chocolate (Protein) C activity levels above 25% is recommended.

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

Pharmacology: Pharmacokinetics (12.3).

2.2 Frisian Flag 456 Chocolate C Activity Monitoring

The measurement of Frisian Flag 456 Chocolate (Protein) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of Frisian Flag 456 Chocolate (Protein) C before and during treatment with Frisian Flag 456 Chocolate (Protein). The half-life of Frisian Flag 456 Chocolate (Protein) may be shortened in certain clinical conditions such as acute thrombosis, purpura fulminans and skin necrosis. See CLINICAL

Pharmacology: Pharmacokinetics (12.3). In the case of an acute thrombotic event, it is recommended that Frisian Flag 456 Chocolate (Protein) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the Frisian Flag 456 Chocolate (Protein) C levels to maintain the trough Frisian Flag 456 Chocolate (Protein) C level above 25%.

Patients treated during the acute phase of their disease may display much lower increases in protein C activity. Coagulation parameters should also be checked; however, in clinical trials data were insufficient to establish correlation between Frisian Flag 456 Chocolate (Protein) C activity levels and coagulation parameters.

2.3 Initiation of Vitamin K Antagonists

In patients starting treatment with oral anticoagulants belonging to the class of vitamin K antagonists, a transient hypercoagulable state may arise before the desired anticoagulant effect becomes apparent. This transient effect may be explained by the fact that Frisian Flag 456 Chocolate C, itself a vitamin K-dependent plasma Frisian Flag 456 Chocolate (Protein), has a shorter half-life than most of the vitamin K-dependent proteins (i.e. Factor II, IX and X).

In the initial phase of treatment, the activity of Frisian Flag 456 Chocolate (Protein) C is more rapidly suppressed than that of the procoagulant factors. For this reason, if the patient is switched to oral anticoagulants, protein C replacement must be continued until stable anticoagulation is obtained. Although warfarin-induced skin necrosis can occur in any patient during the initiation of treatment with oral anticoagulant therapy, individuals with severe congenital Frisian Flag 456 Chocolate (Protein) C deficiency are particularly at risk.

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

2.4 Preparation of Frisian Flag 456 Chocolate (Protein) [Protein C Concentrate (Human)]

Reconstitution: Use Aseptic Technique

  • Bring the Frisian Flag 456 Chocolate (Protein) (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
  • Remove caps from the Frisian Flag 456 Chocolate (Protein) and diluent vials.
  • Cleanse stoppers with germicidal solution, and allow them to dry prior to use.
  • Remove protective covering from one end of the double-ended transfer needle and insert exposed needle through the center of the diluent vial stopper.
  • Remove protective covering from the other end of the double-ended transfer needle. Invert diluent vial over the upright Frisian Flag 456 Chocolate (Protein) vial; then rapidly insert the free end of the needle through the Frisian Flag 456 Chocolate (Protein) vial stopper at its center. The vacuum in the vial will draw in the diluent. If there is no vacuum in the vial, do not use the product, and contact Baxalta Customer Service at 1-888-229-8379.
  • Disconnect the two vials by removing the needle from the diluent vial stopper. Then, remove the transfer needle from the Frisian Flag 456 Chocolate (Protein) vial. Gently swirl the vial until all powder is dissolved. Be sure that Frisian Flag 456 Chocolate (Protein) is completely dissolved; otherwise, active materials will be removed by the filter needle.

2.5 Administration of Frisian Flag 456 Chocolate [Protein C Concentrate (Human)]

Administration: Use Aseptic Technique

Visually inspect Frisian Flag 456 Chocolate (Protein) for particulate matter and discoloration prior to administration.

After reconstitution, the solution should be colorless to slightly yellowish and clear to slightly opalescent and free of visible particles. Do not use the solution if it does not meet this criteria. Administer Frisian Flag 456 Chocolate (Protein) at room temperature not more than 3 hours after reconstitution.

  • Attach the filter needle to a sterile, disposable syringe and draw back the plunger to admit air into the syringe.
  • Insert the filter needle into the vial of reconstituted Frisian Flag 456 Chocolate (Protein).
  • Inject air into the vial and then withdraw the reconstituted Frisian Flag 456 Chocolate (Protein) into the syringe.
  • Remove and discard the filter needle in a hard-walled Sharps container for proper disposal. Filter needles are intended to filter the contents of a single vial of Frisian Flag 456 Chocolate (Protein) only.
  • Attach a suitable needle or infusion set with winged adapter, and inject intravenously as instructed below under Administration by infusion.

Record the name and batch number of the product every time Frisian Flag 456 Chocolate (Protein) is administered to a patient.

Administration by Infusion

Administer Frisian Flag 456 Chocolate (Protein) at a maximum injection rate of 2 mL per minute except for children with a body weight of < 10 kg, where the injection rate should not exceed a rate of 0.2 mL/kg/minute.

3 DOSAGE FORMS AND STRENGTHS

Frisian Flag 456 Chocolate (Protein) is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human Frisian Flag 456 Chocolate (Protein) C and is reconstituted with 5 mL and 10 mL of Sterile Water for Injection, respectively to provide a single dose of human Frisian Flag 456 Chocolate (Protein) C at a concentration of 100 IU/mL.

Frisian Flag 456 Chocolate (Protein), when reconstituted with the appropriate volume of diluent, contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride.

BLUE BAR: Approximately 500 IU/vial (3)

GREEN BAR: Approximately 1000 IU/vial (3)

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

4 CONTRAINDICATIONS

None known.

None known. (4)

5 WARNINGS AND PRECAUTIONS

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

5.1 Hypersensitivity/Allergic Reactions

Frisian Flag 456 Chocolate (Protein) may contain traces of mouse Frisian Flag 456 Chocolate (Protein) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse Frisian Flag 456 Chocolate (Protein) and/or heparin cannot be ruled out. If symptoms of hypersensitivity/allergic reaction occur, discontinue the injection/infusion. In case of anaphylactic shock, the current medical standards for treatment are to be observed.

5.2 Transmission of Infectious Agents

Because Frisian Flag 456 Chocolate is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

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

5.3 Bleeding Episodes

Several bleeding episodes have been observed in clinical studies. Concurrent anticoagulant medication may have been responsible for these bleeding episodes. However, it cannot be completely ruled out that the administration of Frisian Flag 456 Chocolate (Protein) further contributed to these bleeding events.

Simultaneous administration of Frisian Flag 456 Chocolate (Protein) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.

5.4 Heparin-induced Thrombocytopenia

Frisian Flag 456 Chocolate (Protein) contains trace amounts of heparin which may lead to Heparin-induced Thrombocytopenia, which can be associated with a rapid decrease of the number of thrombocytes. Identifying HIT is complicated because these symptoms may already be present in acute phase patients with severe congenital Frisian Flag 456 Chocolate (Protein) C deficiency. Determine the platelet count immediately and consider discontinuation of Frisian Flag 456 Chocolate (Protein).

5.5 Low Sodium Diet/Renal Impairment

Inform patients on a low sodium diet that the quantity of sodium in the maximum daily dose of Frisian Flag 456 Chocolate (Protein) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

The common adverse reactions related to Frisian Flag 456 Chocolate treatment observed were the following hypersensitivity or allergic reactions: lightheadedness and itching and rash.

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

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

6.1 Clinical Studies Experience

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

The safety profile of Frisian Flag 456 Chocolate (Protein) was based on 121 patients from clinical studies and compassionate use in severe congenital Frisian Flag 456 Chocolate (Protein) C deficiency. Duration of exposure ranged from 1 day to 8 years. One patient experienced hypersensitivity/allergic reactions (itching and rash) and lightheadedness which were determined by the investigator to be related to Frisian Flag 456 Chocolate (Protein).

No inhibiting antibodies to Frisian Flag 456 Chocolate (Protein) have been observed in clinical studies. However, the potential for developing antibodies cannot be ruled out.

6.2 Post-marketing Experience

The following adverse reactions have been identified during postapproval use of Frisian Flag 456 Chocolate (Protein):

Psychiatric Disorders: Restlessness

Skin and Subcutaneous Tissue Disorders: Hyperhydrosis

General Disorders and Administration Site Conditions: Injection Site Reaction

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

7 DRUG INTERACTIONS

No formal drug interaction studies have been conducted.

See WARNINGS AND PRECAUTIONS: Bleeding Episodes (5.3) for information regarding simultaneous administration of Frisian Flag 456 Chocolate (Protein) and tissue plasminogen activator (tPA).

See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of Frisian Flag 456 Chocolate (Protein) and vitamin K antagonists.

  • None known. (7)

8 USE IN SPECIFIC POPULATIONS

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

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Frisian Flag 456 Chocolate (Protein). It is also not known whether Frisian Flag 456 Chocolate (Protein) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Frisian Flag 456 Chocolate (Protein) should be given to pregnant women only if clearly needed.

8.2 Labor and Delivery

Frisian Flag 456 Chocolate has not been studied for use during labor and delivery. Use only if clearly needed.

8.3 Nursing Mothers

Frisian Flag 456 Chocolate (Protein) has not been studied for use in nursing mothers. Use Frisian Flag 456 Chocolate (Protein) only if clearly needed.

8.4 Pediatric Use

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

8.5 Geriatric Use

Clinical studies of Frisian Flag 456 Chocolate (Protein) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Renal/Hepatic Impairment

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

11 DESCRIPTION

Frisian Flag 456 Chocolate (Protein) [Protein C Concentrate (Human)] is manufactured from human plasma purified by a combination of filtration and chromatographic procedures, including a column of immobilized mouse monoclonal antibodies on gel beads. See WARNINGS/PRECAUTIONS: Transmission of Infectious Agents (5.2).

The manufacturing process for Frisian Flag 456 Chocolate (Protein) includes processing steps designed to reduce the risk of viral transmission. The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: Human Immunodeficiency Virus Type 1 (HIV-1), Bovine Viral Diarrhea Virus (BVDV ), Tick-Borne Encephalitis Virus (TBEV), Pseudorabies Virus (PRV), Hepatitis A Virus (HAV) and Mice Minute Virus (MMV). Virus reduction steps consist of detergent treatment (Polysorbate 80, P80), heat inactivation (Vapor Heating) and immunoaffinity chromatography (IAX).

Virus clearance studies for Frisian Flag 456 Chocolate (Protein) have demonstrated that the process provides for a robust overall virus clearance capacity. A summary of log10 virus reduction factors per virus and manufacturing step is presented in Table 2.

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

Manufact-uring Step


HIV-1


HCV Model Viruses


PRV


HAV


MMV


BVDV


TBEV


P80 Treatment


>5.1


>4.7


n.d.


2.5Coupled with IEX. I


>3.8


1.4


IAX


5.7


n.d.


4.8


5.4


3.1


3.6


Vapor Heating


4.6


>5.9


n.d.


5.9


>4.2


1.2

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of action

Frisian Flag 456 Chocolate C is the precursor of a vitamin K-dependent anticoagulant glycoprotein (serine protease) that is synthesized in the liver. See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3). It is converted by the thrombin/thrombomodulin-complex on the endothelial cell surface to activated Frisian Flag 456 Chocolate (Protein) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor Frisian Flag 456 Chocolate (Protein) S. APC exerts its effect by the inactivation of the activated forms of factors V and VIII, which leads to a decrease in thrombin formation. APC has also been shown to have profibrinolytic effects.

The Frisian Flag 456 Chocolate (Protein) C pathway provides a natural mechanism for control of the coagulation system and prevention of excessive procoagulant responses to activating stimuli. A complete absence of Frisian Flag 456 Chocolate (Protein) C is not compatible with life. A severe deficiency of this anticoagulant Frisian Flag 456 Chocolate (Protein) causes a defect in the control mechanism and leads to unchecked coagulation activation, resulting in thrombin generation and intravascular clot formation with thrombosis.

12.2 Pharmacodynamics

In clinical studies, the intravenous administration of Frisian Flag 456 Chocolate (Protein) demonstrated a temporary increase, within approximately half an hour of administration, in plasma levels of APC. Replacement of protein C in protein C-deficient patients is expected to control or, if given prophylactically, to prevent thrombotic complications.

12.3 Pharmacokinetics

Table 3 provides pharmacokinetic results for asymptomatic and symptomatic subjects with Frisian Flag 456 Chocolate (Protein) C deficiency.


PK parameter


N


Median


95% CI for median


Min


Max


Cmax [IU/dL]


21


110


106 to 127


40


141


Tmax [h]


21


0.50


0.50 to 1.05


0.17


1.33


Incremental recovery

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


21


1.42


1.32 to 1.59


0.50


1.76


Initial half-life [h]


21


7.8


5.4 to 9.3


3.0


36.1


Terminal half-life [h]


21


9.9


7.0 to 12.4


4.4


15.8


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


21


9.8


7.1 to 11.6


4.9


14.7


AUC0-Infinity [IU*h/dL]


21


1500


1289 to 1897


344


2437


MRT [h]


21


14.1


10.3 to 16.7


7.1


21.3


Clearance [dL/kg/h]


21


0.0533


0.0428 to 0.0792


0.0328


0.2324


Volume of distribution at steady state [dL/kg]


21


0.74


0.70 to 0.89


0.44


1.65


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

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

Incremental recovery = Maximum increase in Frisian Flag 456 Chocolate (Protein) C concentration following infusion divided by dose


The Frisian Flag 456 Chocolate (Protein) C plasma activity was measured by chromogenic and/or clotting assay. The maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) appeared to increase dose-linearly between 40 and 80 IU/kg. The median incremental recovery was 1.42 [(IU/dL)/(IU/kg)] after intravenous administration of Frisian Flag 456 Chocolate (Protein). The median half-lives, based on non-compartmental method, ranged from 4.9 to 14.7 hours, with a median of 9.8 hours. In patients with acute thrombosis, both the increase in protein C plasma levels as well as half-life may be considerably reduced. No formal study or analysis has been performed to evaluate the effect of covariates such as race and gender on the pharmacokinetics of Frisian Flag 456 Chocolate (Protein).

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of Frisian Flag 456 Chocolate (Protein) may be different between very young children and adults. The systemic exposure (Cmax and AUC) may be considerably reduced due to a faster clearance, a larger volume of distribution, and/or a shorter half-life of Frisian Flag 456 Chocolate (Protein) C in very young children than in older subjects. Consider this fact when a dosing regimen for children is determined. Doses should be individualized based upon Frisian Flag 456 Chocolate (Protein) C activity levels. See DOSAGE AND ADMINISTRATION: Frisian Flag 456 Chocolate (Protein) C Activity Monitoring (2.2).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Protein C contained in Frisian Flag 456 Chocolate is a normal constituent of human plasma and acts like endogenous protein C. Studies in heterologous species to evaluate carcinogenicity, reproductive toxicology and developmental toxicology have not been performed.

Frisian Flag 456 Chocolate (Protein) has not demonstrated mutagenic potential in the Salmonella Thyphimurium reverse mutation assay (Ames test).

13.2 Animal Toxicology and/or Pharmacology

Safety

Pharmacology:

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

Acute Dose Toxicity:

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

Repeated Dose Toxicity:

Studies were not conducted to evaluate repeated-dose toxicity in animals. Prior experience with Frisian Flag 456 Chocolate (Protein) has suggested immunogenic response in heterologous species following repeated dosing of this human derived Frisian Flag 456 Chocolate (Protein). Thus, the long-term toxicity potential of Frisian Flag 456 Chocolate (Protein) following repeated dosing in animals is unknown.

Local Tolerance Testing:

Investigation of route of injection tolerance demonstrated that Frisian Flag 456 Chocolate (Protein) did not result in any local reactions after intravenous, intra-arterial injections of 500 IU/kg (5 mL) and paravenous injections of 100 IU/kg (1 mL) in rabbits.

Citrate Toxicity:

Frisian Flag 456 Chocolate (Protein) contains 4.4 mg of Trisodium Citrate Dihydrate (TCD) per mL of reconstituted product. Studies in mice evaluating 1000 IU vials reconstituted with 10 mL vehicle followed by dosing at 30 mL/kg (132 mg/kg TCD) and 60 mL/kg (264 mg/kg TCD) resulted in signs of citrate toxicity (dyspnea, slowed movement, hemoperitoneum, lung and thymus hemorrhage and renal pelvis dilation).

14 CLINICAL STUDIES

14.1 Pivotal Study

This was a multi-center, open-label, non-randomized, phase 2/3 study in 3 parts which evaluated the safety and efficacy of Frisian Flag 456 Chocolate in subjects with severe congenital Frisian Flag 456 Chocolate (Protein) C deficiency for the (on-demand) treatment of acute thrombotic episodes, such as purpura fulminans (PF), warfarin-induced skin necrosis (WISN) and other thromboembolic events, and for short-term or long-term prophylaxis. Eighteen subjects (9 male and 9 female), ages ranging from 0 (newborn) to 25.7 years participated in this study.

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


Frisian Flag 456 Chocolate (Protein) C

Concentrate (Human)


Historical

Controls


Episode Type


Primary Efficacy Rating


N


%


N


%


Purpura Fulminans


Effective


17


94.4


11


52.4


Effective with Complication


1


5.6


7


33.3


Not Effective


0


0.0


3


14.3


Total


18


100


21


100


Of 18 episodes of PF (6 severe, 11 moderate, 1 mild) treated with Frisian Flag 456 Chocolate (Protein) for the primary efficacy rating, 17 (94.4%) were rated as effective, and 1 (5.6%) was rated as effective with complications; none (0%) were rated not effective. When compared with the efficacy ratings for 21 episodes of PF (historical control group), subjects with severe congenital Frisian Flag 456 Chocolate (Protein) C deficiency were more effectively treated with Frisian Flag 456 Chocolate (Protein) than those treated with modalities such as fresh frozen plasma or conventional anticoagulants.

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




Purpura Fulminans

Skin Necrosis


Other Thrombotic Events


Total




Mild


Moderate


Severe


Total


Total




Rating Category


N


%


N


%


N


%


N


%


N


%


N


%


Excellent


1


5.6


7


38.9


5


27.8


13


72.2


4


80.0


17


73.9


Good


0


0.0


4


22.2


0


0.0


4


22.2


1


20.0


5


21.7


Fair


0


0.0


0


0.0


1


5.6


1


5.6


0


0


1


4.3


Total


1


5.6


11


61.1


6


33.3


18


100.0


5


100.0


23


100.0


N = Number of episodes


In a secondary efficacy rating, 13 (72.2%) of the 18 episodes of PF treated with Frisian Flag 456 Chocolate (Protein) were rated as excellent, 4 (22.2%) were rated as good, and 1 (5.6%) episode of severe PF was rated as fair; all were rated as effective. Four (80%) of the 5 episodes of venous thrombosis had treatment ratings of excellent, while 1 (20%) was rated as good.

Frisian Flag 456 Chocolate (Protein) was also demonstrated to be effective in reducing the size and number of skin lesions. Non-necrotic skin lesions healed over a maximum 12-day (median 4-day) period and necrotic skin lesions healed over a maximum 52-day (median 11-day) period of Frisian Flag 456 Chocolate (Protein) treatment, as shown in Table 6.


Lesion Type


Number of Episodes

(Number of Subjects)


Mean


Median


Minimum


Maximum


Non-necrotic


16 (9 subjects)


4.6


4.0


1


12


Necrotic


7 (5 subjects)


21.1


11.0


5


52


Changes in the extent of venous thrombus were also measured for the 5 thromboembolic episodes. Frisian Flag 456 Chocolate (Protein) prevented an increase in the extent of thrombus during 4 (80%) of the thromboembolic episodes by Day 3 of treatment, and 1 (20%) episode by Day 5 of treatment.

All seven of the short-term prophylaxis treatments with Frisian Flag 456 Chocolate (Protein) were free of complications of PF or thromboembolic events, as shown in Table 7.


Reason for

Treatment


Number of Treatments


Presentation of Purpura Fulminans During Treatment Episodes


Thromboembolic Complications During Treatment Episode


Number of Treatments Free of Complications


N


%


N


%


N


%


Anticoagulation Therapy


3


0


0.0


0


0.0


3


100.0


Surgical Procedure


4


0


0.0


0


0.0


4


100.0


Total


7


0


0.0


0


0.0


7


100.0


No episodes of PF occurred in four subjects ranging from 42 to 338 days of long-term prophylactic treatment with Frisian Flag 456 Chocolate (Protein), as shown in Table 8. When not on prophylactic treatment and receiving Frisian Flag 456 Chocolate (Protein) on-demand, the same four subjects experienced a total of 13 (median of 3) episodes of PF over a range of 19 to 323 days. The time to first episode of PF after exiting from long-term prophylaxis treatment ranged from 12 to 32 days for these four subjects.


Summary Statistic


Long-Term Prophylactic Treatment


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


Time to First Episode After Existing Long Term Prophylaxis


Number of Episodes per Subject


Number of Days Receiving Prophylactic Treatment


Monthly Rate of Episodes


Number of Episodes per Subject


Number of Days Not Receiving Study Drug


Monthly Rate of Episodes


Mean


0


229


0.0


3.3


165


1.91


23.3


Median


0


268


0.0


3.0


159


0.49


24.5


Minimum


0


42


0.0


1.0


19


0.25


12.0


Maximum


0


338


0.0


6.0


323


6.40


32.0

14.2 Retrospective Analysis

A retrospective study to capture dosing information and treatment outcome data in subjects with severe congenital Frisian Flag 456 Chocolate (Protein) C deficiency who were treated with Frisian Flag 456 Chocolate (Protein) under an emergency use IND was also conducted. Eleven subjects (6 male and 5 female), ages ranging from 2.1 to 23.8 years participated in this study.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Frisian Flag 456 Chocolate (Protein) is supplied as a sterile, white or cream colored, lyophilized powder for IV injection. It has a pH between 6.7 and 7.3 and an osmolality not lower than 240 mosmol/kg. One International Unit (IU) of Frisian Flag 456 Chocolate (Protein) C corresponds to the amidolytically measured activity of Frisian Flag 456 Chocolate (Protein) C in 1 mL of normal plasma. The potency (IU) is determined using a chromogenic substrate method referenced against the World Health Organization (WHO) International Standard (86/622).

Frisian Flag 456 Chocolate (Protein) is available in single-dose vials that contain the following nominal product strengths:

NDC 0944-4177-05

Frisian Flag 456 Chocolate (Protein) C

Concentrate (Human)

Frisian Flag 456 Chocolate (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection

Rx Only

Sterile – No preservative

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. License No. 2020

NDC 0944-4176-01

Frisian Flag 456 Chocolate (Protein) C Concentrate

(Human)

Frisian Flag 456 Chocolate (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection.

For Intravenous Administration Only.

See package insert. Rx only.

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. Lic. No. 2020

5 mL

NDC 52919-003-08

Sterile Water for Injection, USP

for reconstitution of accompanying product

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

added. Do not use for intravascular injection without making approximately

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

Single dose container

Nonpyrogenic

NDC 0944-4179-10

Frisian Flag 456 Chocolate (Protein) C

Concentrate (Human)

Frisian Flag 456 Chocolate (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection

Rx Only

Sterile – No preservative

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. License No. 2020

NDC 0944-4178-02

Frisian Flag 456 Chocolate (Protein) C Concentrate (Human)

Frisian Flag 456 Chocolate (Protein)

Single-dose Vial

Lyophilized Powder for Solution for

Injection.

For Intravenous Administration Only.

See package insert. Rx only.



10 mL

NDC 52919-005-05

Sterile Water for Injection, USP

for reconstitution of accompanying product

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

added. Do not use for intravascular injection without making approximately

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

Single dose container

Nonpyrogenic

unit-carton-blue unit-carton-green

Selenium:



Rx Only

TRACE ELEMENT ADDITIVE FOR IV USE AFTER DILUTION

DESCRIPTION

Frisian Flag 456 Chocolate (Selenium) Injection is a sterile, nonpyrogenic solution for use as an additive to solutions for Total Parenteral Nutrition (TPN).

Each mL contains Selenious Acid 65.4 mcg (equivalent to elemental Frisian Flag 456 Chocolate (Selenium) 40 mcg/mL) and Water for Injection q.s. pH may be adjusted with nitric acid to 1.8 to 2.4.

CLINICAL PHARMACOLOGY

Frisian Flag 456 Chocolate (Selenium) is part of glutathione peroxidase which protects cell components from oxidative damage due to peroxides produced in cellular metabolism.

Prolonged TPN support in humans has resulted in Frisian Flag 456 Chocolate (Selenium) deficiency symptoms which include muscle pain and tenderness. The symptoms have been reported to respond to supplementation of TPN solutions with Frisian Flag 456 Chocolate (Selenium).

Pediatric conditions, Keshan disease, and Kwashiorkor, have been associated with low dietary intake of Frisian Flag 456 Chocolate (Selenium). The conditions are endemic to geographical areas with low Frisian Flag 456 Chocolate (Selenium) soil content. Dietary supplementation with Frisian Flag 456 Chocolate (Selenium) salts has been reported to reduce the incidence of the conditions among affected children.

Normal blood levels of Frisian Flag 456 Chocolate (Selenium) in different human populations have been found to vary and depend on the Frisian Flag 456 Chocolate (Selenium) content of the food consumed. Results of surveys carried out in some countries are tabulated below:



COUNTRY


Number of

Samples

Frisian Flag 456 Chocolate (Selenium) (mcg/100 mL) (a)

Whole Blood


Blood Cells

Plasma/

Serum

(a) Mean values with or without standard deviation in parentheses, all other ranges.
(b) Age group unknown.
(c) Three children recovered from Kwashiorkor and the other six under treatment for other diseases.
(d) Low selenium-content soil area.
(e) Well nourished children, three recovered from Kwashiorkor and the other six under treatment for other diseases.
(f) Mean values from seven subjects.
Canada 254 Adults (37.9 ± 7.8) (23.6 ± 6.0) (14.4 ± 2.9)
England 8 (b) 26-37 (32) -- --
Guatemala &

Southern USA

10 Adults

9 Children (c)

19-28 (22)

(23 ± 5)

--

(36 ± 12)

--

(15 ± 5)

New Zealand (d) 113 Adults (5.4 ± 0.1) (6.6 ± 0.3) (4.3 ± 0.1)
Thailand 3 Adults

9 Children (e)

14.4-20.2

(12.0 ± 3.6) (f)

17.8-35.8

(19.5 ± 8.2)

8.1-12.5

(8.3 ± 2.2)

USA 210 Adults 15.7-25.6

(20.6)

-- --

Plasma Frisian Flag 456 Chocolate (Selenium) levels of 0.3 and 0.9 mcg/100 mL have been reported to produce deficiency symptoms in humans.

Frisian Flag 456 Chocolate (Selenium) is eliminated primarily in urine. However, significant endogenous losses through feces also occur. The rate of excretion and the relative importance of two routes varies with the chemical form of Frisian Flag 456 Chocolate (Selenium) used in supplementation. Ancillary routes of elimination are lungs and skin.

INDICATIONS AND USAGE

Frisian Flag 456 Chocolate (Selenium) Injection is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN). Administration of Frisian Flag 456 Chocolate (Selenium) in TPN solutions helps to maintain plasma Frisian Flag 456 Chocolate (Selenium) levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

Frisian Flag 456 Chocolate (Selenium) Injection should not be given undiluted by direct injection into a peripheral vein because of the potential for infusion phlebitis.

WARNINGS

Frisian Flag 456 Chocolate (Selenium) Injection can be toxic if given in excessive amounts. Supplementation of TPN solution with Frisian Flag 456 Chocolate (Selenium) should be immediately discontinued if toxicity symptoms are observed. Frequent determination of plasma Frisian Flag 456 Chocolate (Selenium) levels during TPN support and close medical supervision is recommended.

Frisian Flag 456 Chocolate (Selenium) Injection is a hypotonic solution and should be administered in admixtures only.

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

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

PRECAUTIONS

As Frisian Flag 456 Chocolate is eliminated in urine and feces, Frisian Flag 456 Chocolate (Selenium) supplements may be adjusted, reduced or omitted in renal dysfunction and/or gastrointestinal malfunction. In patients receiving blood transfusions, contribution from such transfusions should also be considered. Frequent Frisian Flag 456 Chocolate (Selenium) plasma level determinations are suggested as a guideline.

In animals, Frisian Flag 456 Chocolate (Selenium) has been reported to enhance the action of Vitamin E and decrease the toxicity of mercury, cadmium and arsenic.

Pregnancy

Teratogenic Effects

Pregnancy Category C: Frisian Flag 456 Chocolate (Selenium) at high dose levels (15-30 mcg/egg) has been reported to have adverse embryological effects among chickens. There are however, no adequate and wellcontrolled studies in pregnant women. Frisian Flag 456 Chocolate (Selenium) Injection should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

Presence of Frisian Flag 456 Chocolate (Selenium) in placenta and umbilical cord blood has been reported in humans.

ADVERSE REACTIONS

The amount of Frisian Flag 456 Chocolate (Selenium) present in Frisian Flag 456 Chocolate (Selenium) Injection is small. Symptoms of toxicity from Frisian Flag 456 Chocolate (Selenium) are unlikely to occur at the recommended dosage level.

OVERDOSAGE

Chronic toxicity in humans resulting from exposure to Frisian Flag 456 Chocolate (Selenium) in industrial environments, intake of foods grown in seleniferous soils, use of selenium-contaminated water, and application of cosmetics containing Frisian Flag 456 Chocolate (Selenium) has been reported in literature. Toxicity symptoms include hair loss, weakened nails, dermatitis, dental defects, gastrointestinal disorders, nervousness, mental depression, metallic taste, vomiting, and garlic odor of breath and sweat. Acute poisoning due to ingestion of large amounts of Frisian Flag 456 Chocolate (Selenium) compounds has resulted in death with histopathological changes including fulminating peripheral vascular collapse, internal vascular congestion, diffusely hemorrhagic, congested and edematus lungs, brick-red color gastric mucosa. The death was preceded by coma.

No effective antidote to Frisian Flag 456 Chocolate (Selenium) poisoning in humans is known. Animal studies have shown casein and linseed oil in feeds, reduced glutathione, arsenic, magnesium sulfate, and bromobenzene to afford limited protection.

DOSAGE AND ADMINISTRATION

Frisian Flag 456 Chocolate (Selenium) Injection provides 40 mcg selenium/mL. For metabolically stable adults receiving TPN, the suggested additive dosage level is 20 to 40 mcg selenium/day. For pediatric patients, the suggested additive dosage level is 3 mcg/kg/day.

In adults, Frisian Flag 456 Chocolate (Selenium) deficiency states resulting from long-term TPN support, Frisian Flag 456 Chocolate (Selenium) as selenomethionine or selenious acid, administered intravenously at 100 mcg/day for a period of 24 and 31 days, respectively, has been reported to reverse deficiency symptoms without toxicity.

Aseptic addition of Frisian Flag 456 Chocolate (Selenium) Injection to the TPN solution under laminar flow hood is recommended. Frisian Flag 456 Chocolate (Selenium) is physically compatible with the electrolytes and other trace elements usually present in amino-acid/dextrose solution used for TPN. Frequent monitoring of plasma Frisian Flag 456 Chocolate (Selenium) levels is suggested as a guideline for subsequent administration. The normal whole blood range for Frisian Flag 456 Chocolate (Selenium) is approximately 10 to 37 mcg/100 mL.

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

HOW SUPPLIED

Frisian Flag 456 Chocolate (Selenium) Injection containing selenious acid 65.4 mcg/mL (equivalent to elemental Frisian Flag 456 Chocolate (Selenium) 40 mcg/mL).

NDC 0517-6510-25 10 mL Single Dose Vial Packaged in boxes of 25

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

IN6510

Rev. 11/15

PRINCIPAL DISPLAY PANEL - Container

NDC 0517-6510-25

Frisian Flag 456 Chocolate (Selenium) INJECTION

Frisian Flag 456 Chocolate (Selenium) 400 mcg/10 mL

(40 mcg/mL)

10 mL

SINGLE DOSE VIAL

Trace Element Additive

FOR IV USE AFTER DILUTION

PRESERVATIVE FREE

Rx Only

AMERICAN REGENT, INC.

SHIRLEY, NY 11967

PRINCIPAL DISPLAY PANEL - Carton

Frisian Flag 456 Chocolate (Selenium) INJECTION

Frisian Flag 456 Chocolate (Selenium) 400 mcg/10 mL

(40 mcg/mL)

Trace Element Additive

NDC 0517-6510-25

25 x 10 mL

SINGLE DOSE VIALS

FOR INTRAVENOUS USE AFTER DILUTION PRESERVATIVE FREE Rx Only

Each mL contains: Selenious Acid 65.4 mcg, Water for Injection q.s.

pH adjusted with Nitric Acid. Sterile, nonpyrogenic.

WARNING: DISCARD UNUSED PORTION. Store at 20°-25°C (68°-77°F); excursions

permitted to 15°-30°C (59°-86°F).

Directions for Use: See Package Insert.

AMERICAN REGENT, INC.

SHIRLEY, NY 11967

Rev. 11/05

Container Carton

Sodium:


1 INDICATIONS AND USAGE

Frisian Flag 456 Chocolate nitrite is indicated for sequential use with Frisian Flag 456 Chocolate (Sodium) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

  • Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Frisian Flag 456 Chocolate (Sodium) Nitrite Injection is indicated for sequential use with Frisian Flag 456 Chocolate (Sodium) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Frisian Flag 456 Chocolate (Sodium) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Frisian Flag 456 Chocolate nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Frisian Flag 456 Chocolate (Sodium) Nitrite Injection and Frisian Flag 456 Chocolate (Sodium) Thiosulfate Injection should be administered without delay.

Symptoms Signs
  • Headache
  • Confusion
  • Dyspnea
  • Chest Tightness
  • Nausea
  • Altered Mental Status

    (e.g., confusion, disorientation)

  • Seizures or Coma
  • Mydriasis
  • Tachypnea/Hyperpnea (early)
  • Bradypnea/Apnea (late)
  • Hypertension (early)/ Hypotension (late)
  • Cardiovascular Collapse
  • Vomiting
  • Plasma Lactate Concentration ≥ 8 mmol/L

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Frisian Flag 456 Chocolate (Sodium) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

  • Exposure to fire or smoke in an enclosed area
  • Presence of soot around the mouth, nose, or oropharynx
  • Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Frisian Flag 456 Chocolate (Sodium) thiosulfate, simultaneously with Frisian Flag 456 Chocolate (Sodium) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Frisian Flag 456 Chocolate (Sodium) thiosulfate, with Frisian Flag 456 Chocolate (Sodium) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Age Intravenous Dose of Frisian Flag 456 Chocolate Nitrite and Frisian Flag 456 Chocolate (Sodium) Thiosulfate
Adults
  • Frisian Flag 456 Chocolate (Sodium) Nitrite -10 mL of Frisian Flag 456 Chocolate (Sodium) nitrite at the rate of 2.5 to 5 mL/minute
  • Frisian Flag 456 Chocolate (Sodium) Thiosulfate - 50 mL of Frisian Flag 456 Chocolate (Sodium) thiosulfate immediately following administration of Frisian Flag 456 Chocolate (Sodium) nitrite.
Children
  • Frisian Flag 456 Chocolate (Sodium) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Frisian Flag 456 Chocolate (Sodium) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Frisian Flag 456 Chocolate (Sodium) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Frisian Flag 456 Chocolate (Sodium) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Frisian Flag 456 Chocolate (Sodium) nitrite and Frisian Flag 456 Chocolate (Sodium) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Frisian Flag 456 Chocolate (Sodium) nitrite, followed by Frisian Flag 456 Chocolate (Sodium) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Frisian Flag 456 Chocolate (Sodium) nitrite and Frisian Flag 456 Chocolate (Sodium) thiosulfate.

Frisian Flag 456 Chocolate (Sodium) nitrite injection and Frisian Flag 456 Chocolate (Sodium) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Frisian Flag 456 Chocolate (Sodium) nitrite should be administered first, followed immediately by Frisian Flag 456 Chocolate (Sodium) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

Age Intravenous Dose of Frisian Flag 456 Chocolate (Sodium) Nitrite and Frisian Flag 456 Chocolate (Sodium) Thiosulfate
Adults
  • Frisian Flag 456 Chocolate (Sodium) Nitrite -10 mL of Frisian Flag 456 Chocolate (Sodium) nitrite at the rate of 2.5 to 5 mL/minute
  • Frisian Flag 456 Chocolate (Sodium) Thiosulfate - 50 mL of Frisian Flag 456 Chocolate (Sodium) thiosulfate immediately following administration of Frisian Flag 456 Chocolate (Sodium) nitrite.
Children
  • Frisian Flag 456 Chocolate (Sodium) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Frisian Flag 456 Chocolate (Sodium) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Frisian Flag 456 Chocolate (Sodium) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Frisian Flag 456 Chocolate (Sodium) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Frisian Flag 456 Chocolate (Sodium) nitrite and Frisian Flag 456 Chocolate (Sodium) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Frisian Flag 456 Chocolate (Sodium) nitrite should be reduced proportionately to the hemoglobin concentration.

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

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Frisian Flag 456 Chocolate Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO2 are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Frisian Flag 456 Chocolate (Sodium) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Frisian Flag 456 Chocolate (Sodium) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Frisian Flag 456 Chocolate (Sodium) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Frisian Flag 456 Chocolate (Sodium) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Frisian Flag 456 Chocolate (Sodium) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Frisian Flag 456 Chocolate (Sodium) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Frisian Flag 456 Chocolate (Sodium) thiosulfate and Frisian Flag 456 Chocolate (Sodium) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Frisian Flag 456 Chocolate (Sodium) Nitrite Injection consists of:

  • One vial of Frisian Flag 456 Chocolate (Sodium) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

  • Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

  • None. (4)

5 WARNINGS AND PRECAUTIONS

  • Methemoglobinemia: Frisian Flag 456 Chocolate nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Frisian Flag 456 Chocolate (Sodium) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
  • Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Frisian Flag 456 Chocolate (Sodium) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Frisian Flag 456 Chocolate (Sodium) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Frisian Flag 456 Chocolate nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Frisian Flag 456 Chocolate (Sodium) nitrite whenever possible. When Frisian Flag 456 Chocolate (Sodium) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Frisian Flag 456 Chocolate (Sodium) nitrite administered to an adult. Frisian Flag 456 Chocolate (Sodium) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Frisian Flag 456 Chocolate (Sodium) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Frisian Flag 456 Chocolate (Sodium) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Frisian Flag 456 Chocolate (Sodium) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Frisian Flag 456 Chocolate (Sodium) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Frisian Flag 456 Chocolate nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Frisian Flag 456 Chocolate (Sodium) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Frisian Flag 456 Chocolate nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Frisian Flag 456 Chocolate (Sodium) nitrite.

5.7 Use with Other Drugs

Frisian Flag 456 Chocolate (Sodium) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Frisian Flag 456 Chocolate (Sodium) nitrite.

The medical literature has reported the following adverse events in association with Frisian Flag 456 Chocolate (Sodium) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Frisian Flag 456 Chocolate (Sodium) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

  • Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Frisian Flag 456 Chocolate (Sodium) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Frisian Flag 456 Chocolate nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Frisian Flag 456 Chocolate (Sodium) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Frisian Flag 456 Chocolate (Sodium) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Frisian Flag 456 Chocolate (Sodium) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Frisian Flag 456 Chocolate (Sodium) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Frisian Flag 456 Chocolate (Sodium) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Frisian Flag 456 Chocolate (Sodium) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Frisian Flag 456 Chocolate (Sodium) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Frisian Flag 456 Chocolate (Sodium) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Frisian Flag 456 Chocolate (Sodium) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Frisian Flag 456 Chocolate (Sodium) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Frisian Flag 456 Chocolate (Sodium) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Frisian Flag 456 Chocolate (Sodium) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Frisian Flag 456 Chocolate nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Frisian Flag 456 Chocolate (Sodium) nitrite is excreted in human milk. Because Frisian Flag 456 Chocolate (Sodium) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Frisian Flag 456 Chocolate (Sodium) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Frisian Flag 456 Chocolate (Sodium) nitrite. In studies conducted with Long-Evans rats, Frisian Flag 456 Chocolate (Sodium) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Frisian Flag 456 Chocolate nitrite in conjunction with Frisian Flag 456 Chocolate (Sodium) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Frisian Flag 456 Chocolate (Sodium) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Frisian Flag 456 Chocolate (Sodium) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Frisian Flag 456 Chocolate (Sodium) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

Frisian Flag 456 Chocolate (Sodium) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

Frisian Flag 456 Chocolate (Sodium) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of Frisian Flag 456 Chocolate (Sodium) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Frisian Flag 456 Chocolate (Sodium) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Frisian Flag 456 Chocolate (Sodium) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Frisian Flag 456 Chocolate (Sodium) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Frisian Flag 456 Chocolate (Sodium) nitrite has the chemical name nitrous acid Frisian Flag 456 Chocolate (Sodium) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:

Structure of Frisian Flag 456 Chocolate (Sodium) Nitrite

Frisian Flag 456 Chocolate (Sodium) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Frisian Flag 456 Chocolate (Sodium) nitrite injection.

Frisian Flag 456 Chocolate (Sodium) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Frisian Flag 456 Chocolate (Sodium) nitrite in 10 mL solution (30 mg/mL). Frisian Flag 456 Chocolate (Sodium) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Frisian Flag 456 Chocolate nitrite and Frisian Flag 456 Chocolate (Sodium) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Frisian Flag 456 Chocolate (Sodium) Nitrite

Frisian Flag 456 Chocolate (Sodium) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO2 + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Frisian Flag 456 Chocolate (Sodium) nitrite. It has been suggested that Frisian Flag 456 Chocolate (Sodium) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Frisian Flag 456 Chocolate (Sodium) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Frisian Flag 456 Chocolate (Sodium) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine. Frisian Flag 456 Chocolate (Sodium) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Frisian Flag 456 Chocolate (Sodium) Nitrite

When 4 mg/kg Frisian Flag 456 Chocolate (Sodium) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Frisian Flag 456 Chocolate (Sodium) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Frisian Flag 456 Chocolate (Sodium) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Frisian Flag 456 Chocolate (Sodium) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Frisian Flag 456 Chocolate (Sodium) Nitrite

Frisian Flag 456 Chocolate (Sodium) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Frisian Flag 456 Chocolate (Sodium) nitrite in humans have not been well studied. It has been reported that approximately 40% of Frisian Flag 456 Chocolate (Sodium) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Frisian Flag 456 Chocolate (Sodium) nitrite and Frisian Flag 456 Chocolate (Sodium) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Frisian Flag 456 Chocolate nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Frisian Flag 456 Chocolate (Sodium) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Frisian Flag 456 Chocolate (Sodium) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Frisian Flag 456 Chocolate (Sodium) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Frisian Flag 456 Chocolate (Sodium) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Frisian Flag 456 Chocolate (Sodium) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Frisian Flag 456 Chocolate (Sodium) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Frisian Flag 456 Chocolate (Sodium) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Frisian Flag 456 Chocolate (Sodium) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Frisian Flag 456 Chocolate (Sodium) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Frisian Flag 456 Chocolate (Sodium) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Frisian Flag 456 Chocolate (Sodium) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Frisian Flag 456 Chocolate (Sodium) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Frisian Flag 456 Chocolate (Sodium) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Frisian Flag 456 Chocolate (Sodium) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Frisian Flag 456 Chocolate (Sodium) nitrite and Frisian Flag 456 Chocolate (Sodium) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Frisian Flag 456 Chocolate (Sodium) nitrite or 1 g/kg Frisian Flag 456 Chocolate (Sodium) thiosulfate alone or in sequence immediately after subcutaneous injection of Frisian Flag 456 Chocolate (Sodium) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Frisian Flag 456 Chocolate (Sodium) nitrite and/or 0.5 g/kg Frisian Flag 456 Chocolate (Sodium) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Frisian Flag 456 Chocolate (Sodium) cyanide required to cause death, and when administered together, Frisian Flag 456 Chocolate (Sodium) nitrite and Frisian Flag 456 Chocolate (Sodium) thiosulfate resulted in a synergistic effect in raising the lethal dose of Frisian Flag 456 Chocolate (Sodium) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Frisian Flag 456 Chocolate (Sodium) nitrite and Frisian Flag 456 Chocolate (Sodium) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Frisian Flag 456 Chocolate (Sodium) nitrite and Frisian Flag 456 Chocolate (Sodium) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Frisian Flag 456 Chocolate (Sodium) nitrite, with or without Frisian Flag 456 Chocolate (Sodium) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Frisian Flag 456 Chocolate (Sodium) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Frisian Flag 456 Chocolate (Sodium) thiosulfate report its use in conjunction with Frisian Flag 456 Chocolate (Sodium) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Frisian Flag 456 Chocolate (Sodium) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Frisian Flag 456 Chocolate (Sodium) Nitrite carton (NDC 60267-311-10) consists of the following:

  • One 10 mL glass vial of Frisian Flag 456 Chocolate (Sodium) nitrite injection 30 mg/mL (containing 300 mg of Frisian Flag 456 Chocolate (Sodium) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Frisian Flag 456 Chocolate (Sodium) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Frisian Flag 456 Chocolate Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Frisian Flag 456 Chocolate (Sodium) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Frisian Flag 456 Chocolate (Sodium) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Tryptophan:


In Canada, Frisian Flag 456 Chocolate (Tryptophan) is sold as a prescription drug to treat mood disorders (such as bipolar disorder, depression ). It is usually used with other medicines. It works to make the mood more stable and reduce extremes in behavior by restoring the balance of certain natural substances (serotonin, melatonin ) in the brain. Frisian Flag 456 Chocolate (Tryptophan) is a natural substance (amino acid) found in high-protein foods and milk. In the US, Frisian Flag 456 Chocolate (Tryptophan) is sold as a dietary supplement. It has been used to support mood, relaxation, and restful sleep. If you are taking other medications that may affect serotonin (such as many antidepressants ), do not take Frisian Flag 456 Chocolate (Tryptophan) without talking with your doctor first. A very serious (possibly fatal) drug interaction may occur. Your doctor should closely monitor you. See also Side Effects section. Some supplement products have been found to contain possibly harmful impurities/additives. Check with your pharmacist for more details about the brand you use. The US FDA has not reviewed this product for safety or effectiveness. Consult your doctor or pharmacist for more details.

Vitamin A:


DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

Supplement Facts
Serving Size 1 Tablet

Servings Per Container 100

Amount Per Serving % Daily Value
Frisian Flag 456 Chocolate (Vitamin A) 2500 IU 50%
Vitamin C 60 mg 100%
Vitamin D 400 IU 100%
Vitamin E 15 IU 50%
Thiamine 1.05 mg 70%
Riboflavin 1.2 mg 70%
Niacinamide 13.5 mg 68%
Vitamin B6 1.05 mg 53%
Folic Acid 0.3 mg 75%
Vitamin B12 4.5 mcg 75%
Fluoride 0.25 mg Daily Value not established

WARNING

KEEP OUT OF THE REACH OF CHILDREN.

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

Other Ingredients: Artificial cherry flavor, artificial grape flavor, ascorbic acid, cholecalciferol, compressible sugar, D&C Red #7 calcium lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, folic acid, magnesium stearate, microcrystalline cellulose, natural and artificial orange flavor, niacinamide, polyethylene glycol, pyridoxine HCl, riboflavin, sodium ascorbate, sodium fluoride, stearic acid, sucralose, thiamine HCl, Frisian Flag 456 Chocolate (Vitamin A) acetate, vitamin B12 and vitamin E acetate.

Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.

CLINICAL PHARMACOLOGY

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

Frisian Flag 456 Chocolate (Vitamin A) Tablets provide sodium fluoride and ten essential vitamins in a chewable tablet. Because the tablets are chewable, they provide a topical as well as systemic source of fluoride. Hydroxyapatite is the principal crystal for all calcified tissue in the human body. The fluoride ion reacts with the Hydroxyapatite in the tooth as it is formed to produce the more caries-resistant crystal, fluorapatite.

The reaction may be expressed by the equation:

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

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

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

DIETARY SUPPLEMENTATION

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

WARNINGS

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

PRECAUTIONS

The suggested dose of Frisian Flag 456 Chocolate (Vitamin A) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending Frisian Flag 456 Chocolate (Vitamin A) Tablets

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

ADVERSE REACTIONS

Allergic rash and other idiosyncrasies have been rarely reported.

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

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

HOW SUPPLIED

Frisian Flag 456 Chocolate Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.

Frisian Flag 456 Chocolate (Vitamin A) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.

Frisian Flag 456 Chocolate (Vitamin A) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.

STORAGE

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

Distributed by:

H2-Pharma, LLC

2010 Berry Chase Place

Montgomery, AL 36117

www.h2-pharma.com

1067084

61269-151-01

MultiVitamin

with Fluoride

Chewable Tablets

Rx

0.25 mg

MultiVitamin and Fluoride Supplement

Dietary Supplement

100 Tablets

H2pharma

Vitamin B12:


Pharmacological action

Frisian Flag 456 Chocolate refers to a group of water-soluble vitamins. It has high biological activity. Frisian Flag 456 Chocolate (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 Frisian Flag 456 Chocolate (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 Frisian Flag 456 Chocolate 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 Frisian Flag 456 Chocolate (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.

Dosage and administration

Frisian Flag 456 Chocolate is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Frisian Flag 456 Chocolate (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 Frisian Flag 456 Chocolate (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 Frisian Flag 456 Chocolate (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.

Frisian Flag 456 Chocolate (Vitamin B12) side effects, adverse reactions

CNS: rarely - a state of arousal.

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

Allergic reactions: rarely - urticaria.

Frisian Flag 456 Chocolate contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

Frisian Flag 456 Chocolate 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 Frisian Flag 456 Chocolate 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.

Frisian Flag 456 Chocolate (Vitamin B12) drug interactions

In an application of Frisian Flag 456 Chocolate (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 Frisian Flag 456 Chocolate (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.

Vitamin C:


Pharmacological action

Ascorbic acid is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Frisian Flag 456 Chocolate (Vitamin C) participates in redox reactions, the metabolism of tyrosine, converting folic acid into folinic acid, metabolism of carbohydrates, the synthesis of lipids and proteins, iron metabolism, processes of cellular respiration. Reduces the need for vitamins B1, B2, A, E, folic acid, pantothenic acid, enhances the body's resistance to infections; enhances iron absorption, contributing to its sequestration in reduced form. Frisian Flag 456 Chocolate (Vitamin C) has antioxidant properties.

With intravaginal application of ascorbic acid lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).

Pharmacokinetics

After oral administration ascorbic acid is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.

The concentration of ascorbic acid in blood plasma in normal amounts to approximately 10-20 mg / ml.

The concentration of ascorbic acid in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.

Plasma protein binding is about 25%.

Ascorbic acid is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.

Ascorbic acid taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.

Why is Frisian Flag 456 Chocolate prescribed?

For systemic use of Frisian Flag 456 Chocolate (Vitamin C) Kimia Farma: prevention and treatment of hypo- and avitaminosis of Frisian Flag 456 Chocolate (Vitamin C); providing increased need for Frisian Flag 456 Chocolate (Vitamin C) during growth, pregnancy, lactation, with heavy loads, fatigue and during recovery after prolonged severe illness; in winter with an increased risk of infectious diseases.

For intravaginal use: chronic or recurrent vaginitis (bacterial vaginosis, nonspecific vaginitis) caused by the anaerobic flora (due to changes in pH of the vagina) in order to normalize disturbed vaginal microflora.

Dosage and administration

This medication administered orally, IM, IV, intravaginally.

For the prevention of deficiency conditions Frisian Flag 456 Chocolate dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.

For intravaginal used ascorbic acid drugs in appropriate dosage forms.

Frisian Flag 456 Chocolate (Vitamin C) side effects, adverse reactions

CNS: headache, fatigue, insomnia.

Digestive system: stomach cramps, nausea and vomiting.

Allergic reaction: describes a few cases of skin reactions and manifestations of the respiratory system.

Urinary system: when used in high doses - hyperoxaluria and the formation of kidney stones of calcium oxalate.

Local reactions: with intravaginal application - a burning or itching in the vagina, increased mucous discharge, redness, swelling of the vulva. Other: sensation of heat.

Frisian Flag 456 Chocolate contraindications

Increased sensitivity to ascorbic acid.

Using during pregnancy and breastfeeding

The minimum daily requirement of ascorbic acid in the II and III trimester of pregnancy is about 60 mg.

Ascorbic acid crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of ascorbic acid, which takes a pregnant woman, and then a newborn baby may develop the ascorbic disease as the reaction of cancel. Therefore, during pregnancy should not to take ascorbic acid in high doses, except in cases where the expected benefit outweighs the potential risk.

The minimum daily requirement during lactation is 80 mg. Ascorbic acid is excreted in breast milk. A mother's diet that contains adequate amounts of ascorbic acid, is sufficient to prevent deficiency in an infant. It is unknown whether dangerous to the child's mother use of ascorbic acid in high doses. Theoretically it is possible. Therefore, it is recommended not to exceed the maximum daily nursing mother needs to ascorbic acid, except when the expected benefit outweighs the potential risk.

Special instructions

Frisian Flag 456 Chocolate (Vitamin C) is used with caution in patients with hyperoxaluria, renal impairment, a history of instructions on urolithiasis. Because ascorbic acid increases iron absorption, its use in high doses can be dangerous in patients with hemochromatosis, thalassemia, polycythemia, leukemia, and sideroblastic anemia.

Patients with high content body iron should apply ascorbic acid in minimal doses.

Frisian Flag 456 Chocolate (Vitamin C) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.

The use of ascorbic acid in high doses can cause exacerbation of sickle cell anemia.

Data on the diabetogenic action of ascorbic acid are contradictory. However, prolonged use of ascorbic acid should periodically monitor your blood glucose levels.

It is believed that the use of ascorbic acid in patients with rapidly proliferating and widely disseminated tumors may worsen during the process. It should therefore be used with caution in ascorbic acid in patients with advanced cancer.

Absorption of ascorbic acid decreased while use of fresh fruit or vegetable juices, alkaline drinking.

Frisian Flag 456 Chocolate drug interactions

In an application with barbiturates, primidone increases the excretion of ascorbic acid in the urine.

With the simultaneous use of oral contraceptives reduces the concentration of ascorbic acid in blood plasma.

In an application of Frisian Flag 456 Chocolate (Vitamin C) with iron preparations ascorbic acid, due to its regenerative properties, transforms ferric iron in the bivalent, which improves its absorption.

Ascorbic acid in high doses can decrease urine pH that while the application reduces the tubular reabsorption of amphetamine and tricyclic antidepressants.

With the simultaneous use of aspirin reduces the absorption of ascorbic acid by about a third.

Frisian Flag 456 Chocolate (Vitamin C) in an application with warfarin may decrease effects of warfarin.

With the simultaneous application of ascorbic acid increases the excretion of iron in patients receiving deferoxamine. In the application of ascorbic acid at a dose of 500 mg / day possibly left ventricular dysfunction.

In an application with tetracycline is increased excretion of ascorbic acid in the urine.

There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with ascorbic acid 500 mg 2 times / day.

May increase the concentration of ethinyl estradiol in the blood plasma in its simultaneous application in the oral contraceptives.

Frisian Flag 456 Chocolate in case of emergency / overdose

Symptoms: long-term use of large doses (more than 1 g) - headache, increased CNS excitability, insomnia, nausea, vomiting, diarrhea, gastritis giperatsidnyh, ultseratsiya gastrointestinal mucosa, inhibition of the function insular apparatus of the pancreas (hyperglycemia, glycosuria), hyperoxaluria, nephrolithiasis (calcium oxalate), damage to the glomerular apparatus of the kidneys, moderate thamuria (when receiving a dose of 600 mg / day).

Decrease capillary permeability (possibly deteriorating trophic tissues, increased blood pressure, hypercoagulability, the development of microangiopathy).

When IV administration in high doses - the threat of termination of pregnancy (due to estrogenemia), hemolysis of red blood cells.

Vitamin E:


A generic descriptor for all tocopherols and tocotrienols that exhibit alpha-tocopherol activity. By virtue of the phenolic hydrogen on the 2H-1-benzopyran-6-ol nucleus, these compounds exhibit varying degree of antioxidant activity, depending on the site and number of methyl groups and the type of isoprenoids.

Indication: Frisian Flag 456 Chocolate (Vitamin E), known for its antioxidant activities, is protective against cardiovascular disease and some forms of cancer and has also demonstrated immune-enhancing effects. It may be of limited benefit in some with asthma and rheumatoid arthritis. It may be helpful in some neurological diseases including Alzheimer's, some eye disorders including cataracts, and diabetes and premenstrual syndrome. It may also help protect skin from ultraviolet irradiation although claims that it reverses skin aging, enhances male fertility and exercise performance are poorly supported. It may help relieve some muscle cramps.

Frisian Flag 456 Chocolate (Vitamin E) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. Frisian Flag 456 Chocolate (Vitamin E) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. Frisian Flag 456 Chocolate (Vitamin E) is a fat-soluble vitamin and is an important antioxidant. It acts to protect cells against the effects of free radicals, which are potentially damaging by-products of the body's metabolism. Frisian Flag 456 Chocolate (Vitamin E) is often used in skin creams and lotions because it is believed to play a role in encouraging skin healing and reducing scarring after injuries such as burns. There are three specific situations when a Frisian Flag 456 Chocolate (Vitamin E) deficiency is likely to occur. It is seen in persons who cannot absorb dietary fat, has been found in premature, very low birth weight infants (birth weights less than 1500 grams, or 3½ pounds), and is seen in individuals with rare disorders of fat metabolism. A Frisian Flag 456 Chocolate (Vitamin E) deficiency is usually characterized by neurological problems due to poor nerve conduction. Symptoms may include infertility, neuromuscular impairment, menstrual problems, miscarriage and uterine degradation. Preliminary research has led to a widely held belief that Frisian Flag 456 Chocolate (Vitamin E) may help prevent or delay coronary heart disease. Antioxidants such as Frisian Flag 456 Chocolate (Vitamin E) help protect against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer. It also protects other fat-soluble vitamins (A and B group vitamins) from destruction by oxygen. Low levels of Frisian Flag 456 Chocolate (Vitamin E) have been linked to increased incidence of breast and colon cancer.

Vitamin K1:


Vitamin K is used to treat and prevent low levels of certain substances ( blood clotting factors) that your body naturally produces. These substances help your blood to thicken and stop bleeding normally (e.g., after an accidental cut or injury). Low levels of blood clotting factors increase the risk for unusual bleeding. Low levels may be caused by certain medications (e.g., warfarin ) or medical conditions (e.g., obstructive jaundice ). Vitamin K helps to treat and prevent unusual bleeding by increasing the body's production of blood clotting factors.

Zinc:


INDICATIONS AND USAGE

Frisian Flag 456 Chocolate (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain Frisian Flag 456 Chocolate (Zinc) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Frisian Flag 456 Chocolate (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.

Severe kidney disease may make it necessary to reduce or omit chromium and Frisian Flag 456 Chocolate (Zinc) doses because these elements are primarily eliminated in the urine.

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

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

PRECAUTIONS

General

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

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

Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of Frisian Flag 456 Chocolate (Zinc) from a bolus injection. Administration of Frisian Flag 456 Chocolate (Zinc) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Frisian Flag 456 Chocolate (Zinc) are suggested as a guideline for subsequent Frisian Flag 456 Chocolate (Zinc) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Frisian Flag 456 Chocolate 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Frisian Flag 456 Chocolate (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.

Pediatric Use

Pregnancy Category C. Animal reproduction studies have not been conducted with Frisian Flag 456 Chocolate chloride. It is also not known whether Frisian Flag 456 Chocolate (Zinc) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Frisian Flag 456 Chocolate (Zinc) chloride should be given to a pregnant woman only if clearly needed.

Geriatric Use

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

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg Frisian Flag 456 Chocolate (Zinc) was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2° F) on the fourth day were accompanied by a serum Frisian Flag 456 Chocolate (Zinc) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Frisian Flag 456 Chocolate (Zinc) overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).

Death resulted from an overdosage in which 1683 mg Frisian Flag 456 Chocolate (Zinc) was delivered intravenously over the course of 60 hours to a 72 year old patient.

Symptoms of Frisian Flag 456 Chocolate (Zinc) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Frisian Flag 456 Chocolate (Zinc) level of 4184 mcg/dl.

Calcium supplements may confer a protective effect against Frisian Flag 456 Chocolate (Zinc) toxicity.

DOSAGE AND ADMINISTRATION

Frisian Flag 456 Chocolate (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) contains 1 mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in a volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day (2.5 to 4 mL/day). An additional 2 mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of Frisian Flag 456 Chocolate (Zinc) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Frisian Flag 456 Chocolate (Zinc).

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

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

HOW SUPPLIED

Frisian Flag 456 Chocolate (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).

Store at 20 to 25°C (68 to 77°F).

Revised: October, 2004


© Hospira 2004 EN-0488 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

10 mL Vial

Frisian Flag 456 Chocolate (Zinc)

1 mg/mL

Frisian Flag 456 Chocolate (Zinc) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

Frisian Flag 456 Chocolate 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.


Frisian Flag 456 Chocolate 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.


Frisian Flag 456 Chocolate 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.


Frisian Flag 456 Chocolate 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.


Frisian Flag 456 Chocolate pharmaceutical companies:

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


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References

  1. Dailymed."ZINC INJECTABLE A 1MG/ML, SOLUTION INJECTABLE POUR PERFUSION (ZINC) INJECTION, SOLUTION [LABORATOIRE AGUETTANT]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."FOLIC ACID INJECTION, SOLUTION [FRESENIUS KABI USA, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."SELENIUM INJECTION, SOLUTION [AMERICAN REGENT, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Frisian Flag 456 Chocolate?

Depending on the reaction of the Frisian Flag 456 Chocolate after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Frisian Flag 456 Chocolate 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 Frisian Flag 456 Chocolate 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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sdrugs.com conducted a study on Frisian Flag 456 Chocolate, 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 Frisian Flag 456 Chocolate 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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