Clinical Results Intensive Therapy Serum

Ammonium Stearate:

• Indications and usage
• Contraindications
• Warning
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Clinical Results Intensive Therapy Serum (Ammonium Stearate) reviews

INDICATIONS AND USAGE

Clinical Results Intensive Therapy Serum (Ammonium Stearate) Lactate Lotion, 12% is indicated for the treatment of dry, scaly skin (xerosis) and ichthyosis vulgaris, and for the temporary relief of itching associated with these conditions.

CONTRAINDICATIONS

Clinical Results Intensive Therapy Serum (Ammonium Stearate) Lactate Lotion, 12% is contraindicated in those patients with a history of hypersensitivity to any of the label ingredients.

WARNING

Sun exposure (natural or artificial sunlight) to areas of the skin treated with Clinical Results Intensive Therapy Serum (Ammonium Stearate) Lactate Lotion, 12% should be minimized or avoided (see PRECAUTIONS). The use of Clinical Results Intensive Therapy Serum (Ammonium Stearate) Lactate Lotion, 12% should be discontinued if any hypersensitivity is observed.

PRECAUTIONS

General -

For external use only. Stinging or burning may occur when applied to skin with fissures, erosions, or that is otherwise abraded. Caution is advised when used on the face because of the potential for irritation. The potential for post-inflammatory hypo- or hyperpigmentation has not been studied.

Information for Patients

Patients using Clinical Results Intensive Therapy Serum (Ammonium Stearate) Lactate Lotion, 12% should receive the following information and instructions:

• This medication is to be used as directed by the physician, and should not be used for any disorder other than for which it was prescribed. It is for external use only. Avoid contact with eyes, lips, or mucous membranes.
• Patients should minimize or avoid use of this product on areas of the skin that may be exposed to natural or artificial sunlight, including the face. If sun exposure is unavoidable, clothing should be worn to protect the skin.
• This medication may cause transient stinging or burning when applied to skin with fissures, erosions, or abrasions (for example, after shaving the legs).
• If the skin condition worsens with treatment, the medication should be promptly discontinued.

Carcinogenesis, Mutagenesis, Impairment of Fertility -

The topical treatment of CD-1 mice with 12%, 21% or 30% Clinical Results Intensive Therapy Serum lactate formulations for two-years did not produce a significant increase in dermal or systemic tumors in the absence of increased exposure to ultraviolet radiation. The maximum systemic exposure of the mice in this study was 0.7 times the maximum possible systemic exposure in humans. However, a long-term photocarcinogenicity study in hairless albino mice suggested that topically applied 12% Clinical Results Intensive Therapy Serum (Ammonium Stearate) lactate formulations enhanced the rate of ultraviolet light-induced skin tumor formation.

The mutagenic potential of Clinical Results Intensive Therapy Serum (Ammonium Stearate) lactate formulations was evaluated in the Ames assay and in the mouse in vivo micronucleus assay, both of which were negative.

In dermal Segment I and III studies with Clinical Results Intensive Therapy Serum (Ammonium Stearate) lactate formulations there were no effects observed in fertility or pre- or postnatal development parameters in rats at dose levels of 300 mg/kg/day (1800 mg/m²/day), approximately 0.4 times the human topical dose.

Pregnancy:

Teratogenic effects:

Pregnancy Category B -

Animal reproduction studies have been performed in rats and rabbits at doses up to 0.7 and 1.5 times the human dose, respectively and have revealed no evidence of impaired fertility or harm to the fetus due to Clinical Results Intensive Therapy Serum (Ammonium Stearate) lactate formulations. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Clinical Results Intensive Therapy Serum (Ammonium Stearate) Lactate Lotion, 12% should be used during pregnancy only if clearly needed.

Nursing Mothers -

Although lactic acid is a normal constituent of blood and tissues, it is not known to what extent this drug affects normal lactic acid levels in human milk. Because many drugs are excreted in human milk, caution should be exercised when Clinical Results Intensive Therapy Serum (Ammonium Stearate) lactate is administered to a nursing woman.

Pediatric Use -

Safety and effectiveness of Clinical Results Intensive Therapy Serum lactate have been demonstrated in infants and children. No unusual toxic effects were reported.

Geriatric Use -

Clinical studies of Clinical Results Intensive Therapy Serum (Ammonium Stearate) lactate lotion, 12% did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious.

ADVERSE REACTIONS

The most frequent adverse experiences in patients with xerosis are transient stinging (1 in 30 patients), burning (1 in 30 patients), erythema (1 in 50 patients) and peeling (1 in 60 patients). Other adverse reactions which occur less frequently are irritation, eczema, petechiae, dryness, and hyperpigmentation. Due to the more severe initial skin conditions associated with ichthyosis, there was a higher incidence of transient stinging, burning and erythema (each occurring in 1 in 10 patients).

OVERDOSAGE

The oral administration of Clinical Results Intensive Therapy Serum (Ammonium Stearate) lactate to rats and mice showed this drug to be practically non-toxic (LD₅₀>15 mL/kg).

DOSAGE AND ADMINISTRATION

Shake well. Apply to the affected areas and rub in thoroughly. Use twice daily or as directed by a physician.

HOW SUPPLIED

Clinical Results Intensive Therapy Serum Lactate Lotion, 12% is available as follows:

225 g bottle (NDC 45802-419-54)

400 g bottle (NDC 45802-419-26)

STORAGE

Store at 20-25°C (68-77°F).

Manufactured By Perrigo, Bronx, NY 10457

Distributed By Perrigo, Allegan, MI 49010

0K5A7 RC F6

Rev 01-17

Benzyl Alcohol:

• Active ingredients
• Uses
• Warnings
• Directions
• Other information
• Inactive ingredients
• Clinical Results Intensive Therapy Serum (Benzyl Alcohol) reviews

Active Ingredients

Clinical Results Intensive Therapy Serum Alcohol 10%

Camphor 0.6%

Menthol 0.4%

Purpose

External Analgesic

Uses

for the temporary relief of itching associated with insect bites and minor skin irritations.

Warnings

For external use only.

Do not use

• face or genital areas
• on a reas of blistered or broken skin
• with a compress after application

When using this product

do not get into eyes if contact occurs, flush eyes with water

Stop use and ask a doctor if

• condition worsens
• symptoms last more than 7 days or clear up and occur again within a few days.

If pregnant or breastfeeding

ask a health professional before use.

Keep out of reach of children.

If swallowed, get medical help or contact Poison Control Center right away.

Directions

• Apply to affected area not more than 3 times daily.
• Children under 2 years of age: do not use, ask a doctor.
• Severe reactions to Urushiol (the chemical released by the plant, which causes the irritation) can look like chemical burns and have a thick leathery appearance. Additional applications may be necessary.
  

• Test product on small patch of skin before applying to the entire body.

Other information

• Store at room temperature.
• You may report a serious adverse reaction to Report Reaction, LLC. PO Box 22, Plainsboro, NJ 08536-0222.
  

Inactive Ingredients

Water, Structure XL, Cutina GMS, Phenoxol T, Cremaphor CO 40, Butylene Glycol, Zinc Acetate, Steareth-2,

Steareth-20, Steareth 100, Proaqua ISL, Pelemol IPM, Estol 1543, Glydant Plus, Dimethicone, VE Acetate, Allantoin.

Made in the U.S.A. for:

IVY-DRY, INC.

299-B Fairfield Ave.

Fairfield, NJ 07070

©2012 Ivy-Dry, Inc.

Questions or Comments

www.ivydry.com

If you get Poison Ivy,

you know you’ll want

to use a product with

proven effectiveness

that you can trust.

Look no further than

Clinical Results Intensive Therapy Serum (Benzyl Alcohol) Products

known and trusted

for over 60 years.

TEMPORARY

RELIEF

OF PAIN

AND ITCHING

Associated with Minor Skin

Irritations and Insect Bites

External Analgesic

Clinical Results Intensive Therapy Serum (Benzyl Alcohol) Cream Clinical Results Intensive Therapy Serum (Benzyl Alcohol) Cream

Copper Sulfate:

• Indications:
• General directions:
• Active ingredient:
• Inactive ingredients:
• Caution:
• Storage:
• Net contents:
• Clinical Results Intensive Therapy Serum (Copper Sulfate) reviews

Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Clinical Results Intensive Therapy Serum (Copper Sulfate) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of Clinical Results Intensive Therapy Serum (Copper Sulfate)^®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Clinical Results Intensive Therapy Serum (Copper Sulfate)^® onto hair since contact with Clinical Results Intensive Therapy Serum (Copper Sulfate)^® may cause some hair loss. Do not contaminate feed.

NOTE: Clinical Results Intensive Therapy Serum (Copper Sulfate)^® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

Clinical Results Intensive Therapy Serum (Copper Sulfate) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,^® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Fragrance:

• Pharmacological action
• Pharmacokinetics
• Why is Clinical Results Intensive Therapy Serum prescribed?
• Dosage and administration
• Clinical Results Intensive Therapy Serum (Fragrance) side effects, adverse reactions
• Clinical Results Intensive Therapy Serum contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Clinical Results Intensive Therapy Serum drug interactions
• Clinical Results Intensive Therapy Serum (Fragrance) reviews

Pharmacological action

Clinical Results Intensive Therapy Serum 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.

Clinical Results Intensive Therapy Serum (Fragrance) 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

Clinical Results Intensive Therapy Serum (Fragrance) for external and local application is practically not absorbed.

Why is Clinical Results Intensive Therapy Serum 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.

Clinical Results Intensive Therapy Serum (Fragrance) side effects, adverse reactions

Contact dermatitis, candidiasis, vulvovaginal and allergic reactions.

With prolonged use of Clinical Results Intensive Therapy Serum (Fragrance) it is possible a local irritation.

Clinical Results Intensive Therapy Serum 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

Clinical Results Intensive Therapy Serum 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.

Clinical Results Intensive Therapy Serum drug interactions

Any substance introduced intravaginally can reduce local spermicidal action (including soaps and solutions containing it). Iodine solutions inactivate Clinical Results Intensive Therapy Serum (Fragrance).

Glycerol:

• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Clinical Results Intensive Therapy Serum (Glycerol) reviews

Clinical Results Intensive Therapy Serum (Glycerol) is indicated for use as a nitrogen-binding agent for chronic management of patients 2 months of age and older with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Clinical Results Intensive Therapy Serum (Glycerol) must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).

Limitations of Use:

• Clinical Results Intensive Therapy Serum (Glycerol) is not indicated for the treatment of acute hyperammonemia in patients with UCDs because more rapidly acting interventions are essential to reduce plasma ammonia levels.
• The safety and efficacy of Clinical Results Intensive Therapy Serum (Glycerol) for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.

Clinical Results Intensive Therapy Serum (Glycerol) is a nitrogen-binding agent indicated for chronic management of patients 2 months of age and older with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Clinical Results Intensive Therapy Serum (Glycerol) must be used with dietary protein restriction and, in some cases, dietary supplements. (1)

Limitations of Use:

• Clinical Results Intensive Therapy Serum (Glycerol) is not indicated for treatment of acute hyperammonemia in patients with UCDs. (1)
• Safety and efficacy for treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established. (1)

2 DOSAGE AND ADMINISTRATION

• Clinical Results Intensive Therapy Serum should be prescribed by a physician experienced in management of UCDs. For administration and preparation, see full prescribing information. (2.1, 2.6)

Switching From Sodium Phenylbutyrate Tablets or Powder to Clinical Results Intensive Therapy Serum (Glycerol):

• Patients should receive the dosage of Clinical Results Intensive Therapy Serum (Glycerol) that contains the same amount of phenylbutyric acid, see full prescribing information for conversion. (2.2)

Initial Dosage in Phenylbutyrate-Naïve Patients (2.3):

• Recommended dosage range is 4.5 to 11.2 mL/m²/day (5 to 12.4 g/m²/day).
• For patients with some residual enzyme activity not adequately controlled with dietary restriction, the recommended starting dose is 4.5 mL/m²/day.
• Take into account patient's estimated urea synthetic capacity, dietary protein intake, and diet adherence.

Dosage Adjustment and Monitoring:

• Follow plasma ammonia levels to determine the need for dosage titration. (2.4)

Dosage Modifications in Patients with Hepatic Impairment:

• Start dosage at lower end of range. (2.5, 8.6)

2.1 Important Administration Instructions

Clinical Results Intensive Therapy Serum (Glycerol) should be prescribed by a physician experienced in the management of UCDs.

• Instruct patients to take Clinical Results Intensive Therapy Serum (Glycerol) with food or formula and to administer directly into the mouth via oral syringe or dosing cup.
• For patients who cannot swallow, see the instructions on administration of Clinical Results Intensive Therapy Serum (Glycerol) by nasogastric tube or gastrostomy tube .
• For patients who require a volume of less than 1 mL per dose via nasogastric or gastrostomy tube, the delivered dose may be less than anticipated. Closely monitor these patients using ammonia levels .
• The recommended dosages for patients switching from sodium phenylbutyrate to Clinical Results Intensive Therapy Serum (Glycerol) and patients naïve to phenylbutyric acid are different . For both subpopulations:
  • Patients 2 years of age and older: Give Clinical Results Intensive Therapy Serum (Glycerol) in 3 equally divided dosages, each rounded up to the nearest 0.5 mL
  • Patients 2 months of age to less than 2 years: Give Clinical Results Intensive Therapy Serum (Glycerol) in 3 or more equally divided dosages, each rounded up to the nearest 0.1 mL.
  • The maximum total daily dosage is 17.5 mL (19 g).
  • Clinical Results Intensive Therapy Serum (Glycerol) must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).

2.2 Switching From Sodium Phenylbutyrate to Clinical Results Intensive Therapy Serum

Patients switching from sodium phenylbutyrate to Clinical Results Intensive Therapy Serum (Glycerol) should receive the dosage of Clinical Results Intensive Therapy Serum (Glycerol) that contains the same amount of phenylbutyric acid. The conversion is as follows:

Total daily dosage of Clinical Results Intensive Therapy Serum (Glycerol) (mL) = total daily dosage of sodium phenylbutyrate tablets (g) × 0.86

Total daily dosage of Clinical Results Intensive Therapy Serum (Glycerol) (mL) = total daily dosage of sodium phenylbutyrate powder (g) × 0.81

2.3 Initial Dosage in Phenylbutyrate-Naïve Patients

The recommended dosage range, based upon body surface area, in patients naïve to phenylbutyrate is 4.5 to 11.2 mL/m²/day (5 to 12.4 g/m²/day). For patients with some residual enzyme activity who are not adequately controlled with protein restriction, the recommended starting dosage is 4.5 mL/m²/day.

In determining the starting dosage of Clinical Results Intensive Therapy Serum (Glycerol) in treatment-naïve patients, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered PBA dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated Clinical Results Intensive Therapy Serum (Glycerol) dose for a 24-hour period is 0.6 mL Clinical Results Intensive Therapy Serum (Glycerol) per gram of dietary protein ingested per 24-hour period. The total daily dosage should not exceed 17.5 mL.

2.4 Dosage Adjustment and Monitoring

During treatment with Clinical Results Intensive Therapy Serum (Glycerol), patients should be followed clinically and with plasma ammonia levels to determine the need for dosage titration. Closely monitor ammonia levels after changing the dosage of Clinical Results Intensive Therapy Serum (Glycerol).

Normal Ammonia Levels

If patients experience symptoms of vomiting, nausea, headache, somnolence or confusion in the absence of high ammonia levels or other intercurrent illnesses, reduce the Clinical Results Intensive Therapy Serum (Glycerol) dosage and monitor patients clinically. If available, obtain measurements of plasma phenylacetate (PAA) concentrations and the ratio of plasma PAA to PAGN to guide dosing. A high PAA to PAGN ratio may indicate the saturation of the conjugation reaction to form PAGN. The PAA to PAGN ratio has been observed to be generally less than 1 in patients with UCDs without significant PAA accumulation .

Elevated Ammonia Levels

When plasma ammonia is elevated, increase the Clinical Results Intensive Therapy Serum (Glycerol) dosage to reduce the fasting ammonia level to less than half the upper limit of normal (ULN) in patients 6 years and older. In infants and pediatric patients (generally below 6 years of age), where obtaining fasting ammonia is problematic due to frequent feedings, adjust the dosage to keep the first ammonia of the morning below the ULN.

Urinary Phenylacetylglutamine: If available, U-PAGN measurements may be used to help guide Clinical Results Intensive Therapy Serum (Glycerol) dosage adjustment. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the ULN, the Clinical Results Intensive Therapy Serum (Glycerol) dosage should be adjusted upward. The amount of dosage adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-hour U-PAGN level and the estimated Clinical Results Intensive Therapy Serum (Glycerol) dose needed per gram of dietary protein ingested and the maximum total daily dosage (i.e., 17.5 mL).

Consider a patient's use of concomitant medications, such as probenecid, when making dosage adjustment decisions based on U-PAGN. Probenecid may result in a decrease of the urinary excretion of PAGN .

Plasma Phenylacetate and Phenylacetylglutamine: If available, the ratio of PAA to PAGN in plasma may provide additional information to assist in dosage adjustment decisions. In patients with a high PAA to PAGN ratio, a further increase in Clinical Results Intensive Therapy Serum (Glycerol) dosage may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction .

2.5 Dosage Modifications in Patients with Hepatic Impairment

For patients with moderate to severe hepatic impairment, the recommended starting dosage is at the lower end of the recommended dosing range and kept at the lowest dose necessary to control the patient's ammonia levels .

2.6 Preparation for Nasogastric Tube or Gastrostomy Tube Administration

It is recommended that all patients who can swallow take Clinical Results Intensive Therapy Serum (Glycerol) orally, even those with nasogastric and/or gastrostomy tubes. However, for patients who cannot swallow, a nasogastric tube or gastrostomy tube may be used to administer Clinical Results Intensive Therapy Serum (Glycerol) as follows:

• Utilize an oral syringe to withdraw the prescribed dosage of Clinical Results Intensive Therapy Serum (Glycerol) from the bottle.
• Place the tip of the syringe into the nasogastric/gastrostomy tube.
• Utilizing the plunger of the syringe, administer Clinical Results Intensive Therapy Serum (Glycerol) into the tube.
• Flush once with 10 mL of water or formula and allow the flush to drain.
• If needed, flush a second time with an additional 10 mL of water or formula to clear the tube.

For patients who require a volume of less than 1 mL per dose via nasogastric or gastrostomy tube, the delivered dosage may be less than anticipated due to adherence of Clinical Results Intensive Therapy Serum (Glycerol) to the plastic tubing. Therefore, these patients should be closely monitored using ammonia levels following initiation of Clinical Results Intensive Therapy Serum (Glycerol) dosing or dosage adjustments.

3 DOSAGE FORMS AND STRENGTHS

Oral liquid: colorless to pale yellow, 1.1 g/mL of Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate).

Oral liquid: 1.1 g/mL. (3)

4 CONTRAINDICATIONS

Clinical Results Intensive Therapy Serum (Glycerol) is contraindicated in patients

• Less than 2 months of age. Pediatric patients less than 2 months of age may have immature pancreatic exocrine function, which could impair hydrolysis of Clinical Results Intensive Therapy Serum (Glycerol), leading to impaired absorption of phenylbutyrate and hyperammonemia .
• With known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.

• Patients less than 2 months of age. (4)
• Known hypersensitivity to phenylbutyrate. (4)

5 WARNINGS AND PRECAUTIONS

• Neurotoxicity: Phenylacetate, the active moiety of Clinical Results Intensive Therapy Serum (Glycerol), may be toxic; reduce dosage for symptoms of neurotoxicity. (5.1)
• Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption: Monitor ammonia levels closely. (5.2)

5.1 Neurotoxicity

The major metabolite of Clinical Results Intensive Therapy Serum (Glycerol), PAA, is associated with neurotoxicity. Signs and symptoms of PAA neurotoxicity, including somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of preexisting neuropathy, were observed at plasma PAA concentrations of 500 micrograms/mL in a study of adult cancer patients who were administered PAA intravenously. In this study, adverse reactions were reversible.

In healthy subjects, after administration of 4 mL and 6 mL Clinical Results Intensive Therapy Serum (Glycerol) 3 times daily for 3 days, a dose-dependent increase in all-grade nervous system adverse reactions was observed, even at exposure levels of PAA less than 100 micrograms/mL.

In clinical trials in patients with UCDs who had been on sodium phenylbutyrate prior to administration of Clinical Results Intensive Therapy Serum (Glycerol), peak PAA concentrations after dosing with Clinical Results Intensive Therapy Serum (Glycerol) ranged from 1.6 to 178 micrograms/mL (mean: 39 micrograms/mL) in adult patients, from 1 to 410 micrograms/mL (mean: 70 micrograms/mL; median: 50 micrograms/mL) in pediatric patients ages 2 years and older, and from 1 to 1215 micrograms/mL (mean: 142 micrograms/mL; median: 35 micrograms/mL) in pediatric patients ages 2 months to less than 2 years. Some patients with UCDs experienced headache, fatigue, symptoms of peripheral neuropathy, seizures, tremor and/or dizziness. No correlation between PAA levels and neurotoxicity symptoms was identified but PAA levels were generally not measured at the time of neurotoxicity symptoms.

If symptoms of vomiting, nausea, headache, somnolence or confusion, are present in the absence of high ammonia or other intercurrent illnesses, reduce the Clinical Results Intensive Therapy Serum (Glycerol) dosage .

5.2 Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption

Exocrine pancreatic enzymes hydrolyze Clinical Results Intensive Therapy Serum (Glycerol) in the small intestine, separating the active moiety, phenylbutyrate, from Clinical Results Intensive Therapy Serum (Glycerol). This process allows phenylbutyrate to be absorbed into the circulation. Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorption may result in reduced or absent digestion of Clinical Results Intensive Therapy Serum (Glycerol) and/or absorption of phenylbutyrate and reduced control of plasma ammonia. Monitor ammonia levels closely in patients with pancreatic insufficiency or intestinal malabsorption.

6 ADVERSE REACTIONS

Most common adverse reactions in adults are: diarrhea, flatulence, and headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Horizon Therapeutics at 1-855-823-7878 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials 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 clinical practice.

Assessment of adverse reactions was based on exposure of 45 adult patients (31 female and 14 male) with UCD subtype deficiencies of ornithine transcarbamylase (OTC, n=40), carbamyl phosphate synthetase (CPS, n=2), and argininosuccinate synthetase (ASS, n=1) in a randomized, double-blind, active-controlled (RAVICTI vs sodium phenylbutyrate), crossover, 4-week study (Study 1) that enrolled patients 18 years of age and older . One of the 45 patients received only sodium phenylbutyrate prior to withdrawing on day 1 of the study due to an adverse reaction.

The most common adverse reactions (occurring in at least 10% of patients) reported during short-term treatment with Clinical Results Intensive Therapy Serum (Glycerol) were diarrhea, flatulence, and headache. Table 1 summarizes adverse reactions occurring in 2 or more patients treated with Clinical Results Intensive Therapy Serum (Glycerol) or sodium phenylbutyrate (incidence of at least 4% in either treatment arm).

Other Adverse Reactions

Clinical Results Intensive Therapy Serum (Glycerol) has been evaluated in 77 patients with UCDs (51 adult and 26 pediatric patients ages 2 years to 17 years) in 2 open-label long-term studies, in which 69 patients completed 12 months of treatment with Clinical Results Intensive Therapy Serum (Glycerol) (median exposure = 51 weeks). During these studies there were no deaths.

Adverse reactions occurring in at least 10% of adult patients were nausea, vomiting, diarrhea, decreased appetite, dizziness, headache, and fatigue.

Adverse reactions occurring in at least 10% of pediatric patients ages 2 years to 17 years were upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, and headache.

Clinical Results Intensive Therapy Serum (Glycerol) has also been evaluated in 17 patients with UCDs ages 2 months to less than 2 years in 3 open-label studies. The median exposure was 6 months (range 0.2 to 18 months). Adverse reactions occurring in at least 10% of pediatric patients aged 2 months to less than 2 years were neutropenia, vomiting, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash and papule.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Clinical Results Intensive Therapy Serum (Glycerol). 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:

• Abnormal body odor, including from skin, hair and urine
• Retching and gagging
• Dysgeusia or burning sensation in mouth

7 DRUG INTERACTIONS

• Corticosteroids, valproic acid, or haloperidol: May increase plasma ammonia level; monitor ammonia levels closely.
• Probenecid: May affect renal excretion of metabolites of Clinical Results Intensive Therapy Serum (Glycerol), including phenylacetylglutamine (PAGN) and PAA. (7.2)
• CYP3A4 Substrates with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine): Clinical Results Intensive Therapy Serum (Glycerol) may decrease exposure; monitor for decreased efficacy of the narrow therapeutic index drug. (7.3)
• Midazolam: Decreased exposure; monitor for suboptimal effect of midazolam. (7.3)

7.1 Potential for Other Drugs to Affect Ammonia

Corticosteroids

Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels. Monitor ammonia levels closely when corticosteroids and Clinical Results Intensive Therapy Serum (Glycerol) are used concomitantly.

Valproic Acid and Haloperidol

Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor ammonia levels closely when use of valproic acid or haloperidol is necessary in patients with UCDs.

7.2 Potential for Other Drugs to Affect Clinical Results Intensive Therapy Serum

Probenecid

Probenecid may inhibit the renal excretion of metabolites of Clinical Results Intensive Therapy Serum (Glycerol) including PAGN and PAA.

7.3 Potential for Clinical Results Intensive Therapy Serum to Affect Other Drugs

Drugs with narrow therapeutic index that are substrates of CYP3A4

Clinical Results Intensive Therapy Serum (Glycerol) is a weak inducer of CYP3A4 in humans. Concomitant use of Clinical Results Intensive Therapy Serum (Glycerol) may decrease the systemic exposure to drugs that are substrates of CYP3A4. Monitor for decreased efficacy of drugs with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine) .

Midazolam

Concomitant use of Clinical Results Intensive Therapy Serum (Glycerol) decreased the systemic exposure of midazolam. Monitor for suboptimal effect of midazolam in patients who are being treated with Clinical Results Intensive Therapy Serum (Glycerol).

8 USE IN SPECIFIC POPULATIONS

Lactation: Breastfeeding is not recommended.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Clinical Results Intensive Therapy Serum (Glycerol) during pregnancy. Healthcare providers are encouraged to report any prenatal exposure to Clinical Results Intensive Therapy Serum (Glycerol) by calling the Pregnancy Registry at 1-855-823-2595 or visiting www.ucdregistry.com.

Risk Summary

Limited available data with Clinical Results Intensive Therapy Serum (Glycerol) use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. In an animal reproduction study, administration of oral Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate to pregnant rabbits during organogenesis at doses up to 2.7–times the dose of 6.87 mL/m²/day in adult patients resulted in maternal toxicity, but had no effects on embryo-fetal development. In addition, there were no adverse developmental effects with administration of oral Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate to pregnant rats during organogenesis at 1.9 times the dose of 6.87 mL/m²/day in adult patients; however, maternal toxicity, reduced fetal weights, and variations in skeletal development were observed in pregnant rats administered oral Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate during organogenesis at doses greater than or equal to 5.7 times the dose of 6.87 mL/m²/day in adult patients [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Oral administration of Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate during the period of organogenesis up to 350 mg/kg/day in rabbits produced maternal toxicity, but no effects on embryo-fetal development. The dose of 350 mg/kg/day in rabbits is approximately 2.7 times the dose of 6.87 mL/m²/day in adult patients, based on combined area under the plasma concentration-time curve [AUCs] for PBA and PAA. In rats, at an oral dose of 300 mg/kg/day of Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate (1.9 times the dose of 6.87 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA) during the period of organogenesis, no effects on embryo-fetal development were observed. Doses of 650 mg/kg/day or greater produced maternal toxicity and adverse effects on embryo-fetal development including reduced fetal weights and cervical ribs at the 7th cervical vertebra. The dose of 650 mg/kg/day in rats is approximately 5.7 times the dose of 6.87 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA. No developmental abnormalities, effects on growth, or effects on learning and memory were observed through maturation of offspring following oral administration in pregnant rats with up to 900 mg/kg/day of Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate (8.5 times the dose of 6.87 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA) during organogenesis and lactation.

8.2 Lactation

Risk Summary

There are no data on the presence of Clinical Results Intensive Therapy Serum in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including neurotoxicity and tumorigenicity in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Clinical Results Intensive Therapy Serum (Glycerol).

8.4 Pediatric Use

Safety and efficacy of Clinical Results Intensive Therapy Serum (Glycerol) have been established in pediatric patients 2 months of age and older with UCDs.

Clinical Results Intensive Therapy Serum (Glycerol) is contraindicated in pediatric patients less than 2 months of age .

Patients 2 Years to Less Than 18 Years of Age

The safety and efficacy of Clinical Results Intensive Therapy Serum (Glycerol) in patients 2 years to less than 18 years of age were established in 2 open-label, sodium phenylbutyrate to Clinical Results Intensive Therapy Serum (Glycerol), fixed-sequence, switchover clinical studies .

Patients 2 Months to Less Than 2 Years of Age

The safety and efficacy of Clinical Results Intensive Therapy Serum (Glycerol) in patients with UCDs, 2 months to less than 2 years of age were established in 3 open-label studies. Pharmacokinetics and pharmacodynamics (plasma ammonia), and safety were studied in 17 patients between 2 months and less than 2 years of age .

Patients Less Than 2 Months of Age

Clinical Results Intensive Therapy Serum (Glycerol) is contraindicated in patients less than 2 months of age . Pediatric patients less than 2 months of age may have immature pancreatic exocrine function, which could impair hydrolysis of Clinical Results Intensive Therapy Serum (Glycerol). Pancreatic lipases may be necessary for intestinal hydrolysis of Clinical Results Intensive Therapy Serum (Glycerol), allowing release of phenylbutyrate and subsequent formation of PAA, the active moiety. It is not known whether pancreatic and extrapancreatic lipases are sufficient for hydrolysis of Clinical Results Intensive Therapy Serum (Glycerol). If there is inadequate intestinal hydrolysis of Clinical Results Intensive Therapy Serum (Glycerol), impaired absorption of phenylbutyrate and hyperammonemia could occur.

Juvenile Animal Toxicity Data

In a juvenile rat study with daily oral dosing performed on postpartum day 2 through mating and pregnancy after maturation, terminal body weight was dose-dependently reduced by up to 16% in males and 12% in females at 900 mg/kg/day or higher (3 times the dose of 6.87 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA). Learning, memory, and motor activity endpoints were not affected. However, fertility (number of pregnant rats) was decreased by up to 25% at 650 mg/kg/day or higher (2.6 times the dose of 6.87 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA).

8.5 Geriatric Use

Clinical studies of Clinical Results Intensive Therapy Serum did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the 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.

8.6 Renal Impairment

The efficacy and safety of Clinical Results Intensive Therapy Serum (Glycerol) in patients with renal impairment are unknown. Monitor ammonia levels closely when starting patients with impaired renal function on Clinical Results Intensive Therapy Serum (Glycerol).

8.7 Hepatic Impairment

No studies were conducted in patients with UCDs and hepatic impairment. Because conversion of PAA to PAGN occurs in the liver, patients with hepatic impairment may have reduced conversion capability and higher plasma PAA and PAA to PAGN ratio . Therefore, dosage for patients with moderate to severe hepatic impairment should be started at the lower end of the recommended dosing range and should be kept on the lowest dose necessary to control their ammonia levels .

10 OVERDOSAGE

While there is no experience with overdosage in human clinical trials, PAA, a toxic metabolite of Clinical Results Intensive Therapy Serum (Glycerol), can accumulate in patients who receive an overdose .

If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

11 DESCRIPTION

Clinical Results Intensive Therapy Serum (Glycerol) (glycerol phenylbutyrate) is a clear, colorless to pale yellow oral liquid. It is insoluble in water and most organic solvents, and it is soluble in dimethylsulfoxide (DMSO) and greater than 65% acetonitrile.

Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate is a nitrogen-binding agent. It is a triglyceride containing 3 molecules of PBA linked to a Clinical Results Intensive Therapy Serum (Glycerol) backbone, the chemical name of which is benzenebutanoic acid, 1', 1' ' –(1,2,3-propanetriyl) ester with a molecular weight of 530.67. It has a molecular formula of C₃₃H₃₈O₆. The structural formula is:

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia. Absence of these enzymes or transporters results in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Clinical Results Intensive Therapy Serum (Glycerol) is a triglyceride containing 3 molecules of phenylbutyrate (PBA). PAA, the major metabolite of PBA, is the active moiety of Clinical Results Intensive Therapy Serum (Glycerol). PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form PAGN, which is excreted by the kidneys (Figure 1). On a molar basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.

Figure 1: RAVICTI Mechanism of Action

12.2 Pharmacodynamics

Pharmacological Effects

In clinical studies, total 24-hour area under the plasma concentration-time curve (AUC) of ammonia concentration was comparable at steady state during the switchover period between Clinical Results Intensive Therapy Serum (Glycerol) and sodium phenylbutyrate .

Cardiac Electrophysiology

The effect of multiple doses of Clinical Results Intensive Therapy Serum (Glycerol) 13.2 g/day and 19.8 g/day (approximately 69% and 104% of the maximum recommended daily dosage) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg), four-treatment-arm, crossover study in 57 healthy subjects. The upper bound of the one-sided 95% CI for the largest placebo-adjusted, baseline-corrected QTc, based on individual correction method (QTcI) for Clinical Results Intensive Therapy Serum (Glycerol), was below 10 ms. However, assay sensitivity was not established in this study because the moxifloxacin time-profile was not consistent with expectation. Therefore, an increase in mean QTc interval of 10 ms cannot be ruled out.

12.3 Pharmacokinetics

Absorption

Clinical Results Intensive Therapy Serum (Glycerol) is a pro-drug of PBA. Upon oral ingestion, PBA is released from the Clinical Results Intensive Therapy Serum (Glycerol) backbone in the gastrointestinal tract by lipases. PBA derived from Clinical Results Intensive Therapy Serum (Glycerol) is further converted by β-oxidation to PAA.

In healthy, fasting adult subjects receiving a single oral dose of 2.9 mL/m² of Clinical Results Intensive Therapy Serum (Glycerol), peak plasma levels of PBA, PAA, and PAGN occurred at 2 hours, 4 hours, and 4 hours, respectively. Upon single-dose administration of Clinical Results Intensive Therapy Serum (Glycerol), plasma concentrations of PBA were quantifiable in 15 of 22 participants at the first sample time postdose (0.25 hours). Mean maximum concentration (C_max) for PBA, PAA, and PAGN was 37.0 micrograms/mL, 14.9 micrograms/mL, and 30.2 micrograms/mL, respectively. In healthy subjects, intact Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate was detected in plasma. While the study was inconclusive, the incomplete hydrolysis of Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate cannot be ruled out.

In healthy subjects, the systemic exposure to PAA, PBA, and PAGN increased in a dose-dependent manner. Following 4 mL of Clinical Results Intensive Therapy Serum (Glycerol) 3 times a day for 3 days, the mean C_max and AUC were 66 micrograms/mL and 930 micrograms∙h/mL for PBA and 28 micrograms/mL and 942 micrograms∙h/mL for PAA, respectively. In the same study, following 6 mL of Clinical Results Intensive Therapy Serum (Glycerol) three times a day for 3 days, mean C_max and AUC were 100 micrograms/mL and 1400 micrograms∙h/mL for PBA and 65 µg/mL and 2064 micrograms∙h/mL for PAA, respectively.

In adult patients with UCDs receiving multiple doses of Clinical Results Intensive Therapy Serum (Glycerol), maximum plasma concentrations at steady state (C_max,ss) of PBA, PAA, and PAGN occurred at 8 hours, 12 hours, and 10 hours, respectively, after the first dose in the day. Intact Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate was not detectable in plasma in patients with UCDs.

Distribution

In vitro, the extent of plasma protein binding for ¹⁴C-labeled metabolites was 81% to 98% for PBA (over 1 to 250 micrograms/mL), and 37% to 66% for PAA (over 5 to 500 micrograms/mL). The protein binding for PAGN was 7% to 12% and no concentration effects were noted.

Elimination

Metabolism

Upon oral administration, pancreatic lipases hydrolyze Clinical Results Intensive Therapy Serum (Glycerol) (i.e., Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate), and release PBA. PBA undergoes β-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidney through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGN. PAGN is subsequently eliminated in the urine.

Saturation of conjugation of PAA and glutamine to form PAGN was suggested by increases in the ratio of plasma PAA to PAGN with increasing dose and with increasing severity of hepatic impairment.

In healthy subjects, after administration of 4 mL, 6 mL, and 9 mL 3 times daily for 3 days, the ratio of mean AUC_0-23h of PAA to PAGN was 1, 1.25, and 1.6, respectively. In a separate study, in patients with hepatic impairment (Child-Pugh B and C), the ratios of mean C_max values for PAA to PAGN among all patients dosed with 6 mL and 9 mL twice daily were 3 and 3.7.

In in vitro studies, the specific activity of lipases for Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate was in the following decreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and pancreatic lipase–related protein 2. Further, Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate was hydrolyzed in vitro by esterases in human plasma. In these in vitro studies, a complete disappearance of Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate did not produce molar equivalent PBA, suggesting the formation of mono- or bis-ester metabolites. However, the formation of mono- or bis-esters was not studied in humans.

Excretion

The mean (SD) percentage of administered PBA excreted as PAGN was approximately 69% (17) in adults and 66% (24) in pediatric patients with UCDs at steady state. PAA and PBA represented minor urinary metabolites, each accounting for less than 1% of the administered dose of PBA.

Specific Populations

Age: Pediatric Population

Population pharmacokinetic modeling and dosing simulations suggest body surface area to be the most significant covariate explaining the variability of PAA clearance. PAA clearance was 10.9 L/h, 16.4 L/h, and 24.4 L/h, respectively, for patients ages 3 to 5, 6 to 11, and 12 to 17 years with UCDs.

In pediatric patients with UCDs (n = 14) ages 2 months to less than 2 years, PAA clearance was 6.8 L/h.

Sex

In healthy adult subjects, a gender effect was found for all metabolites, with women generally having higher plasma concentrations of all metabolites than men at a given dose level. In healthy female subjects, mean C_max for PAA was 51 and 120% higher than in male volunteers after administration of 4 mL and 6 mL 3 times daily for 3 days, respectively. The dose normalized mean AUC_0-23h for PAA was 108% higher in females than in males.

Renal Impairment

The pharmacokinetics of Clinical Results Intensive Therapy Serum (Glycerol) in patients with impaired renal function, including those with end-stage renal disease (ESRD) or those on hemodialysis, have not been studied .

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of Clinical Results Intensive Therapy Serum (Glycerol) were studied in patients with mild, moderate and severe hepatic impairment of (Child-Pugh class A, B, and C, respectively) receiving 100 mg/kg of Clinical Results Intensive Therapy Serum (Glycerol) twice daily for 7 days.

Plasma Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate was not measured in patients with hepatic impairment.

After multiple doses of Clinical Results Intensive Therapy Serum (Glycerol) in patients with hepatic impairment of Child-Pugh A, B, and C, geometric mean AUC_t of PBA was 42%, 84%, and 50% higher, respectively, while geometric mean AUC_t of PAA was 22%, 53%, and 94% higher, respectively, than in healthy subjects.

In patients with hepatic impairment of Child-Pugh A, B, and C, geometric mean AUC_t of PAGN was 42%, 27%, and 22% lower, respectively, than that in healthy subjects.

The proportion of PBA excreted as PAGN in the urine in Child-Pugh A, B, and C was 80%, 58%, and 85%, respectively, and, in healthy volunteers, was 67%.

In another study in patients with moderate and severe hepatic impairment (Child-Pugh B and C), mean C_max of PAA was 144 micrograms/mL (range: 14 to 358 micrograms/mL) after daily dosing of 6 mL of Clinical Results Intensive Therapy Serum (Glycerol) twice daily, while mean C_max of PAA was 292 micrograms/mL (range: 57 to 655 micrograms/mL) after daily dosing of 9 mL of Clinical Results Intensive Therapy Serum (Glycerol) twice daily. The ratio of mean C_max values for PAA to PAGN among all patients dosed with 6 mL and 9 mL twice daily were 3 and 3.7, respectively.

After multiple doses, a PAA concentration greater than 200 micrograms/mL was associated with a ratio of plasma PAA to PAGN concentrations higher than 2.5 .

Drug Interaction Studies

In vitro PBA or PAA did not induce CYP1A2, suggesting that in vivo drug interactions via induction of CYP1A2 is unlikely.

In in vitro studies, PBA at a concentration of 800 micrograms/mL caused greater than 60% reversible inhibition of cytochrome P450 isoenzymes CYP2C9, CYP2D6, and CYP3A4/5 (testosterone 6β-hydroxylase activity). The in vitro study suggested that in vivo drug interactions with substrates of CYP2D6 cannot be ruled out. The inhibition of CYP isoenzymes 1A2, 2C8, 2C19, and 2D6 by PAA at the concentration of 2.8 mg/mL was observed in vitro. Clinical implication of these results is unknown.

Effects of Clinical Results Intensive Therapy Serum (Glycerol) on other drugs

Midazolam

In healthy subjects, when oral midazolam was administered after multiple doses of Clinical Results Intensive Therapy Serum (Glycerol) (4 mL three times a day for 3 days) under fed conditions, the mean C_max and AUC for midazolam were 25% and 32% lower, respectively, compared to administration of midazolam alone. In addition the mean C_max and AUC for 1-hydroxy midazolam were 28% and 58% higher, respectively, compared to administration of midazolam alone .

Celecoxib

Concomitant administration of Clinical Results Intensive Therapy Serum (Glycerol) did not significantly affect the pharmacokinetics of celecoxib, a substrate of CYP2C9. When 200 mg of celecoxib was orally administered with Clinical Results Intensive Therapy Serum (Glycerol) after multiple doses of Clinical Results Intensive Therapy Serum (Glycerol) (4 mL three times a day for 6 days) under fed conditions (a standard breakfast was consumed 5 minutes after celecoxib administration), the mean C_max and AUC for celecoxib were 13% and 8% lower than after administration of celecoxib alone.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 2-year study in Sprague-Dawley rats, Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate caused a statistically significant increase in the incidence of pancreatic acinar cell adenoma, carcinoma, and combined adenoma or carcinoma at a dose of 650 mg/kg/day in males (4.7 times the dose of 6.9 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA) and 900 mg/kg/day in females (8.4 times the dose of 6.9 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA). The incidence of the following tumors was also increased in female rats at a dose of 900 mg/kg/day: thyroid follicular cell adenoma, carcinoma and combined adenoma or carcinoma, adrenal cortical combined adenoma or carcinoma, uterine endometrial stromal polyp, and combined polyp or sarcoma. The dose of 650 mg/kg/day in male rats is 3 times the dose of 7.5 mL/m²/day in pediatric patients, based on combined AUCs for PBA and PAA. The dose of 900 mg/kg/day in female rats is 5.5 times the dose of 7.5 mL/m²/day in pediatric patients, based on combined AUCs for PBA and PAA. In a 26-week study in transgenic (Tg.rasH2) mice, Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate was not tumorigenic at doses up to 1000 mg/kg/day.

Mutagenesis

Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate was not genotoxic in the Ames test, the in vitro chromosomal aberration test in human peripheral blood lymphocytes, or the in vivo rat micronucleus test. The metabolites PBA, PAA, PAGN, and phenylacetylglycine were not genotoxic in the Ames test or in vitro chromosome aberration test in Chinese hamster ovary cells.

Impairment of Fertility

Clinical Results Intensive Therapy Serum (Glycerol) phenylbutyrate had no effect on fertility or reproductive function in male and female rats at oral doses up to 900 mg/kg/day. At doses of 1200 mg/kg/day (approximately 7 times the dose of 6.9 mL/m²/day in adult patients, based on combined AUCs for PBA and PAA), maternal toxicity was observed and the number of nonviable embryos was increased.

14 CLINICAL STUDIES

14.1 Clinical Studies in Adult Patients with UCDs

Active-Controlled, 4-Week, Noninferiority Study

A randomized, double-blind, active-controlled, crossover, noninferiority study (Study 1) compared Clinical Results Intensive Therapy Serum (Glycerol) to sodium phenylbutyrate by evaluating venous ammonia levels in patients with UCDs who had been on sodium phenylbutyrate prior to enrollment for control of their UCD. Patients were required to have a confirmed diagnosis of UCD involving deficiencies of CPS, OTC, or ASS, confirmed via enzymatic, biochemical, or genetic testing. Patients had to have no clinical evidence of hyperammonemia at enrollment and were not allowed to receive drugs known to increase ammonia levels (e.g., valproate), increase protein catabolism (e.g., corticosteroids), or significantly affect renal clearance (e.g., probenecid).

The primary endpoint was the 24-hour AUC (a measure of exposure to ammonia over 24 hours) for venous ammonia on days 14 and 28 when the drugs were expected to be at steady state. Statistical noninferiority would be established if the upper limit of the 2-sided 95% CI for the ratio of the geometric means (RAVICTI/sodium phenylbutyrate) for the endpoint was 1.25 or less.

Forty-five patients were randomized 1:1 to 1 of 2 treatment arms to receive either

• Sodium phenylbutyrate for 2 weeks → Clinical Results Intensive Therapy Serum (Glycerol) for 2 weeks; or
• Clinical Results Intensive Therapy Serum (Glycerol) for 2 weeks → sodium phenylbutyrate for 2 weeks.

Sodium phenylbutyrate or Clinical Results Intensive Therapy Serum (Glycerol) were administered three times daily with meals. The dose of Clinical Results Intensive Therapy Serum (Glycerol) was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dose the patients were taking when they entered the study. Forty-four patients received at least 1 dose of Clinical Results Intensive Therapy Serum (Glycerol) in the study.

Patients adhered to a low-protein diet and received amino acid supplements throughout the study. After 2 weeks of dosing, by which time patients had reached steady state on each treatment, all patients had 24 hours of ammonia measurements.

Demographic characteristics of the 45 patients enrolled in Study 1 were as follows: mean age at enrollment was 33 years (range: 18 to 75 years); 69% were female; 33% had adult-onset disease; 89% had OTC deficiency; 7% had ASS deficiency; 4% had CPS deficiency.

Clinical Results Intensive Therapy Serum (Glycerol) was non-inferior to sodium phenylbutyrate with respect to the 24-hour AUC for ammonia. Forty-four patients were evaluated in this analysis. Mean 24-hour AUCs for venous ammonia during steady-state dosing were 866 micromol∙h/L and 977 micromol∙h/L with Clinical Results Intensive Therapy Serum (Glycerol) and sodium phenylbutyrate, respectively. The ratio of geometric means was 0.91 [95% CI 0.8, 1.04].

The mean venous ammonia levels over 24-hours after 2 weeks of dosing (on day 14 and 28) in the double-blind short-term study (Study 1) are displayed in Figure 2 below. The mean and median maximum venous ammonia concentration (C_max) over 24 hours and 24-hour AUC for venous ammonia are summarized in Table 2. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L using the following formula after standardization of the units to micromol/L:

Normalized ammonia (micromol/L) = ammonia readout in micromol/L × (35/ULN of a laboratory reference range specified for each assay)

Figure 2: Venous Ammonia Response in Adult Patients with UCDs in Short-Term Treatment Study 1

Open-Label, Uncontrolled, Extension Study in Adults

A long-term (12-month), uncontrolled, open-label study (Study 2) was conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period. A total of 51 adults were in the study and all but 6 had been converted from sodium phenylbutyrate to Clinical Results Intensive Therapy Serum (Glycerol). Venous ammonia levels were monitored monthly. Mean fasting venous ammonia values in adults in Study 2 were within normal limits during long-term treatment with Clinical Results Intensive Therapy Serum (Glycerol) (range: 6 to 30 micromol/L). Of 51 adult patients participating in the 12-month, open-label treatment with Clinical Results Intensive Therapy Serum (Glycerol), 7 patients (14%) reported a total of 10 hyperammonemic crises. The fasting venous ammonia measured during Study 2 is displayed in Figure 3. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L.

Figure 3: Venous Ammonia Response in Adult Patients with UCDs in Long-Term Treatment Study 2

Open-Label, Long-Term Study in Adults

An open-label long-term, study (Study 5) was conducted to assess ammonia control in adult patients with UCDs. The study enrolled patients with UCDs who had completed the safety extensions of Study 1, Study 3 or Study 4 (Study 2, 3E and 4E, respectively). A total of 43 adult patients between the ages of 19 and 61 years were in the study. The median length of study participation was 1.9 years (range 0 to 4.5 years). Venous ammonia levels were monitored at a minimum of every 6 months. Mean fasting venous ammonia values in adult patients in Study 5 were within normal limits during long-term (24 months) treatment with Clinical Results Intensive Therapy Serum (Glycerol) (range: 24.2 to 31.4 micromol/L). Of the 43 adult patients participating in the open-label treatment with Clinical Results Intensive Therapy Serum (Glycerol), 9 patients (21%) reported a total of 21 hyperammonemic crises. Ammonia values across different laboratories were normalized to a common normal range of 10 to 35 micromol/L.

14.2 Clinical Studies in Pediatric Patients Ages 2 to 17 Years with UCDs

The efficacy of Clinical Results Intensive Therapy Serum (Glycerol) in pediatric patients 2 to 17 years of age with UCDs was evaluated in 2 fixed-sequence, open-label, sodium phenylbutyrate to Clinical Results Intensive Therapy Serum (Glycerol) switchover studies (Studies 3 and 4). Study 3 was 7 days in duration and Study 4 was 10 days in duration.

These studies compared blood ammonia levels of patients on Clinical Results Intensive Therapy Serum (Glycerol) to venous ammonia levels of patients on sodium phenylbutyrate in 26 pediatric patients between 2 months and 17 years of age with UCDs. Four patients less than 2 years of age are excluded for this analysis due to insufficient data. The dose of Clinical Results Intensive Therapy Serum (Glycerol) was calculated to deliver the same amount of PBA as the dose of sodium phenylbutyrate patients were taking when they entered the trial. Sodium phenylbutyrate or Clinical Results Intensive Therapy Serum (Glycerol) were administered in divided doses with meals. Patients adhered to a low-protein diet throughout the study. After a dosing period with each treatment, all patients underwent 24 hours of venous ammonia measurements, as well as blood and urine pharmacokinetic assessments.

UCD subtypes included OTC (n=12), argininosuccinate lyase (ASL) (n=8), and ASS deficiency (n=2), and patients received a mean Clinical Results Intensive Therapy Serum (Glycerol) dose of 8 mL/m²/day (8.8 g/m²/day), with doses ranging from 1.4 to 13.1 mL/m²/day (1.5 to 14.4 g/m²/day). Doses in these patients were based on previous dosing of sodium phenylbutyrate.

The 24-hour AUCs for blood ammonia (AUC_0-24h) in 11 pediatric patients 6 to 17 years of age with UCDs (Study 3) and 11 pediatric patients 2 years to 5 years of age with UCDs (Study 4) were similar between treatments. In children 6 to 17 years of age, the ammonia AUC_0-24h was 604 micromol∙h/L vs 815 micromol∙h/L on Clinical Results Intensive Therapy Serum (Glycerol) vs sodium phenylbutyrate. In the patients between 2 years and 5 years of age with UCDs, the ammonia AUC_0-24h was 632 micromol∙h/L vs 720 micromol∙h/L on Clinical Results Intensive Therapy Serum (Glycerol) versus sodium phenylbutyrate.

The mean venous ammonia levels over 24 hours in open-label, short-term Studies 3 and 4 at common time points are displayed in Figure 4. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L using the following formula after standardization of the units to micromol/L:

Normalized ammonia (micromol/L) = ammonia readout in micromol/L × (35/ULN of a laboratory reference range specified for each assay)

Figure 4: Venous Ammonia Response in Pediatric Patients Ages 2 to 17 Years with UCDs in Short-Term Treatment Studies 3 and 4

Open-Label, Uncontrolled, Extension Studies in Children Ages 2 to 17 Years

Long-term (12-month), uncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period. In two studies (Study 2, which also enrolled adults, and an extension of Study 3, referred to here as Study 3E), a total of 26 children ages 6 to 17 were enrolled and all but 1 had been converted from sodium phenylbutyrate to Clinical Results Intensive Therapy Serum (Glycerol). Mean fasting venous ammonia values were within normal limits during long-term treatment with Clinical Results Intensive Therapy Serum (Glycerol) (range: 17 to 23 micromol/L). Of the 26 pediatric patients 6 to 17 years of age participating in these two trials, 5 patients (19%) reported a total of 5 hyperammonemic crises. The fasting venous ammonia measured during these two extension studies in patients 6 to 17 years is displayed in Figure 5. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L.

Figure 5: Venous Ammonia Response in Pediatric Patients Ages 2 to 17 Years with UCDs in Long-Term Treatment Studies 2 and 3E

In an extension of Study 4, after a median time on study of 4.5 months (range: 1 to 5.7 months), 2 of 16 pediatric patients ages 2 to 5 years had experienced three hyperammonemic crises.

Open-Label, Long-Term Study in Children Ages 1 to 17 Years of Age

An open-label, long-term study (Study 5) was conducted to assess ammonia control in pediatric patients with UCD. The study enrolled patients with UCD who had completed the safety extensions of Study 1, Study 3 or Study 4 (Study 2, 3E and 4E, respectively). A total of 45 pediatric patients between the ages of 1 and 17 years were in the study. The median length of study participation was 1.7 years (range 0.2 to 4.6 years). Venous ammonia levels were monitored at a minimum of every 6 months. Mean venous ammonia values in pediatric patients in Study 5 were within normal limits during long-term (24 months) treatment with Clinical Results Intensive Therapy Serum (Glycerol) (range: 15.4 to 25.1 micromol/L). Of the 45 pediatric patients participating in the open-label treatment with Clinical Results Intensive Therapy Serum (Glycerol), 11 patients (24%) reported a total of 22 hyperammonemic crises. Ammonia values across different laboratories were normalized to a common normal range of 10 to 35 micromol/L.

14.3 Clinical Studies in Pediatric Patients Ages 2 Months to Less Than 2 Years with UCDs

Uncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonemic crisis of Clinical Results Intensive Therapy Serum (Glycerol) in pediatric patients with UCDs 2 months to less than 2 years of age (Study 4/4E, Study 5, and Study 6). Patients in Study 5 previously participated in Study 4/4E. A total of 17 pediatric patients with UCDs aged 2 months to less than 2 years participated in the studies.

Uncontrolled, Open-Label Study in Children Under 2 Years of Age (Study 6)

A total of 10 pediatric patients with UCDs aged 2 months to less than 2 years participated in Study 6, of which 7 patients converted from sodium phenylbutyrate to Clinical Results Intensive Therapy Serum (Glycerol). The dosage of Clinical Results Intensive Therapy Serum (Glycerol) was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dosage the patients were taking when they entered the trial. Two patients were treatment naïve and received Clinical Results Intensive Therapy Serum (Glycerol) dosage of 7.5 mL/m²/day and 9.4 mL/m²/day, respectively. One additional patient was gradually discontinued from intravenous sodium benzoate and sodium phenylacetate while Clinical Results Intensive Therapy Serum (Glycerol) was initiated. The dosage of Clinical Results Intensive Therapy Serum (Glycerol) after transition was 8.5 mL/m²/day.

In Study 6, there were 9, 7 and 3 pediatric patients who completed 1, 3 and 6 months, respectively (mean and median exposure of 4 and 5 months, respectively).

Patients received a mean Clinical Results Intensive Therapy Serum (Glycerol) dose of 8 mL/m²/day (8.8 g/m²/day), with doses ranging from 4.8 to 11.5 mL/m²/day (5.3 to 12.6 g/m²/day). Patients were dosed three times a day (n=6), four times a day (n = 2), or five or more times a day (n=2).

The primary efficacy endpoint was successful transition to Clinical Results Intensive Therapy Serum (Glycerol) within a period of 4 days followed by 3 days of observation for a total of 7 days, where successful transition was defined as no signs and symptoms of hyperammonemia and a venous ammonia value less than 100 micromol/L. Venous ammonia levels were monitored for up to 4 days during transition and on day 7. Nine patients successfully transitioned as defined by the primary endpoint. One additional patient developed hyperammonemia on day 3 of dosing and experienced surgical complications (bowel perforation and peritonitis) following jejunal tube placement on day 4. This patient developed hyperammonemic crisis on day 6, and subsequently died of sepsis from peritonitis unrelated to drug. Although two patients had day 7 ammonia values of 150 micromol/L and 111 micromol/L respectively, neither had associated signs and symptoms of hyperammonemia.

During the extension phase, venous ammonia levels were monitored monthly. Ammonia values across different laboratories were normalized (transformed) to a common normal pediatric range of 28 to 57 micromol/L for comparability. The mean normalized venous ammonia values in pediatric patients at month 1, 2, 3, 4, 5 and 6 were 67, 53, 78, 99, 56 and 61 micromol/L during treatment with Clinical Results Intensive Therapy Serum (Glycerol), respectively. Three patients reported a total of 7 hyperammonemic crises defined as having signs and symptoms consistent with hyperammonemia (such as frequent vomiting, nausea, headache, lethargy, irritability, combativeness, and/or somnolence) associated with high venous ammonia levels and requiring medical intervention. Hyperammonemic crises were precipitated by vomiting, upper respiratory tract infection, gastroenteritis, decreased caloric intake or had no identified precipitating event (3 events). There were three additional patients who had one venous ammonia level that exceeded 100 micromol/L which was not associated with a hyperammonemic crisis.

Uncontrolled, Open-Label Studies in Children Under 2 Years of Age (Studies 4/4E, 5)

A total of 7 patients with UCDs aged 2 months to less than 2 years participated in Studies 4/4E and 5. In these studies, there were 7, 6, 6, 6 and 3 pediatric patients who completed 1, 6, 9, 12 and 18 months, respectively (mean and median exposure of 15 and 17 months, respectively). Patients were converted from sodium phenylbutyrate to Clinical Results Intensive Therapy Serum (Glycerol). The dosage of Clinical Results Intensive Therapy Serum (Glycerol) was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dosage the patients were taking when they entered the study.

Patients received a mean Clinical Results Intensive Therapy Serum (Glycerol) dose of 7.5 mL/m²/day (8.2 g/m²/day), with doses ranging from 3.3 to 12.3 mL/m²/day (3.7 to 13.5 g/m²/day). Patients were dosed three times a day (n=3) or four times a day (n = 4).

Venous ammonia levels were monitored on days 1, 3 and 10 in Study 4 and at week 1 in Study 4E. Two patients had day 1 ammonia values of 122 micromol/L and 111 micromol/L respectively, neither had associated signs and symptoms of hyperammonemia. At day 10/week 1, six of the 7 patients had venous ammonia levels less than 100 micromol/L the remaining patient had a day 10 ammonia value of 168 micromol/L and was asymptomatic.

During the extension period, venous ammonia levels were monitored monthly. Ammonia values across different laboratories were normalized (transformed) to a common normal pediatric range of 28 to 57 micromol/L for comparability. The mean venous ammonia values in pediatric patients at month 1, 3, 6, 9 and 12 were 58, 49, 34, 65, and 31 micromol/L during treatment with Clinical Results Intensive Therapy Serum (Glycerol), respectively.

Three patients reported a total of 3 hyperammonemic crises, as defined in Study 6. Hyperammonemic crises were precipitated by gastroenteritis, vomiting, infection or no precipitating event (one patient). There were 4 patients who had one venous ammonia level that exceeded 100 micromol/L which was not associated with a hyperammonemic crisis.

16 HOW SUPPLIED/STORAGE AND HANDLING

Clinical Results Intensive Therapy Serum (Glycerol) ^® (glycerol phenylbutyrate) oral liquid 1.1 g/mL is supplied in multi-use, 25-mL glass bottles. The bottles are supplied in the following configurations:

• NDC 75987-050-06: Single 25-mL bottle per carton
• NDC 75987-050-07: Four 25-mL bottles per carton

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

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Neurotoxicity .

• Inform patients/caregivers that adverse reactions of Clinical Results Intensive Therapy Serum (Glycerol) are sometimes the same as symptoms of high blood ammonia. Neurological adverse events may also be associated with the major metabolite of Clinical Results Intensive Therapy Serum (Glycerol), PAA, and may be reversible. Blood tests for PAA may be done to measure the amount of PAA in the blood. Instruct the patient/caregiver to contact the healthcare provider immediately if the patient experiences: nausea, vomiting, headache, fatigue, somnolence, lightheadedness, confusion, exacerbation of preexisting neuropathy, disorientation, impaired memory, dysgeusia, or hypoacusis.

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Clinical Results Intensive Therapy Serum (Glycerol) during pregnancy .

Lactation

Advise patients that breastfeeding is not recommended during treatment with Clinical Results Intensive Therapy Serum (Glycerol) .

Administration

• Instruct patients to take Clinical Results Intensive Therapy Serum (Glycerol) with food or formula and to administer directly into the mouth via oral syringe or dosing cup.
• Instruct patients to take Clinical Results Intensive Therapy Serum (Glycerol) orally, even if they have a nasogastric and/or gastrostomy tube. For patients who cannot swallow and who have a nasogastric tube or gastrostomy tube in place, instruct patients/caregivers to administer Clinical Results Intensive Therapy Serum (Glycerol) as follows:
  • Utilize an oral syringe to withdraw the prescribed dosage of Clinical Results Intensive Therapy Serum (Glycerol) from the bottle.
  • Place the tip of the syringe into the gastrostomy/nasogastric tube.
  • Utilizing the plunger of the syringe, administer Clinical Results Intensive Therapy Serum (Glycerol) into the tube.
  • Flush once with 10 mL of water or formula and allow the flush to drain.
  • If needed, flush a second time with an additional 10 mL of water or formula to clear the tube.

Distributed by:

Horizon Pharma USA, Inc.

Lake Forest, IL 60045

Horizon Therapeutics, LLC.

All rights reserved.

Clinical Results Intensive Therapy Serum (Glycerol) is a registered trademark of Horizon Therapeutics, LLC.

Hyaluronate Sodium:

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CAUTION:

Federal law restricts this drug to use by or on the order of a licensed veterinarian.

DESCRIPTION:

Clinical Results Intensive Therapy Serum (Hyaluronate Sodium)^TM (hyaluronate sodium) injectable solution is a clear, colorless solution of low viscosity. Clinical Results Intensive Therapy Serum (Hyaluronate Sodium)^TM injectable solution is pyrogen free, sterile and does not contain a preservative. It is administered by intravenous injection. Hyaluronic acid, the conjugate acid of Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) sodium, is extracted from the capsule of Streptococcus spp. and purified, resulting in a form which is essentially free of protein and nucleic acids. Clinical Results Intensive Therapy Serum (Hyaluronate Sodium)^TM injectable solution is supplied in 4 mL (40 mg) vials.

Each mL contains 10 mg Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) sodium, 8.5 mg sodium chloride, 0.223 mg sodium phosphate dibasic and 0.04 mg sodium phosphate monobasic. The pH is adjusted to between 6.5 and 8.0 with sodium hydroxide or hydrochloric acid.

CHEMISTRY:

Hyaluronic acid, a glycosaminoglycan, can exist in the following forms depending upon the chemical environment in which it is found: as the acid, hyaluronic acid; as the sodium salt, sodium Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) (hyaluronate sodium); or as the Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) anion. These terms may be used interchangeably but in all cases, reference is made to the glycosaminoglycan composed of repeating subunits of D-glucuronic acid and N-acetyl-Dglucosamine linked together by glycosidic bonds. Since this product originates from a microbial source, there is no potential for contamination with dermatan or chondroitin sulfate or any other glycosaminoglycan.

CLINICAL

Pharmacology:

Hyaluronic acid is a naturally occurring substance present in connective tissue, skin, vitreous humor and the umbilical cord in all mammals. High concentrations of hyaluronic acid are also found in the synovial fluid. It also constitutes the major component of the capsule of certain microorganisms. The hyaluronic acid produced by bacteria is the same structure and configuration as that found in mammals.

The actual mechanism of action for Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) sodium in the healing of degenerative joint disease is not completely understood. One major function appears to be the regulation of normal cellular constituents. This effect decreases the impact of exudation, enzyme release and subsequent degradation of joint integrity. Additionally, Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) sodium exerts an anti-inflammatory action by inhibiting the movement of granulocytes and macrophages.¹

Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) molecules are long chains which form a filter network interspersed with normal cellular fluids. It is widely accepted that injection directly into the joint pouch enhances the healing of inflamed synovium by restoring lubrication of the joint fluid. This further supplements the visco-elastic properties of normal joint fluid.

INDICATIONS:

Clinical Results Intensive Therapy Serum (Hyaluronate Sodium)^TM (hyaluronate sodium) injectable solution is indicated in the treatment of joint dysfunction of the carpus or fetlock in horses due to non-infectious synovitis associated with equine osteoarthritis.

DOSAGE AND ADMINISTRATION:

4 mL (40 mg) injected intravenously. Treatment may be repeated at weekly intervals for a total of three treatments. Use aseptic technique and inject slowly into the jugular vein. Horses should be given stall rest after treatment before gradually resuming normal activity.

Discard any unused portion of the drug and the empty vial after opening.

CONTRAINDICATIONS:

There are no known contraindications for the use of Clinical Results Intensive Therapy Serum (Hyaluronate Sodium)^TM (hyaluronate sodium) injectable solution in horses.

WARNING:

Do not use in horses intended for human consumption.

HUMAN WARNINGS:

Not for use in humans. Keep this and all other drugs out of reach of children.

ANIMAL SAFETY WARNING:

Not for intra-articular use.

PRECAUTIONS:

Radiographic evaluation should be carried out in cases of acute lameness to ensure that the joint is free from serious fractures.

The safety of Clinical Results Intensive Therapy Serum (Hyaluronate Sodium)^TM injectable solution has not been evaluated in breeding stallions or in breeding, pregnant or lactating mares.

ADVERSE REACTIONS:

No local or systemic side effects were observed in the clinical field studies using Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) sodium injectable solution.

POST-APPROVAL EXPERIENCE:

While all adverse reactions are not reported, the following adverse reactions are based on voluntary post-approval reporting for Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) sodium injectable solution: Occasional depression, lethargy, and fever.

For medical emergencies or to report adverse reactions, call 1-888-549-4503.

EFFECTIVENESS:

Forty-six horses with lameness in either the carpal or fetlock joints were treated intravenously or intra-articularly with Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) sodium injectable solution in a well controlled clinical field trial conducted at four locations. One, two or three injections were given based on clinical improvement. Overall clinical improvement was judged as excellent or good in 90% of the cases treated intravenously and 96% of those treated intra-articularly with Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) sodium injectable solution.

ANIMAL SAFETY:

Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) sodium injectable solution was administered to normal horses at one, three and five times the recommended intra-articular dosage of 20 mg and the intravenous dosage of 40 mg. Treatments were given once weekly for nine consecutive weeks (three times the maximum duration). No systemic clinical signs were observed nor were there any adverse effects upon hematology or clinical chemistry parameters. A transient, slight to mild post-injection swelling of the joint capsule occurred in some of the animals treated intra-articularly with Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) sodium injectable solution as it did in the saline treated control horses. No gross or histological lesions were observed in the soft tissues or the surface areas of the treated joint.

STORAGE:

Store below 25°C (77°F).

HOW SUPPLIED:

Clinical Results Intensive Therapy Serum (Hyaluronate Sodium)^TM injectable solution is supplied in cartons containing twelve x 4 mL (40 mg) vials.

REFERENCES:

1 Swanstrom, O.G. 1978. Clinical Results Intensive Therapy Serum (Hyaluronate Sodium) (hyaluronic acid) and its use, Proc. American Assoc. Equine Pract., 24th annual convention, pp. 345-348.

For customer service or to obtain product information, including a Material Safety Data Sheet, call:1-706-549-4503. After hours, call 1-706-353-2442 or 1-706-714-7373.

February 2011

ANADA 200-432, Approved by FDA

Oatmeal Colloidal:

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• Clinical Results Intensive Therapy Serum (Oatmeal Colloidal) reviews

OTC- Active Ingredients Section

Organic Colloidal Oatmeal 1.25%... Skin Protectant

Sto use and see a doctor if:

Conditions worsen

Symptoms last more than 7 days

Symptoms clear up and reoccur within a few days.

OTC- Warnings Section

For external use only

when using this product: Keep away from face to avoid inhalation

Avoid contact with eyes

Do not use on wet hair, or allow to dry on wet hair

Other information

Store in a dry place

protect from moisture

OTC- Purpose Section

Uses: Helps treat and prevent diaper rash

Temporarily protects and helps relieve minor skin irritation and itching due to diaper rash.

Inactive Ingredients

Powdered White Soft Wheat

Keep Out of Reach

Keep out of reach of Children

Dosage section

Apply as Needed

Use Generous amounts for best results

Indications and usage

Uses: Helps treat and prevent diaper rash

Comfy Bottoms Baby Power Comfy Bottoms Sports Powder Comfy Bottoms Foot Powder

Sodium Hydroxide:

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• Clinical Results Intensive Therapy Serum (Sodium Hydroxide) reviews

1 INDICATIONS AND USAGE

Clinical Results Intensive Therapy Serum nitrite is indicated for sequential use with Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite Injection is indicated for sequential use with Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum 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, Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite Injection and Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Thiosulfate Injection should be administered without delay.

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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate, simultaneously with Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate, with Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite and Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite, followed by Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite and Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate.

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite injection and Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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. Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite should be administered first, followed immediately by Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite and Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate and Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite Injection consists of:

• One vial of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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: Clinical Results Intensive Therapy Serum 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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. Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite whenever possible. When Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite administered to an adult. Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Clinical Results Intensive Therapy Serum 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite.

5.7 Use with Other Drugs

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite.

The medical literature has reported the following adverse events in association with Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Clinical Results Intensive Therapy Serum 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. Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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, Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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, Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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, Clinical Results Intensive Therapy Serum 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite is excreted in human milk. Because Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite. In studies conducted with Long-Evans rats, Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum nitrite in conjunction with Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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.

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite has the chemical name nitrous acid Clinical Results Intensive Therapy Serum (Sodium Hydroxide) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite injection.

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite in 10 mL solution (30 mg/mL). Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum nitrite and Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite. It has been suggested that Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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. Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite

When 4 mg/kg Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite in humans have not been well studied. It has been reported that approximately 40% of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite and Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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. Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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. Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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. Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite and Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite or 1 g/kg Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate alone or in sequence immediately after subcutaneous injection of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite and/or 0.5 g/kg Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) cyanide required to cause death, and when administered together, Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite and Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate resulted in a synergistic effect in raising the lethal dose of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite and Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite and Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite, with or without Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) thiosulfate report its use in conjunction with Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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 Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) nitrite injection 30 mg/mL (containing 300 mg of Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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: Clinical Results Intensive Therapy Serum (Sodium Hydroxide) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Clinical Results Intensive Therapy Serum 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

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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

Clinical Results Intensive Therapy Serum (Sodium Hydroxide) 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

Water Purified:

• Active ingredient
• Purpose
• Uses
• Warnings
• Directions
• Other information
• Inactive ingredients
• Questions?
• Clinical Results Intensive Therapy Serum (Water Purified) reviews

Active ingredient

Clinical Results Intensive Therapy Serum (Water Purified) 99.8%

Purpose

Emergency eyewash

Uses

• for flushing or irrigating the eye to reduce chances of severe injury caused by acid, alkali, or particulate contamination.

Warnings

For external use only

Do not use

• if solution changes color or gets cloudy
• with contact lenses
• if twist-off top is broken or missing
• in open wounds in or near the eyes
  

When using this product

• avoid contamination, do not touch tip of container to any surface
  

When using this product

• avoid contamination, do not touch tip of container to any surface
  

Stop use and consult a doctor if you have

• changes in vision
• eye pain
• continued redness or irritation of the eye, or if the condition worsens or persists
  

Keep out of reach of children.

If swallowed, get medical help or contact a Poison Control Center right away.

Directions

• remove contacts before using
• twist top to remove
• flush the affected eye as needed, controlling the rate of flow of the solution by pressure on the bottle
  

• if necessary, continue flushing with emergency eyewash or shower
  

• do not reuse
• once opened, discard
  

• obtain medical treatment
  

Other information

• store at room temperature, 15^o to 30^o C (59^o to 86^o F)
• do not freeze
  

Inactive ingredients

Questions?

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(a Honeywell Company)

825 East Highway 151

Platteville, WI 53818 USA