Lubriderm Nutritiva

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Lubriderm Nutritiva uses

Lubriderm Nutritiva consists of BHT, Carbomer 940, Cetyl Alcohol, Cyclomethicone, Diazolidinyl Urea, Edetate Disodium, Fragrance, Glycerol, Iodopropynyl Butylcarbamate, Isopropyl Isostearate, Lecithin, Mineral Oil, PEG-40 Stearate, Polypropylene Glycol Dicaprylate, Sodium Benzoate, Sodium Hydroxide, Sodium Pyruvate, Titanium Dioxide, Tri (PPG-3 Myristyl Ether) Citrate, Vitamin A (Retinol Palmitate), Vitamin E (Tocopherol Acetate), Water, Wax Emulsifier, Xanthan Gum.

Edetate Disodium:


INDICATIONS AND USAGE

Lubriderm Nutritiva (Edetate Disodium) calcium disodium is indicated for the reduction of blood levels and depot stores of lead in lead poisoning (acute and chronic) and lead encephalopathy, in both pediatric populations and adults.

Chelation therapy should not replace effective measures to eliminate or reduce further exposure to lead.

CONTRAINDICATIONS

Lubriderm Nutritiva (Edetate Disodium) calcium disodium should not be given during periods of anuria, nor to patients with active renal disease or hepatitis.

WARNINGS

PRECAUTIONS

General Precautions

Lubriderm Nutritiva calcium disodium may produce the same renal damage as lead poisoning, such as proteinuria and microscopic hematuria. Treatment-induced nephrotoxicity is dose-dependent and may be reduced by assuring adequate diuresis before therapy begins. Urine flow must be monitored throughout therapy which must be stopped if anuria or severe oliguria develop. The proximal tubule hydropic degeneration usually recovers upon cessation of therapy. Lubriderm Nutritiva (Edetate Disodium) calcium disodium must be used in reduced doses in patients with pre-existing mild renal disease. Patients should be monitored for cardiac rhythm irregularities and other ECG changes during intravenous therapy.

Information for patients

Patients should be instructed to immediately inform their physician if urine output stops for a period of 12 hours.

Laboratory tests

Urinalysis and urine sediment, renal and hepatic function and serum electrolyte levels should be checked before each course of therapy and then be monitored daily during therapy in severe cases, and in less serious cases after the second and fifth day of therapy. Therapy must be discontinued at the first sign of renal toxicity. The presence of large renal epithelial cells or increasing number of red blood cells in urinary sediment or greater proteinuria call for immediate stopping of Lubriderm Nutritiva calcium disodium administration. Alkaline phosphatase values are frequently depressed (possibly due to decreased serum zinc levels), but return to normal within 48 hours after cessation of therapy. Elevated erythrocyte protoporphyrin levels (> 35 mcg/dl of whole blood) indicate the need to perform a venous blood lead determination. If the whole blood lead concentration is between 25–55 mcg/dl a mobilization test can be considered.7,8 (See Diagnostic Test .) An elevation of urinary coproporphyrin (adults: > 250 mcg/day; pediatric patients under 80 lbs: > 75 mcg/day) and elevation of urinary delta aminolevulinic acid (ALA) (adults: > 4 mg/day; pediatric patients: > 3 mg/m2/day) are associated with blood lead levels > 40 mcg/dl. Urinary coproporphyrin may be falsely negative in terminal patients and in severely iron-depleted pediatric patients who are not regenerating heme.9 In growing pediatric patients long bone x-rays showing lead lines and abdominal x-rays showing radio-opaque material in the abdomen may be of help in estimating the level of exposure to lead.

Drug Interactions

There is no known drug interference with standard clinical laboratory tests. Steroids enhance the renal toxicity of Lubriderm Nutritiva (Edetate Disodium) calcium disodium in animals.7 Lubriderm Nutritiva (Edetate Disodium) calcium disodium interferes with the action of zinc insulin preparations by chelating the zinc.7

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term animal studies have not been conducted with Lubriderm Nutritiva calcium disodium to evaluate its carcinogenic potential, mutagenic potential or its effect on fertility.

Pregnancy

Category B

One reproduction study was performed in rats at doses up to 13 times the human dose and revealed no evidence of impaired fertility or harm to the fetus due to Lubriderm Nutritiva.10 Another reproduction study performed in rats at doses up to about 25 to 40 times the human dose revealed evidence of fetal malformations due to Lubriderm Nutritiva (Edetate Disodium), which were prevented by simultaneous supplementation of dietary zinc.11 There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Lubriderm Nutritiva (Edetate Disodium) has no recognized use during labor and delivery, and its effects during these processes are unknown.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lubriderm Nutritiva is administered to a nursing woman.

Pediatric Use

Since lead poisoning occurs in pediatric populations and adults but is frequently more severe in pediatric patients, Lubriderm Nutritiva (Edetate Disodium) is used in patients of all ages. The intramuscular route is preferred by some for young pediatric patients. In cases where the intravenous route is necessary, avoid rapid infusion. (See WARNINGS.) Urine flow must be monitored throughout therapy; Lubriderm Nutritiva (Edetate Disodium) therapy must be stopped if anuria or severe oliguria develops. (See General Precautions .) At no time should the recommended daily dosage be exceeded. (See DOSAGE AND ADMINISTRATION .)

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ADVERSE REACTIONS

The following adverse effects have been associated with the use of Lubriderm Nutritiva (Edetate Disodium) calcium disodium:

Body as a Whole: pain at intramuscular injection site, fever, chills, malaise, fatigue, myalgia, arthralgia.

Cardiovascular: hypotension, cardiac rhythm irregularities.

Renal: acute necrosis of proximal tubules (which may result in fatal nephrosis), infrequent changes in distal tubules and glomeruli.

Urinary: glycosuria, proteinuria, microscopic hematuria and large epithelial cells in urinary sediment.

Nervous System: tremors, headache, numbness, tingling.

Gastrointestinal: cheilosis, nausea, vomiting, anorexia, excessive thirst.

Hepatic: mild increases in SGOT and SGPT are common, and return to normal within 48 hours after cessation of therapy.

Immunogenic: histamine-like reactions (sneezing, nasal congestion, lacrimation), rash.

Hematopoietic: transient bone marrow depression, anemia.

Metabolic: zinc deficiency, hypercalcemia.

OVERDOSAGE

Symptoms

Inadvertent administration of 5 times the recommended dose, infused intravenously over a 24 hour period, to an asymptomatic 16 month old patient with a blood lead content of 56 mcg/dl did not cause any ill effects. Lubriderm Nutritiva calcium disodium can aggravate the symptoms of severe lead poisoning, therefore, most toxic effects (cerebral edema, renal tubular necrosis) appear to be associated with lead poisoning. Because of cerebral edema, a therapeutic dose may be lethal to an adult or a pediatric patient with lead encephalopathy. Higher dosage of Lubriderm Nutritiva (Edetate Disodium) calcium disodium may produce a more severe zinc deficiency.

Treatment

Cerebral edema should be treated with repeated doses of mannitol. Steroids enhance the renal toxicity of Lubriderm Nutritiva (Edetate Disodium) calcium disodium in animals and, therefore, are no longer recommended.7 Zinc levels must be monitored. Good urinary output must be maintained because diuresis will enhance drug elimination. It is not known if Lubriderm Nutritiva (Edetate Disodium) calcium disodium is dialyzable.

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DOSAGE AND ADMINISTRATION

When a source for the lead intoxication has been identified, the patient should be removed from the source, if possible. The recommended dose of Lubriderm Nutritiva for asymptomatic adults and pediatric patients whose blood lead level is < 70 mcg/dl but > 20 mcg/dl (World Health Organization recommended upper allowable level) is 1000 mg/m2/day whether given intravenously or intramuscularly.

For adults with lead nephropathy, the following dosing regimen has been suggested: 500 mg/m2 every 24 hours for 5 days for patients with serum creatinine levels of 2–3 mg/dl, every 48 hours for 3 doses for patients with creatinine levels of 3–4 mg/dl, and once weekly for patients with creatinine levels above 4 mg/dl. These regimens may be repeated at one month intervals.12

Lubriderm Nutritiva (Edetate Disodium), used alone, may aggravate symptoms in patients with very high blood lead levels. When the blood lead level is > 70 mcg/dl or clinical symptoms consistent with lead poisoning are present, it is recommended that Lubriderm Nutritiva (Edetate Disodium) be used in conjunction with BAL (dimercaprol). Please consult published protocols and specialized references for dosage recommendations of combination therapy.14–18

Therapy of lead poisoning in adults and pediatric patients with Lubriderm Nutritiva (Edetate Disodium) is continued over a period of five days. Therapy is then interrupted for 2 to 4 days to allow redistribution of the lead and to prevent severe depletion of zinc and other essential metals. Two courses of treatment are usually employed; however, it depends on severity of the lead toxicity and the patient's tolerance of the drug.

Lubriderm Nutritiva (Edetate Disodium) is equally effective whether administered intravenously or intramuscularly. The intramuscular route is used for all patients with overt lead encephalopathy and this route is preferred by some for young pediatric patients.

Acutely ill individuals may be dehydrated from vomiting. Since Lubriderm Nutritiva (Edetate Disodium) calcium disodium is excreted almost exclusively in the urine, it is very important to establish urine flow with intravenous fluid administration before the first dose of the chelating agent is given; however, excessive fluid must be avoided in patients with encephalopathy. Once urine flow is established, further intravenous fluid is restricted to basal water and electrolyte requirements. Administration of Lubriderm Nutritiva (Edetate Disodium) should be stopped whenever there is cessation of urine flow in order to avoid unduly high tissue levels of the drug. Lubriderm Nutritiva (Edetate Disodium) calcium disodium must be used in reduced doses in patients with pre-existing mild renal disease.

Intravenous Administration

Add the total daily dose of Lubriderm Nutritiva (Edetate Disodium) (1000 mg/m2/day) to 250–500 ml of 5% dextrose or 0.9% sodium chloride injection. The total daily dose should be infused over a period of 8–12 hours. Lubriderm Nutritiva (Edetate Disodium) injection is incompatible with 10% dextrose, 10% invert sugar in 0.9% sodium chloride, lactate Ringer's, Ringer's, one-sixth molar sodium lactate injections, and with injectable amphotericin B and hydralazine hydrochloride.

Intramuscular Administration

The total daily dosage should be divided into equal doses spaced 8–12 hours apart. Lidocaine or procaine should be added to the Lubriderm Nutritiva (Edetate Disodium) injection to minimize pain at the injection site. The final lidocaine or procaine concentration of 5 mg/ml (0.5%) can be obtained as follows: 0.25 ml of 10% lidocaine solution per 5 ml concentrated Lubriderm Nutritiva (Edetate Disodium); 1 ml of 1% lidocaine or procaine solution per ml of concentrated Lubriderm Nutritiva (Edetate Disodium). When used alone, regardless of method of administration, Lubriderm Nutritiva (Edetate Disodium) should not be given at doses larger than those recommended.

Diagnostic Test

Several methods have been described for lead mobilization tests using Lubriderm Nutritiva (Edetate Disodium) calcium disodium to assess body stores.7, 9,12,13,18

These procedures have advantages and disadvantages that should be reviewed in current references. Lubriderm Nutritiva (Edetate Disodium) calcium disodium mobilization tests should not be performed in symptomatic patients and in patients with blood lead levels above 55 mcg/dl for whom appropriate therapy is indicated.

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

SURFACE AREA NOMOGRAM FIGURE

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HOW SUPPLIED

Lubriderm Nutritiva (Edetate Disodium) injection, 5 mL ampul containing 200 mg of Lubriderm Nutritiva (Edetate Disodium) calcium disodium per ml (1000 mg per ampul), in boxes containing 5 ampuls (NDC 99207-240-05).

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

Rx Only

This product is non-returnable.

REFERENCES

  • Thomas DJ, Chisolm JJ. Lead, zinc and copper decorporation during calcium disodium ethylenediamine tetraacetate treatment of lead-poisoned children. J Pharmacol Exp Therapeu 1986; 239: 829–835.
  • The Pharmacological Basis of Therapeutics, 7th edition, Goodman and Gilman, editors. MacMillan Publishing Company, New York, 1985, pp. 1619–1622.
  • Hammond PB, Aronson AL, Olson WC. The mechanism of mobilization of lead by ethylenediaminetetraacetate. J Pharmacol Exp Therapeu 1967; 157: 196–206.
  • Van deVyver FL, D'Haese PC, Visser WJ, et al. Bone lead in dialysis patients. Kidney Intl 1988; 33: 601–607.
  • Cory-Slecta DA, Weiss B, Cox C. Mobilization and redistribution of lead over the course of calcium disodium ethylenediamine tetraacetate chelation therapy. J Pharmacol Exp Therapeu 1987; 243: 804–813.
  • Chisolm JJ. Mobilization of lead by calcium disodium Lubriderm Nutritiva (Edetate Disodium). Am J Dis Child 1987; 141: 1256–1257.
  • Drug Evaluations, 6th Edition, American Medical Association, Saunders, Philadelphia, 1986, pp. 1637–1639.
  • Centers for Disease Control: Preventing lead poisoning in young children. Atlanta, GA, Department of Health and Human Services, 1985 Jan.
  • Finberg L, Rajagopal V. Diagnosis and treatment of lead poisoning in children. J Family Med 1985 April: 3–12.
  • Schardein JL, Sakowski R, Petrere J, et al. Teratogenesis studies with EDTA and its salts in rats. Toxicol Appl Pharmacol 1981; 61: 423–428.
  • Swenerton H, Hurley LS. Teratogenic effects of a chelating agent and their prevention by zinc. Science 1971; 173: 62–64.
  • American Hospital Formulary Service, Drug Information, 1988, pp. 1695–1698.
  • Markowitz ME, Rosen JF. Assessment of lead stores in children: Validation of an 8-hour CaNa2EDTA (Calcium Disodium Versenate) provocative test. J Pediatrics 1984; 104: 337–341.
  • Piomelli S, Rosen JF, Chisolm JJ, et al. Management of childhood lead poisoning. J Pediatrics 1984; 105: 523–532.
  • Sachs HK, Blanksma LA, Murray EF, et al. Ambulatory treatment of lead poisoning: Report of 1,155 cases. Pediatrics 1970; 46: 389.
  • Chisolm JJ. The use of chelating agents in the treatment of acute and chronic lead intoxication in childhood. J Pediatrics 1968; 73: 1.
  • Coffin R, Phillips JL, Staples WI, et al. Treatment of lead encephalopathy in children. J Pediatrics 1966; 69: 198–206.
  • Chisolm JJ. Increased lead absorption and acute lead poisoning. Current Pediatric Therapy 12, Gillis and Kagan, editors, WB Saunders, Philadelphia, 1986, pp. 667–671.

Manufactured for:

Medicis, The Dermatology Company

Scottsdale, AZ 85256

By: CP Pharmaceuticals, Ltd.

Wrexham LL13 9UF, U.K.

Product of UK

106055/1

Rev. 10/12

MEDICIS Logo

Fragrance:


Pharmacological action

Lubriderm Nutritiva 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.

Lubriderm Nutritiva (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

Lubriderm Nutritiva (Fragrance) for external and local application is practically not absorbed.

Why is Lubriderm Nutritiva prescribed?

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

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

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

Liquid concentrate - disinfection of facilities and medical products.

Dosage and administration

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

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

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

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

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Lubriderm Nutritiva (Fragrance) side effects, adverse reactions

Contact dermatitis, candidiasis, vulvovaginal and allergic reactions.

With prolonged use of Lubriderm Nutritiva (Fragrance) it is possible a local irritation.

Lubriderm Nutritiva 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

Lubriderm Nutritiva 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.

Lubriderm Nutritiva drug interactions

Any substance introduced intravaginally can reduce local spermicidal action (including soaps and solutions containing it). Iodine solutions inactivate Lubriderm Nutritiva (Fragrance).

Glycerol:


Indications and Usage (1) 04/2017
Dosage and Administration (2.1) 04/2017
Dosage and Administration (2.2) 04/2017

Lubriderm Nutritiva (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. Lubriderm Nutritiva (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:

  • Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.

Lubriderm Nutritiva (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. Lubriderm Nutritiva (Glycerol) must be used with dietary protein restriction and, in some cases, dietary supplements. (1)

Limitations of Use:

  • Lubriderm Nutritiva (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

  • Lubriderm Nutritiva 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 Lubriderm Nutritiva (Glycerol):

  • Patients should receive the dosage of Lubriderm Nutritiva (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

Lubriderm Nutritiva (Glycerol) should be prescribed by a physician experienced in the management of UCDs.

  • Instruct patients to take Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) and patients naïve to phenylbutyric acid are different . For both subpopulations:
    • Patients 2 years of age and older: Give Lubriderm Nutritiva (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 Lubriderm Nutritiva (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).
    • Lubriderm Nutritiva (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 Lubriderm Nutritiva

Patients switching from sodium phenylbutyrate to Lubriderm Nutritiva (Glycerol) should receive the dosage of Lubriderm Nutritiva (Glycerol) that contains the same amount of phenylbutyric acid. The conversion is as follows:

Total daily dosage of Lubriderm Nutritiva (Glycerol) (mL) = total daily dosage of sodium phenylbutyrate tablets (g) × 0.86

Total daily dosage of Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) dose for a 24-hour period is 0.6 mL Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) as follows:

  • Utilize an oral syringe to withdraw the prescribed dosage of Lubriderm Nutritiva (Glycerol) from the bottle.
  • Place the tip of the syringe into the nasogastric/gastrostomy tube.
  • Utilizing the plunger of the syringe, administer Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) to the plastic tubing. Therefore, these patients should be closely monitored using ammonia levels following initiation of Lubriderm Nutritiva (Glycerol) dosing or dosage adjustments.

3 DOSAGE FORMS AND STRENGTHS

Oral liquid: colorless to pale yellow, 1.1 g/mL of Lubriderm Nutritiva (Glycerol) phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate).

Oral liquid: 1.1 g/mL. (3)

4 CONTRAINDICATIONS

Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol), peak PAA concentrations after dosing with Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) dosage .

5.2 Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption

Exocrine pancreatic enzymes hydrolyze Lubriderm Nutritiva (Glycerol) in the small intestine, separating the active moiety, phenylbutyrate, from Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) were diarrhea, flatulence, and headache. Table 1 summarizes adverse reactions occurring in 2 or more patients treated with Lubriderm Nutritiva (Glycerol) or sodium phenylbutyrate (incidence of at least 4% in either treatment arm).

Number (%) of Patients in Study 1
Sodium Phenylbutyrate

(N = 45)

Lubriderm Nutritiva (Glycerol)

(N = 44)

Diarrhea 3 (7) 7 (16)
Headache 4 (9) 6 (14)
Flatulence 1 (2) 6 (14)
Abdominal pain 2 (4) 3 (7)
Vomiting 2 (4) 3 (7)
Decreased appetite 2 (4) 3 (7)
Fatigue 1 (2) 3 (7)
Dyspepsia 3 (7) 2 (5)
Nausea 3 (7) 1 (2)
Dizziness 4 (9) 0
Abdominal discomfort 3 (7) 0

Other Adverse Reactions

Lubriderm Nutritiva (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 Lubriderm Nutritiva (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.

Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol), including phenylacetylglutamine (PAGN) and PAA. (7.2)
  • CYP3A4 Substrates with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine): Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva

Probenecid

Probenecid may inhibit the renal excretion of metabolites of Lubriderm Nutritiva (Glycerol) including PAGN and PAA.

7.3 Potential for Lubriderm Nutritiva to Affect Other Drugs

Drugs with narrow therapeutic index that are substrates of CYP3A4

Lubriderm Nutritiva (Glycerol) is a weak inducer of CYP3A4 in humans. Concomitant use of Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) decreased the systemic exposure of midazolam. Monitor for suboptimal effect of midazolam in patients who are being treated with Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) during pregnancy. Healthcare providers are encouraged to report any prenatal exposure to Lubriderm Nutritiva (Glycerol) by calling the Pregnancy Registry at 1-855-823-2595 or visiting www.ucdregistry.com.

Risk Summary

Limited available data with Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva 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 Lubriderm Nutritiva (Glycerol).

8.4 Pediatric Use

Safety and efficacy of Lubriderm Nutritiva (Glycerol) have been established in pediatric patients 2 months of age and older with UCDs.

Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) in patients 2 years to less than 18 years of age were established in 2 open-label, sodium phenylbutyrate to Lubriderm Nutritiva (Glycerol), fixed-sequence, switchover clinical studies .

Patients 2 Months to Less Than 2 Years of Age

The safety and efficacy of Lubriderm Nutritiva (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

Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol). Pancreatic lipases may be necessary for intestinal hydrolysis of Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol). If there is inadequate intestinal hydrolysis of Lubriderm Nutritiva (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 Lubriderm Nutritiva 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 Lubriderm Nutritiva (Glycerol) in patients with renal impairment are unknown. Monitor ammonia levels closely when starting patients with impaired renal function on Lubriderm Nutritiva (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 Lubriderm Nutritiva (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

Lubriderm Nutritiva (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.

Lubriderm Nutritiva (Glycerol) phenylbutyrate is a nitrogen-binding agent. It is a triglyceride containing 3 molecules of PBA linked to a Lubriderm Nutritiva (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. Lubriderm Nutritiva (Glycerol) is a triglyceride containing 3 molecules of phenylbutyrate (PBA). PAA, the major metabolite of PBA, is the active moiety of Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) and sodium phenylbutyrate .

Cardiac Electrophysiology

The effect of multiple doses of Lubriderm Nutritiva (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 Lubriderm Nutritiva (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

Lubriderm Nutritiva (Glycerol) is a pro-drug of PBA. Upon oral ingestion, PBA is released from the Lubriderm Nutritiva (Glycerol) backbone in the gastrointestinal tract by lipases. PBA derived from Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol), peak plasma levels of PBA, PAA, and PAGN occurred at 2 hours, 4 hours, and 4 hours, respectively. Upon single-dose administration of Lubriderm Nutritiva (Glycerol), plasma concentrations of PBA were quantifiable in 15 of 22 participants at the first sample time postdose (0.25 hours). Mean maximum concentration (Cmax) for PBA, PAA, and PAGN was 37.0 micrograms/mL, 14.9 micrograms/mL, and 30.2 micrograms/mL, respectively. In healthy subjects, intact Lubriderm Nutritiva (Glycerol) phenylbutyrate was detected in plasma. While the study was inconclusive, the incomplete hydrolysis of Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) 3 times a day for 3 days, the mean Cmax 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 Lubriderm Nutritiva (Glycerol) three times a day for 3 days, mean Cmax 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 Lubriderm Nutritiva (Glycerol), maximum plasma concentrations at steady state (Cmax,ss) of PBA, PAA, and PAGN occurred at 8 hours, 12 hours, and 10 hours, respectively, after the first dose in the day. Intact Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) (i.e., Lubriderm Nutritiva (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 AUC0-23h 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 Cmax 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 Lubriderm Nutritiva (Glycerol) phenylbutyrate was in the following decreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and pancreatic lipase–related protein 2. Further, Lubriderm Nutritiva (Glycerol) phenylbutyrate was hydrolyzed in vitro by esterases in human plasma. In these in vitro studies, a complete disappearance of Lubriderm Nutritiva (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 Cmax 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 AUC0-23h for PAA was 108% higher in females than in males.

Renal Impairment

The pharmacokinetics of Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) twice daily for 7 days.

Plasma Lubriderm Nutritiva (Glycerol) phenylbutyrate was not measured in patients with hepatic impairment.

After multiple doses of Lubriderm Nutritiva (Glycerol) in patients with hepatic impairment of Child-Pugh A, B, and C, geometric mean AUCt of PBA was 42%, 84%, and 50% higher, respectively, while geometric mean AUCt 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 AUCt 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 Cmax of PAA was 144 micrograms/mL (range: 14 to 358 micrograms/mL) after daily dosing of 6 mL of Lubriderm Nutritiva (Glycerol) twice daily, while mean Cmax of PAA was 292 micrograms/mL (range: 57 to 655 micrograms/mL) after daily dosing of 9 mL of Lubriderm Nutritiva (Glycerol) twice daily. The ratio of mean Cmax 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 Lubriderm Nutritiva (Glycerol) on other drugs

Midazolam

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

Celecoxib

Concomitant administration of Lubriderm Nutritiva (Glycerol) did not significantly affect the pharmacokinetics of celecoxib, a substrate of CYP2C9. When 200 mg of celecoxib was orally administered with Lubriderm Nutritiva (Glycerol) after multiple doses of Lubriderm Nutritiva (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 Cmax 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, Lubriderm Nutritiva (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, Lubriderm Nutritiva (Glycerol) phenylbutyrate was not tumorigenic at doses up to 1000 mg/kg/day.

Mutagenesis

Lubriderm Nutritiva (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

Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 → Lubriderm Nutritiva (Glycerol) for 2 weeks; or
  • Lubriderm Nutritiva (Glycerol) for 2 weeks → sodium phenylbutyrate for 2 weeks.

Sodium phenylbutyrate or Lubriderm Nutritiva (Glycerol) were administered three times daily with meals. The dose of Lubriderm Nutritiva (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 Lubriderm Nutritiva (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.

Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 (Cmax) 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

Timepoint Ammonia (n=44)
Mean (SD) Median (min, max)
Daily Cmax (micromol/L)
RAVICTI 61 (46) 51 (12, 245)
Sodium phenylbutyrate 71 (67) 46 (14, 303)
24-Hour AUC (micromol∙h/L)
RAVICTI 866 (661) 673 (206, 3351)
Sodium phenylbutyrate 977 (865) 653 (302, 4666)

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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) (range: 6 to 30 micromol/L). Of 51 adult patients participating in the 12-month, open-label treatment with Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) (range: 24.2 to 31.4 micromol/L). Of the 43 adult patients participating in the open-label treatment with Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) in pediatric patients 2 to 17 years of age with UCDs was evaluated in 2 fixed-sequence, open-label, sodium phenylbutyrate to Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 (AUC0-24h) 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 AUC0-24h was 604 micromol∙h/L vs 815 micromol∙h/L on Lubriderm Nutritiva (Glycerol) vs sodium phenylbutyrate. In the patients between 2 years and 5 years of age with UCDs, the ammonia AUC0-24h was 632 micromol∙h/L vs 720 micromol∙h/L on Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol). Mean fasting venous ammonia values were within normal limits during long-term treatment with Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) (range: 15.4 to 25.1 micromol/L). Of the 45 pediatric patients participating in the open-label treatment with Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol). The dosage of Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) was initiated. The dosage of Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol). The dosage of Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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

Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) are sometimes the same as symptoms of high blood ammonia. Neurological adverse events may also be associated with the major metabolite of Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) during pregnancy .

Lactation

Advise patients that breastfeeding is not recommended during treatment with Lubriderm Nutritiva (Glycerol) .

Administration

  • Instruct patients to take Lubriderm Nutritiva (Glycerol) with food or formula and to administer directly into the mouth via oral syringe or dosing cup.
  • Instruct patients to take Lubriderm Nutritiva (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 Lubriderm Nutritiva (Glycerol) as follows:
    • Utilize an oral syringe to withdraw the prescribed dosage of Lubriderm Nutritiva (Glycerol) from the bottle.
    • Place the tip of the syringe into the gastrostomy/nasogastric tube.
    • Utilizing the plunger of the syringe, administer Lubriderm Nutritiva (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.

Lubriderm Nutritiva (Glycerol) is a registered trademark of Horizon Therapeutics, LLC.

MEDICATION GUIDE

Lubriderm Nutritiva (Glycerol) (rah-VIK- tee)

(glycerol phenylbutyrate)

oral liquid

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2017
What is the most important information I should know about Lubriderm Nutritiva (Glycerol)?

Lubriderm Nutritiva (Glycerol) may cause serious side effects, including:

Nervous system problems (Neurotoxicity). Phenylacetate (PAA), a breakdown product of Lubriderm Nutritiva (Glycerol), may cause nervous system side effects. Call your doctor or get medical help right away if you get any of these symptoms while taking Lubriderm Nutritiva (Glycerol):

  • sleepiness
  • lightheadedness
  • change in taste
  • problems with hearing
  • confusion
  • problems with memory
  • worsening of numbness, tingling, or burning in your hands or feet
  • headache
  • feeling very tired (fatigue)
  • nausea
  • vomiting

Your doctor may do blood tests to measure the amount of PAA in your blood during your treatment with Lubriderm Nutritiva (Glycerol).


What is Lubriderm Nutritiva (Glycerol)?

  • Lubriderm Nutritiva (Glycerol) is a prescription medicine used in adults and in children 2 months of age and older for long-term management of high blood levels of ammonia (hyperammonemia) caused by a condition called a urea cycle disorder (UCD). Lubriderm Nutritiva (Glycerol) should be used if the UCD cannot be managed with a low protein diet and dietary supplements alone. Lubriderm Nutritiva (Glycerol) must be used along with a low protein diet and in some cases dietary supplements.
  • Lubriderm Nutritiva (Glycerol) is not used for the acute treatment of hyperammonemia in people with UCD.
  • It is not known if Lubriderm Nutritiva (Glycerol) is safe and effective for the treatment of N-acetylglutamate synthase (NAGS) deficiency.

Who should not take Lubriderm Nutritiva (Glycerol)?

  • Children less than 2 months of age should not take Lubriderm Nutritiva (Glycerol) because it may not be digested in children less than 2 months of age.
  • Do not take Lubriderm Nutritiva (Glycerol) if you are allergic to phenylbutyrate. Call your doctor or go to the nearest hospital emergency room if you have wheezing, shortness of breath, cough, low blood pressure, flushing, nausea or a rash while taking Lubriderm Nutritiva (Glycerol).

Before taking Lubriderm Nutritiva (Glycerol), tell your doctor about any medical conditions and if you:

  • Have liver or kidney problems.
  • Have pancreas or bowel (intestine) problems.
  • Are pregnant or plan to become pregnant. It is not known if Lubriderm Nutritiva (Glycerol) will harm your unborn baby.
  • Pregnancy Registry: There is a Pregnancy Registry for women who take Lubriderm Nutritiva (Glycerol) just before becoming pregnant or who become pregnant during treatment with Lubriderm Nutritiva (Glycerol). The purpose of this registry is to collect information about the health of you and your baby. Talk to your doctor about how you can join the Pregnancy Registry. For more information about this registry, call 1-855-823-2595 or visit www.ucdregistry.com.
  • Are breastfeeding or plan to breastfeed. It is not known if Lubriderm Nutritiva (Glycerol) passes into your breast milk. Breastfeeding is not recommended during treatment with Lubriderm Nutritiva (Glycerol). Talk to your doctor about the best way to feed your baby if you take Lubriderm Nutritiva (Glycerol).

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, dietary and herbal supplements.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.


How should I take Lubriderm Nutritiva (Glycerol)?

  • Take Lubriderm Nutritiva (Glycerol) exactly as your doctor tells you.
  • Your doctor will tell you how much Lubriderm Nutritiva (Glycerol) to take and when to take it.
  • Your doctor may change your dose if needed.
  • Take Lubriderm Nutritiva (Glycerol) with food or formula.
  • Lubriderm Nutritiva (Glycerol) is an oral liquid that is taken by mouth using an oral syringe or dosing cup. Ask your pharmacist for an oral syringe or dosing cup if you do not have one.
  • If you have a nasogastric or gastrostomy tube in place and can swallow, you should take Lubriderm Nutritiva (Glycerol) by mouth.
  • Stay on the diet that your doctor gives you.
  • If you take too much Lubriderm Nutritiva (Glycerol), call your doctor or your poison control center at 1-800-222-1222 or go to the nearest hospital emergency room right away.

For people who cannot swallow and who have a nasogastric or gastrostomy tube in place, Lubriderm Nutritiva (Glycerol) should be given as follows:

  • Use an oral syringe to withdraw the prescribed dose of Lubriderm Nutritiva (Glycerol) from the bottle.
  • Place the tip of the syringe into the nasogastric or gastrostomy tube and push the plunger of the syringe to give Lubriderm Nutritiva (Glycerol) into the tube.
  • Add 10 mL of water or formula to the syringe and push the plunger of the syringe to flush any remaining medicine from the nasogastric or gastrostomy tube into the stomach.
  • If needed, flush the nasogastric or gastrostomy tube again with 10 mL of water or formula to clear the nasogastric or gastrostomy tube.

What are the possible side effects of Lubriderm Nutritiva (Glycerol)?

Lubriderm Nutritiva (Glycerol) may cause serious side effects, including:

  • See " What is the most important information I should know about Lubriderm Nutritiva (Glycerol)? "

The most common side effects of Lubriderm Nutritiva (Glycerol) in adults include:

  • diarrhea
  • gas
  • headache
  • abdomen (stomach) pain
  • vomiting
  • tiredness
  • decreased appetite
  • indigestion or heartburn

The most common side effects of Lubriderm Nutritiva (Glycerol) in children 2 years to 17 years of age include:

  • upper abdomen (stomach) pain
  • rash
  • nausea
  • vomiting
  • diarrhea
  • decreased appetite
  • headache

The most common side effects of Lubriderm Nutritiva (Glycerol) in children 2 months to less than 2 years of age include:

  • low white blood cell count (neutropenia)
  • vomiting
  • diarrhea
  • fever
  • reduced food intake
  • cough
  • stuffy nose
  • runny nose
  • skin rash
  • small round bumps on the skin

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of Lubriderm Nutritiva (Glycerol).

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.


How should I store Lubriderm Nutritiva (Glycerol)?

  • Store Lubriderm Nutritiva (Glycerol) between 68ºF to 77ºF (20°C to 25°C).

Keep Lubriderm Nutritiva (Glycerol) and all medicines out of the reach of children.


General information about the safe and effective use of Lubriderm Nutritiva (Glycerol).

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Lubriderm Nutritiva (Glycerol) for a condition for which it was not prescribed. Do not give Lubriderm Nutritiva (Glycerol) to other people, even if they have the same symptoms you have. It may harm them.

You can ask your doctor or pharmacist for information about Lubriderm Nutritiva (Glycerol) that is written for health professionals.


What are the ingredients in Lubriderm Nutritiva (Glycerol)?

Active ingredient: Lubriderm Nutritiva (Glycerol) phenylbutyrate

Distributed by: Horizon Pharma USA, Inc., Lake Forest, IL 60045.

© Horizon Therapeutics, LLC. All rights reserved. Lubriderm Nutritiva (Glycerol) is a registered trademark of Horizon Therapeutics, LLC.

For more information, go to www. RAVICTI.com or call 1-855-823-7878.

Isopropyl Isostearate:



Active Ingredients Purpose

Lubriderm Nutritiva (Isopropyl Isostearate) alcohol 62% by weight Antiseptic

Benzyl Alcohol 6.1% Bacteriacide

Tannic Acid 1.5% Astringent

Picric Acid 0.2% Bacteriacide

Uses

Lubriderm Nutritiva (Isopropyl Isostearate) is a highly effective germicide, formulated expressly for minor wounds and burns. Its four-way action reduces pain, checks capillary bleeding, promotes healing, and aids in the prevention of infection.

Warnings

For external use only.

FLAMMABLE. Do not spray while smoking or near fire. Contents under pressure. Do not puncture or incinerate container or place where temperature exceeds 120 F. Use only as directed. Intentional misuse by concentrating and inhaling the contents can be harmful or fatal. In case of accidental ingestion, seek professional assistance or contact a Poison Control Center immediately. If irritation occurs or if there is no improvement within 2 weeks, discontinue use and consult a doctor. Keep this and all drugs out of the reach of children.

Directions

Cleanse wound with Cinder Suds® soap. Saturate sterile dressing with Lubriderm Nutritiva (Isopropyl Isostearate). Leave in place at least five minutes; add Nitrotan® to keep dressing wet. Remove dressing, allow to dry, and apply antiseptic dressing. Renew at least once daily.

Inactive Ingredients

Isobutane and propane

Mfd. by Cramer Products, Inc. Gardner, Kansas 66030

QUESTIONS? (800) 345-2231 (M-F 8:00AM-5:00PM CST)

Purpose

Antiseptic

Bacteriacide

Astringent

Bacteriacide

Keep this and all drugs out of the reach of children.

Germicidal Wound Care Spray

Prevents Infection

Promotes Healing

Reduces Pain

Checks Capillary Bleeding

WARNING:

EXTREMELY FLAMMABLE

CONTENTS UNDER PRESSURE

READ WARNINGS ON BACK PANEL

NET WT 8 OZ (226 g)

Mineral Oil:


DRUG FACTS

ACTIVE INGREDIENTS

Lubriderm Nutritiva (Mineral Oil) oil 14%

Petrolatum 74.9%

Phenylephrine HCl 0.25%

PURPOSES

Protectant

Protectant

Vasoconstrictor

USES

  • helps relieve the local itching and discomfort associated with hemorrhoids
  • temporarily shrinks hemorrhoidal tissue and relieves burning
  • temporarily provides a coating for relief of anorectal discomforts
  • temporarily protects the inflamed, irritated anorectal surface to help make bowel movements less painful

WARNINGS

For external and/or intrarectal use only

Ask a doctor before use if you have

  • heart disease
  • high blood pressure
  • thyroid disease
  • diabetes
  • difficulty in urination due to enlargement of the prostate gland

Ask a doctor or pharmacist before use if you are

presently taking a prescription drug for high blood pressure or depression.

When using this product

do not exceed the recommended daily dosage unless directed by a doctor.

Stop use and ask a doctor if

  • bleeding occurs
  • condition worsens or does not improve within 7 days
  • introduction of applicator into the rectum causes additional pain

If pregnant or breast-feeding,

ask a health professional before use.

Keep out of reach of children.

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

DIRECTIONS

  • adults: when practical, cleanse the affected area by patting or blotting with an appropriate cleansing wipe. Gently dry by patting or blotting with a tissue or a soft cloth before applying ointment.
  • when first opening the tube, puncture foil seal with top end of cap
  • apply to the affected area up to 4 times daily, especially at night, in the morning or after each bowel movement
  • intrarectal use:
    • remove cover from applicator, attach applicator to tube, lubricate applicator well and gently insert applicator into the rectum
    • thoroughly cleanse applicator after each use and replace cover
  • also apply ointment to external area
  • regular use provides continual therapy for relief of symptoms
  • children under 12 years of age: ask a doctor

OTHER INFORMATION

store at 20-25°C (68-77°F)

INACTIVE INGREDIENTS

benzoic acid, butylated hydroxyanisole, corn oil, glycerin, lanolin, lanolin alcohols, methylparaben, Lubriderm Nutritiva (Mineral Oil) oil, paraffin, propylparaben, purified water, thymus vulgaris (thyme) flower/leaf oil, tocopherols excipient, white wax

QUESTIONS OR COMMENTS?

Call weekdays 9 AM to 5 PM EST at 1-800-99PrepH or 1-800-997-7374.

THIS PACKAGE CONTAINS AN OUTER CARTON. DO NOT BUY IF OUTER CARTON IS MISSING.

Lubriderm Nutritiva (Mineral Oil)®

HEMORRHOIDAL OINTMENT

Prevents Further

Irritation

  • Prompt, Soothing Relief from Painful

    Burning, Itching and Discomfort

  • Shrinks Swollen Hemorrhoidal Tissue
  • Protects Irritated Tissue
  • Relieves Internal and External Discomfort

NET WT 1 OZ (28 g)

Sodium Benzoate:


1 INDICATIONS AND USAGE

Lubriderm Nutritiva nitrite is indicated for sequential use with Lubriderm Nutritiva (Sodium Benzoate) 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

Lubriderm Nutritiva (Sodium Benzoate) Nitrite Injection is indicated for sequential use with Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva 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, Lubriderm Nutritiva (Sodium Benzoate) Nitrite Injection and Lubriderm Nutritiva (Sodium Benzoate) Thiosulfate Injection should be administered without delay.

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

    (e.g., confusion, disorientation)

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

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

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

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) thiosulfate, simultaneously with Lubriderm Nutritiva (Sodium Benzoate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Lubriderm Nutritiva (Sodium Benzoate) thiosulfate, with Lubriderm Nutritiva (Sodium Benzoate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

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

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

Lubriderm Nutritiva (Sodium Benzoate) nitrite injection and Lubriderm Nutritiva (Sodium Benzoate) 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. Lubriderm Nutritiva (Sodium Benzoate) nitrite should be administered first, followed immediately by Lubriderm Nutritiva (Sodium Benzoate) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

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

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Lubriderm Nutritiva (Sodium Benzoate) nitrite and Lubriderm Nutritiva (Sodium Benzoate) thiosulfate.

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

3 DOSAGE FORMS AND STRENGTHS

Lubriderm Nutritiva (Sodium Benzoate) Nitrite Injection consists of:

  • One vial of Lubriderm Nutritiva (Sodium Benzoate) 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: Lubriderm Nutritiva 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 Lubriderm Nutritiva (Sodium Benzoate) 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. Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva nitrite.

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

5.3 Anemia

Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Lubriderm Nutritiva 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 Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva 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 Lubriderm Nutritiva (Sodium Benzoate) nitrite.

5.7 Use with Other Drugs

Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) nitrite.

The medical literature has reported the following adverse events in association with Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Lubriderm Nutritiva 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. Lubriderm Nutritiva (Sodium Benzoate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) 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, Lubriderm Nutritiva (Sodium Benzoate) 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, Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

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

Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) 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

Lubriderm Nutritiva (Sodium Benzoate) 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

Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) 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

Lubriderm Nutritiva (Sodium Benzoate) nitrite has the chemical name nitrous acid Lubriderm Nutritiva (Sodium Benzoate) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:

Structure of Lubriderm Nutritiva (Sodium Benzoate) Nitrite

Lubriderm Nutritiva (Sodium Benzoate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Lubriderm Nutritiva (Sodium Benzoate) nitrite injection.

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

Lubriderm Nutritiva (Sodium Benzoate) Nitrite

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

Lubriderm Nutritiva (Sodium Benzoate) 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. Lubriderm Nutritiva (Sodium Benzoate) 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

Lubriderm Nutritiva (Sodium Benzoate) Nitrite

When 4 mg/kg Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Lubriderm Nutritiva (Sodium Benzoate) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

The human data supporting the use of Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) thiosulfate report its use in conjunction with Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) 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 Lubriderm Nutritiva (Sodium Benzoate) Nitrite carton (NDC 60267-311-10) consists of the following:

  • One 10 mL glass vial of Lubriderm Nutritiva (Sodium Benzoate) nitrite injection 30 mg/mL (containing 300 mg of Lubriderm Nutritiva (Sodium Benzoate) 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: Lubriderm Nutritiva (Sodium Benzoate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Lubriderm Nutritiva 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

Lubriderm Nutritiva (Sodium Benzoate) 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

Lubriderm Nutritiva (Sodium Benzoate) 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

Sodium Hydroxide:


1 INDICATIONS AND USAGE

Lubriderm Nutritiva nitrite is indicated for sequential use with Lubriderm Nutritiva (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

Lubriderm Nutritiva (Sodium Hydroxide) Nitrite Injection is indicated for sequential use with Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva 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, Lubriderm Nutritiva (Sodium Hydroxide) Nitrite Injection and Lubriderm Nutritiva (Sodium Hydroxide) Thiosulfate Injection should be administered without delay.

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

    (e.g., confusion, disorientation)

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

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

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

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) thiosulfate, simultaneously with Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) thiosulfate, with Lubriderm Nutritiva (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

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

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Lubriderm Nutritiva (Sodium Hydroxide) nitrite and Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) nitrite, followed by Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) nitrite and Lubriderm Nutritiva (Sodium Hydroxide) thiosulfate.

Lubriderm Nutritiva (Sodium Hydroxide) nitrite injection and Lubriderm Nutritiva (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. Lubriderm Nutritiva (Sodium Hydroxide) nitrite should be administered first, followed immediately by Lubriderm Nutritiva (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.

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

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Lubriderm Nutritiva (Sodium Hydroxide) nitrite and Lubriderm Nutritiva (Sodium Hydroxide) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Lubriderm Nutritiva (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 Lubriderm Nutritiva 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 Lubriderm Nutritiva (Sodium Hydroxide) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Lubriderm Nutritiva (Sodium Hydroxide) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Lubriderm Nutritiva (Sodium Hydroxide) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) thiosulfate and Lubriderm Nutritiva (Sodium Hydroxide) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Lubriderm Nutritiva (Sodium Hydroxide) Nitrite Injection consists of:

  • One vial of Lubriderm Nutritiva (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: Lubriderm Nutritiva 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 Lubriderm Nutritiva (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. Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva nitrite.

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

5.3 Anemia

Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Lubriderm Nutritiva 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 Lubriderm Nutritiva (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 Lubriderm Nutritiva 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 Lubriderm Nutritiva (Sodium Hydroxide) nitrite.

5.7 Use with Other Drugs

Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) nitrite.

The medical literature has reported the following adverse events in association with Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Lubriderm Nutritiva 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. Lubriderm Nutritiva (Sodium Hydroxide) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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, Lubriderm Nutritiva (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, Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Lubriderm Nutritiva (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, Lubriderm Nutritiva 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 Lubriderm Nutritiva (Sodium Hydroxide) nitrite is excreted in human milk. Because Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Lubriderm Nutritiva (Sodium Hydroxide) nitrite. In studies conducted with Long-Evans rats, Lubriderm Nutritiva (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 Lubriderm Nutritiva nitrite in conjunction with Lubriderm Nutritiva (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 Lubriderm Nutritiva (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.

Lubriderm Nutritiva (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 Lubriderm Nutritiva (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

Lubriderm Nutritiva (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

Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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

Lubriderm Nutritiva (Sodium Hydroxide) nitrite has the chemical name nitrous acid Lubriderm Nutritiva (Sodium Hydroxide) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:

Structure of Lubriderm Nutritiva (Sodium Hydroxide) Nitrite

Lubriderm Nutritiva (Sodium Hydroxide) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Lubriderm Nutritiva (Sodium Hydroxide) nitrite injection.

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

Lubriderm Nutritiva (Sodium Hydroxide) Nitrite

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

Lubriderm Nutritiva (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. Lubriderm Nutritiva (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

Lubriderm Nutritiva (Sodium Hydroxide) Nitrite

When 4 mg/kg Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Lubriderm Nutritiva (Sodium Hydroxide) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

The human data supporting the use of Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) thiosulfate report its use in conjunction with Lubriderm Nutritiva (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 Lubriderm Nutritiva (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 Lubriderm Nutritiva (Sodium Hydroxide) Nitrite carton (NDC 60267-311-10) consists of the following:

  • One 10 mL glass vial of Lubriderm Nutritiva (Sodium Hydroxide) nitrite injection 30 mg/mL (containing 300 mg of Lubriderm Nutritiva (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: Lubriderm Nutritiva (Sodium Hydroxide) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Lubriderm Nutritiva 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

Lubriderm Nutritiva (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

Lubriderm Nutritiva (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

Titanium Dioxide:


Sunscreens are used to protect the skin from the harmful effects of the sun. They help to prevent sunburn and premature aging (e.g., wrinkles, leathery skin). Sunscreens also help to decrease the risk of skin cancer and also of sunburn-like skin reactions (sun sensitivity) caused by some medications (e.g., tetracyclines, sulfa drugs, phenothiazines such as chlorpromazine ). The active ingredients in sunscreens work either by absorbing the sun's ultraviolet (UV) radiation, preventing it from reaching the deeper layers of the skin, or by reflecting the radiation. Wearing sunscreen does not mean that you can stay out longer in the sun. Sunscreens cannot protect against all of the sun's radiation. There are various types of sunscreens available in many forms (e.g., cream, lotion, gel, stick, spray, lip balm). See the Notes section for information about selecting a sunscreen.

Tri (PPG-3 Myristyl Ether) Citrate:


This combination hormone medication is used to prevent pregnancy. It contains 2 hormones: a progestin and an estrogen. It works mainly by preventing the release of an egg ( ovulation ) during your menstrual cycle. It also makes vaginal fluid thicker to help prevent sperm from reaching an egg (fertilization) and changes the lining of the uterus (womb) to prevent attachment of a fertilized egg. If a fertilized egg does not attach to the uterus, it passes out of the body. Besides preventing pregnancy, birth control pills may make your periods more regular, decrease blood loss and painful periods, and decrease your risk of ovarian cysts. Using this medication does not protect you or your partner against sexually transmitted diseases (such as HIV, gonorrhea, chlamydia ).

Vitamin A (Retinol Palmitate):


DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

Supplement Facts
Serving Size 1 Tablet

Servings Per Container 100

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

WARNING

KEEP OUT OF THE REACH OF CHILDREN.

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

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

Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.

CLINICAL PHARMACOLOGY

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

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

The reaction may be expressed by the equation:

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

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

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

DIETARY SUPPLEMENTATION

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

WARNINGS

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

PRECAUTIONS

The suggested dose of Lubriderm Nutritiva (Vitamin A (Retinol Palmitate)) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending Lubriderm Nutritiva (Vitamin A (Retinol Palmitate)) Tablets

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

ADVERSE REACTIONS

Allergic rash and other idiosyncrasies have been rarely reported.

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

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

HOW SUPPLIED

Lubriderm Nutritiva ) Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.

Lubriderm Nutritiva (Vitamin A (Retinol Palmitate)) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.

Lubriderm Nutritiva (Vitamin A (Retinol Palmitate)) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.

STORAGE

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

Distributed by:

H2-Pharma, LLC

2010 Berry Chase Place

Montgomery, AL 36117

www.h2-pharma.com

1067084

61269-151-01

MultiVitamin

with Fluoride

Chewable Tablets

Rx

0.25 mg

MultiVitamin and Fluoride Supplement

Dietary Supplement

100 Tablets

H2pharma

Vitamin E (Tocopherol Acetate):


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

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

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

Water:


Active ingredient

Lubriderm Nutritiva (Water) 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, 15o to 30o C (59o to 86o F)
  • do not freeze

Inactive ingredients

sodium chloride, sodium phosphate dibasic, sodium phosphate monobasic

Questions?

1-800 - 430-5490

Sperian Eye and Face Protection, Inc.

(a Honeywell Company)

825 East Highway 151

Platteville, WI 53818 USA

Lubriderm Nutritiva pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Lubriderm Nutritiva available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Lubriderm Nutritiva destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Lubriderm Nutritiva Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Lubriderm Nutritiva pharmaceutical companies:

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


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References

  1. Dailymed."SPERIAN EYESALINE EYEWASH (WATER) LIQUID [SPERIAN EYE & FACE PROTECTION INC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."PAN AROMAS BABY (MINERAL OIL) OIL [PAN AROMAS LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."SODIUM HYDROXIDE LIQUID [GORDON LABORATORIES]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Lubriderm Nutritiva?

Depending on the reaction of the Lubriderm Nutritiva after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Lubriderm Nutritiva not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Lubriderm Nutritiva addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Lubriderm Nutritiva, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Lubriderm Nutritiva consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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