Gly Thymol

Glycerol:

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

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

Gly Thymol (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. Gly Thymol (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:

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

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

Limitations of Use:

• Gly Thymol (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

• Gly Thymol 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 Gly Thymol (Glycerol):

• Patients should receive the dosage of Gly Thymol (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

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

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

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

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

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

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

3 DOSAGE FORMS AND STRENGTHS

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

Oral liquid: 1.1 g/mL. (3)

4 CONTRAINDICATIONS

Gly Thymol (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 Gly Thymol (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 Gly Thymol (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 Gly Thymol (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 Gly Thymol (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 Gly Thymol (Glycerol), peak PAA concentrations after dosing with Gly Thymol (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 Gly Thymol (Glycerol) dosage .

5.2 Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption

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

	Number (%) of Patients in Study 1
	Sodium Phenylbutyrate (N = 45)	Gly Thymol (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

Gly Thymol (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 Gly Thymol (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.

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

Probenecid

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

7.3 Potential for Gly Thymol to Affect Other Drugs

Drugs with narrow therapeutic index that are substrates of CYP3A4

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

Risk Summary

Limited available data with Gly Thymol (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 Gly Thymol (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 Gly Thymol (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 Gly Thymol (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 Gly Thymol (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 Gly Thymol (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 Gly Thymol (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 Gly Thymol 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 Gly Thymol (Glycerol).

8.4 Pediatric Use

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

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

Patients 2 Months to Less Than 2 Years of Age

The safety and efficacy of Gly Thymol (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

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

Gly Thymol (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.

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

Cardiac Electrophysiology

The effect of multiple doses of Gly Thymol (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 Gly Thymol (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

Gly Thymol (Glycerol) is a pro-drug of PBA. Upon oral ingestion, PBA is released from the Gly Thymol (Glycerol) backbone in the gastrointestinal tract by lipases. PBA derived from Gly Thymol (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 Gly Thymol (Glycerol), peak plasma levels of PBA, PAA, and PAGN occurred at 2 hours, 4 hours, and 4 hours, respectively. Upon single-dose administration of Gly Thymol (Glycerol), plasma concentrations of PBA were quantifiable in 15 of 22 participants at the first sample time postdose (0.25 hours). Mean maximum concentration (C_max) for PBA, PAA, and PAGN was 37.0 micrograms/mL, 14.9 micrograms/mL, and 30.2 micrograms/mL, respectively. In healthy subjects, intact Gly Thymol (Glycerol) phenylbutyrate was detected in plasma. While the study was inconclusive, the incomplete hydrolysis of Gly Thymol (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 Gly Thymol (Glycerol) 3 times a day for 3 days, the mean C_max and AUC were 66 micrograms/mL and 930 micrograms∙h/mL for PBA and 28 micrograms/mL and 942 micrograms∙h/mL for PAA, respectively. In the same study, following 6 mL of Gly Thymol (Glycerol) three times a day for 3 days, mean C_max and AUC were 100 micrograms/mL and 1400 micrograms∙h/mL for PBA and 65 µg/mL and 2064 micrograms∙h/mL for PAA, respectively.

In adult patients with UCDs receiving multiple doses of Gly Thymol (Glycerol), maximum plasma concentrations at steady state (C_max,ss) of PBA, PAA, and PAGN occurred at 8 hours, 12 hours, and 10 hours, respectively, after the first dose in the day. Intact Gly Thymol (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 Gly Thymol (Glycerol) (i.e., Gly Thymol (Glycerol) phenylbutyrate), and release PBA. PBA undergoes β-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidney through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGN. PAGN is subsequently eliminated in the urine.

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

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

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

Excretion

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

Specific Populations

Age: Pediatric Population

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

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

Sex

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

Renal Impairment

The pharmacokinetics of Gly Thymol (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 Gly Thymol (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 Gly Thymol (Glycerol) twice daily for 7 days.

Plasma Gly Thymol (Glycerol) phenylbutyrate was not measured in patients with hepatic impairment.

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

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

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

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

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

Drug Interaction Studies

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

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

Effects of Gly Thymol (Glycerol) on other drugs

Midazolam

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

Celecoxib

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 2-year study in Sprague-Dawley rats, Gly Thymol (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, Gly Thymol (Glycerol) phenylbutyrate was not tumorigenic at doses up to 1000 mg/kg/day.

Mutagenesis

Gly Thymol (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

Gly Thymol (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 Gly Thymol (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 → Gly Thymol (Glycerol) for 2 weeks; or
• Gly Thymol (Glycerol) for 2 weeks → sodium phenylbutyrate for 2 weeks.

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

Gly Thymol (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 Gly Thymol (Glycerol) and sodium phenylbutyrate, respectively. The ratio of geometric means was 0.91 [95% CI 0.8, 1.04].

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

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

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

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 Gly Thymol (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 Gly Thymol (Glycerol) (range: 6 to 30 micromol/L). Of 51 adult patients participating in the 12-month, open-label treatment with Gly Thymol (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 Gly Thymol (Glycerol) (range: 24.2 to 31.4 micromol/L). Of the 43 adult patients participating in the open-label treatment with Gly Thymol (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 Gly Thymol (Glycerol) in pediatric patients 2 to 17 years of age with UCDs was evaluated in 2 fixed-sequence, open-label, sodium phenylbutyrate to Gly Thymol (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 Gly Thymol (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 Gly Thymol (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 Gly Thymol (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 Gly Thymol (Glycerol) dose of 8 mL/m²/day (8.8 g/m²/day), with doses ranging from 1.4 to 13.1 mL/m²/day (1.5 to 14.4 g/m²/day). Doses in these patients were based on previous dosing of sodium phenylbutyrate.

The 24-hour AUCs for blood ammonia (AUC_0-24h) in 11 pediatric patients 6 to 17 years of age with UCDs (Study 3) and 11 pediatric patients 2 years to 5 years of age with UCDs (Study 4) were similar between treatments. In children 6 to 17 years of age, the ammonia AUC_0-24h was 604 micromol∙h/L vs 815 micromol∙h/L on Gly Thymol (Glycerol) vs sodium phenylbutyrate. In the patients between 2 years and 5 years of age with UCDs, the ammonia AUC_0-24h was 632 micromol∙h/L vs 720 micromol∙h/L on Gly Thymol (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 Gly Thymol (Glycerol). Mean fasting venous ammonia values were within normal limits during long-term treatment with Gly Thymol (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 Gly Thymol (Glycerol) (range: 15.4 to 25.1 micromol/L). Of the 45 pediatric patients participating in the open-label treatment with Gly Thymol (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 Gly Thymol (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 Gly Thymol (Glycerol). The dosage of Gly Thymol (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 Gly Thymol (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 Gly Thymol (Glycerol) was initiated. The dosage of Gly Thymol (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 Gly Thymol (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 Gly Thymol (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 Gly Thymol (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 Gly Thymol (Glycerol). The dosage of Gly Thymol (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 Gly Thymol (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 Gly Thymol (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

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

Lactation

Advise patients that breastfeeding is not recommended during treatment with Gly Thymol (Glycerol) .

Administration

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

Gly Thymol (Glycerol) is a registered trademark of Horizon Therapeutics, LLC.

MEDICATION GUIDE Gly Thymol (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 Gly Thymol (Glycerol)? Gly Thymol (Glycerol) may cause serious side effects, including: Nervous system problems (Neurotoxicity). Phenylacetate (PAA), a breakdown product of Gly Thymol (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 Gly Thymol (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 Gly Thymol (Glycerol).
What is Gly Thymol (Glycerol)? Gly Thymol (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). Gly Thymol (Glycerol) should be used if the UCD cannot be managed with a low protein diet and dietary supplements alone. Gly Thymol (Glycerol) must be used along with a low protein diet and in some cases dietary supplements. Gly Thymol (Glycerol) is not used for the acute treatment of hyperammonemia in people with UCD. It is not known if Gly Thymol (Glycerol) is safe and effective for the treatment of N-acetylglutamate synthase (NAGS) deficiency.
Who should not take Gly Thymol (Glycerol)? Children less than 2 months of age should not take Gly Thymol (Glycerol) because it may not be digested in children less than 2 months of age. Do not take Gly Thymol (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 Gly Thymol (Glycerol).
Before taking Gly Thymol (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 Gly Thymol (Glycerol) will harm your unborn baby. Pregnancy Registry: There is a Pregnancy Registry for women who take Gly Thymol (Glycerol) just before becoming pregnant or who become pregnant during treatment with Gly Thymol (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 Gly Thymol (Glycerol) passes into your breast milk. Breastfeeding is not recommended during treatment with Gly Thymol (Glycerol). Talk to your doctor about the best way to feed your baby if you take Gly Thymol (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 Gly Thymol (Glycerol)? Take Gly Thymol (Glycerol) exactly as your doctor tells you. Your doctor will tell you how much Gly Thymol (Glycerol) to take and when to take it. Your doctor may change your dose if needed. Take Gly Thymol (Glycerol) with food or formula. Gly Thymol (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 Gly Thymol (Glycerol) by mouth. Stay on the diet that your doctor gives you. If you take too much Gly Thymol (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, Gly Thymol (Glycerol) should be given as follows: Use an oral syringe to withdraw the prescribed dose of Gly Thymol (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 Gly Thymol (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 Gly Thymol (Glycerol)? Gly Thymol (Glycerol) may cause serious side effects, including:
	See " What is the most important information I should know about Gly Thymol (Glycerol)? "
The most common side effects of Gly Thymol (Glycerol) in adults include:
	diarrhea gas headache abdomen (stomach) pain	vomiting tiredness decreased appetite indigestion or heartburn
The most common side effects of Gly Thymol (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 Gly Thymol (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 Gly Thymol (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 Gly Thymol (Glycerol)? Store Gly Thymol (Glycerol) between 68ºF to 77ºF (20°C to 25°C). Keep Gly Thymol (Glycerol) and all medicines out of the reach of children.
General information about the safe and effective use of Gly Thymol (Glycerol). Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Gly Thymol (Glycerol) for a condition for which it was not prescribed. Do not give Gly Thymol (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 Gly Thymol (Glycerol) that is written for health professionals.
What are the ingredients in Gly Thymol (Glycerol)? Active ingredient: Gly Thymol (Glycerol) phenylbutyrate Distributed by: Horizon Pharma USA, Inc., Lake Forest, IL 60045. © Horizon Therapeutics, LLC. All rights reserved. Gly Thymol (Glycerol) is a registered trademark of Horizon Therapeutics, LLC. For more information, go to www. RAVICTI.com or call 1-855-823-7878.

Menthol:

• Gly Thymol (Menthol) reviews

Gly Thymol (Menthol) is a covalent organic compound made synthetically or obtained from peppermint or other mint oils. It is a waxy, crystalline substance, clear or white in color, which is solid at room temperature and melts slightly above. The main form of Gly Thymol (Menthol) occurring in nature is (-)-menthol, which is assigned the (1R,2S,5R) configuration. Gly Thymol (Menthol) has local anesthetic and counterirritant qualities, and it is widely used to relieve minor throat irritation.

Indication: Used to treat occasional minor irritation, pain, sore mouth, and sore throat as well as cough associated with a cold or inhaled irritants.

Gly Thymol (Menthol) is a covalent organic compound made synthetically or obtained from peppermint or other mint oils. Menthol's ability to chemically trigger cold-sensitive receptors in the skin is responsible for the well known cooling sensation that it provokes when inhalated, eaten, or applied to the skin. It should be noted that Gly Thymol (Menthol) does not cause an actual drop in temperature.

Methyl Salicylate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Gly Thymol (Methyl Salicylate) reviews

INDICATIONS AND USAGE

Gly Thymol (Methyl Salicylate) Cream in combination with 570 to 670 nm wavelength red light illumination using the CureLight BroadBand Model CureLight 01 lamp is indicated for treatment of non-hyperkeratotic actinic keratoses of the face and scalp in immunocompetent patients when used in conjunction with lesion preparation (debridement using a sharp dermal curette) in the physician’s office when other therapies are unacceptable or considered medically less appropriate.

CONTRAINDICATIONS

Gly Thymol (Methyl Salicylate) Cream is contraindicated in patients with cutaneous photosensitivity, or known allergies to porphyrins, and in patients with known sensitivities to any of the components of Gly Thymol (Methyl Salicylate) Cream, which includes peanut and almond oil Cream).

This product contains refined peanut oil.

WARNINGS

Gly Thymol (Methyl Salicylate) Cream is intended for topical use in the physician’s office by trained physicians only. Do not apply to the eyes or to mucous membranes.

Gly Thymol (Methyl Salicylate) Cream has demonstrated a high rate of contact sensitization (allergenicity). Care should be taken by the physician applying Gly Thymol (Methyl Salicylate) Cream to avoid inadvertent skin contact. Nitrile gloves should be worn when applying and removing the cream. Vinyl and latex gloves do not provide adequate protection when using this product.Gly Thymol (Methyl Salicylate) Cream when used with CureLight BroadBand Model CureLight 01 lamp must be used with appropriate protective sleeves obtained from the product manufacturer to decrease the risk of blood-borne transmitted diseases (hepatitis, HIV, etc.). Change the disposable covers for the device (probe and horseshoe positioning device) between patients. Universal Precautions should be used with this treatment.

PRECAUTIONS

The safety and efficacy have not been established for the treatment of cutaneous malignancies and for skin lesions other than non-hyperkeratotic face and scalp actinic keratoses using PDT with Gly Thymol Cream. Thick (hyperkeratotic) actinic keratoses should not be treated with Gly Thymol (Methyl Salicylate) Cream. The safety and efficacy of Gly Thymol (Methyl Salicylate) Cream has not been established in patients with immunosuppression, porphyria or pigmented actinic keratoses.

General

Gly Thymol (Methyl Salicylate) Cream Application

During the time period between the application of Gly Thymol (Methyl Salicylate) (methyl aminolevulinate) Cream and exposure to red light illumination, the treatment site will become photosensitive. After Gly Thymol (Methyl Salicylate) Cream application, patients should avoid exposure of the photosensitive treatment sites to sunlight or bright indoor light (e.g., examination lamps, operating room lamps, tanning beds, or lights at close proximity) during the period prior to red light treatment. Exposure to light may result in a stinging and/or burning sensation and may cause erythema and/or edema of the lesions. Before exposure to sunlight, patients should, therefore, protect treated lesions from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque material. Sunscreens will not protect against photosensitivity reactions caused by visible light. The treated site should be protected from extreme cold with adequate clothing or remaining indoors between application of Gly Thymol (Methyl Salicylate) and PDT light treatment. After illumination of Gly Thymol (Methyl Salicylate) Cream, the area treated should be kept covered and away from light for at least 48 hours. Because of the potential for skin to become photosensitized, the Gly Thymol (Methyl Salicylate) Cream should be used by a trained physician to apply drug only to non-hyperkeratotic actinic keratoses and perilesional skin within 5 mm of the lesion. Redness, swelling, burning, and stinging are expected as a result of therapy; however, if these symptoms increase in severity and persist longer than 3 weeks, the patient should contact their doctor. Metvixia Cream has not been studied for more than two treatment sessions. Information regarding further treatments for residual or new AK lesions performed after 3 months is not available..

Photosensitivity and Device Precautions.

The patient, operator and other persons present should wear protective goggles that sufficiently screen out light with wavelengths from 570 to 670 nm during red light treatment.

If for any reason the patient cannot have the red light treatment after application of Gly Thymol Cream, the cream should be rinsed off, and the patient should protect the treated area from sunlight, prolonged or intense light for two days. Prolonged exposure for greater than 4 hours to Gly Thymol (Methyl Salicylate) Cream should be avoided.

Coagulation defects

Gly Thymol (Methyl Salicylate) Cream has not been tested on patients with inherited or acquired coagulation defects.

Hypersensitivity

Gly Thymol Cream is formulated with refined peanut and almond oil.

Gly Thymol (Methyl Salicylate) (methyl aminolevulinate) Cream has not been tested in patients who are allergic to peanuts. Gly Thymol (Methyl Salicylate) (methyl aminolevulinate) Cream has demonstrated a high rate of contact sensitization (allergenicity). 

Information for Patients

The physician should provide and discuss the attached Patient Package Insert with each patient.

Drug Interactions

There have been no studies of the interaction of Gly Thymol Cream with any other drugs, including local anesthetics. It is possible that concomitant use of other known photosensitizing agents might increase the photosensitivity reaction of actinic keratoses treated with Gly Thymol (Methyl Salicylate) Cream.

Carcinogenesis, Mutagenesis, Impairment to Fertility

Long-term studies to evaluate the carcinogenic potential of Gly Thymol (Methyl Salicylate) Cream have not been performed. 

Gly Thymol (Methyl Salicylate) aminolevulinate was negative for genetic toxicity in the Ames assay, and the chromosomal aberration assay in Chinese hamster ovary cells, tested with and without metabolic activation and in the presence and absence of light. Gly Thymol (Methyl Salicylate) aminolevulinate was also negative in the in vivo micronucleus assay in the rat. In contrast, at least one report in the literature has noted genotoxic effects in cultured rat hepatocytes after aminolevulinate (ALA) exposure with PpIX formation. Other studies have documented oxidative DNA damage in vivo and in vitro as a result of ALA exposure. No animal fertility studies have been conducted.

Pregnancy

Teratogenic effects

Pregnancy Category C: Animal reproduction studies have not been conducted with Gly Thymol Cream. It is also not known whether Gly Thymol (Methyl Salicylate) Cream can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Gly Thymol (Methyl Salicylate) Cream should be given to a pregnant woman only if clearly needed.

Nursing Mothers

The amount of Gly Thymol (Methyl Salicylate) aminolevulinate secreted into human breast milk following topical administration of Gly Thymol (Methyl Salicylate) Cream is not known. Because many drugs are secreted in human milk, caution should be exercised when Gly Thymol (Methyl Salicylate) Cream is administered to a nursing mother. If Gly Thymol (Methyl Salicylate) Cream is used in a nursing mother, a decision should be made whether or not to stop nursing.

Pediatric Use

It is not recommended that Gly Thymol Cream be used in pediatric patients. Actinic keratosis is rarely found in pediatric patients. 

Geriatric Use

Seventy percent (269 among 383) of the patients treated with Gly Thymol (Methyl Salicylate) Cream in all clinical studies of actinic keratosis were 65 years of age or older. No overall differences in safety and efficacy were observed between patients aged 65 years and older and those who were younger.

ADVERSE REACTIONS

Dermal Safety Studies

Provocative studies to evaluate irritancy and sensitization have demonstrated that Gly Thymol Cream is an irritant and sensitizer. A provocative cumulative irritancy and sensitization (allergenicity) study of Gly Thymol (Methyl Salicylate) Cream with a cross-sensitization challenge with ALA was performed in 156 subjects. Only 98 of the 156 subjects tested entered the challenge phase. Fifty-two percent of the subjects (30/58), who agreed to challenge with Gly Thymol (Methyl Salicylate) Cream, were positive (sensitized). Forty subjects refused challenge with Gly Thymol (Methyl Salicylate) Cream and 60 withdrew. At least 58 of the 60 subjects who withdrew from the study discontinued due to irritation/sensitization.

Ninety-eight subjects agreed to challenge with ALA. Two percent of the ALA challenged subjects (2/98) were scored as equivocal reactions and 2% in the paraffin vehicle group were scored as positive.

Adverse Events

In vehicle-controlled phase 3 studies of actinic keratosis, 88% of patients treated with Gly Thymol (Methyl Salicylate) Cream reported one or more adverse events.

Burning was the most frequent complaint, reported by 50% of patients (ranging from mild, to severe) and 9% of those patients reported severe burning sensation. Pain in the skin was reported by 21% of patients and 7% had severe pain. Local erythema lasting up to two weeks and edema up to one week after treatment were reported by 31% and 6% of patients. Symptoms and signs of local phototoxicity were observed in 88% of patients treated with Gly Thymol (Methyl Salicylate) Cream in all clinical studies of Gly Thymol (Methyl Salicylate) -PDT for actinic keratoses.

Events	Metvixia-PDT (n=130)	Vehicle PDT* (n=61)
	n (%) of patients with AEs	n (%) of patients with AEs
Burning sensation skin	65 (50.0%)	9 (14.8%)
Erythema	60 (46.2%)	12 (19.7%)
Skin pain	27 (20.8%)	6 (9.8%)
Stinging skin	25 (19.2%)	2 (3.3%)
Crusting	20 (15.4%)	6 (9.8%)
Edema skin	20 (15.4%)	1 (1.6%)
Skin peeling	14 (10.8%)	2 (3.3%)
Blisters	14 (10.8%)	2 (3.3%)
Bleeding skin	11 (8.5%)	2 (3.3%)
Pruritus/Itching	17 (13.1%)	2 (3.3%)
Skin ulceration	7 (5.4%)	0 (0%)
Skin infection	3 (2.3%)	1 (1.6%)
Skin hyper-pigmentation	1 (0.8%)	0 (0%)

The majority of patients in all the clinical trials had local pain or discomfort upon illumination. There were 4 (1.0%) withdrawals/discontinuations among 383 patients treated with Gly Thymol (Methyl Salicylate) Cream in all the clinical trials of actinic keratosis, all of which were due to the adverse event of local pain on illumination.

There have been reported instances of patients treated with Gly Thymol (Methyl Salicylate) Cream (2 out of 130) who have developed squamous cell and basal cell carcinoma at the site of treatment. The relationship to treatment with Gly Thymol (Methyl Salicylate) Cream is unknown. Serious erythema and facial edema have been described in European post-marketing reports.

OVERDOSAGE

Gly Thymol Cream Overdose

Gly Thymol (Methyl Salicylate) Cream overdose has not been reported. If the patient for any reason cannot have the red light treatment during the prescribed period after application (the 3 hour timespan), the cream should be rinsed off, and the patient should protect the exposed area from sunlight, prolonged or intense light for two days.  

Red Light Overdose

There is no information on overdose of red light following Gly Thymol (Methyl Salicylate) Cream application.

In case of red light overexposure and skin burn occurs, the patient should be treated according to standard of practice guidelines for treatment of cutaneous burns.

DOSAGE AND ADMINISTRATION

Photodynamic therapy for non-hyperkeratotic actinic keratoses with Gly Thymol (Methyl Salicylate) Cream is a multi-stage process as described below: Two treatment sessions 7 days apart should be conducted. Not more than one gram (half a tube) of Gly Thymol (Methyl Salicylate) Cream should be applied per treatment session.

One Gly Thymol (Methyl Salicylate) -PDT session consists of: 1) Lesion debriding –

Before applying Gly Thymol (Methyl Salicylate) Cream, the surface of the lesions should be prepared with a small dermal curette to remove scales and crusts and roughen the surface of the lesion. This is to facilitate access of the cream and light to all parts of the lesion.

Figure 1 A Lesion debriding  Only nitrile gloves should be worn during this and subsequent steps and Universal Precautions should be taken. Vinyl and latex gloves do not provide adequate protection when using this product.

Figure 1B Lesion debriding2) Application of Gly Thymol (Methyl Salicylate) Cream –

Using a spatula, apply a layer of Gly Thymol (Methyl Salicylate) Cream about 1 mm thick to the lesion and the surrounding 5 mm of normal skin. Do not apply more than one gram of Gly Thymol (Methyl Salicylate) Cream for each patient per treatment session.

Figure 2: Cream applicationThe area to which the cream has been applied should then be covered with an occlusive, non-absorbent dressing for 3 hours. Multiple lesions may be treated during the same treatment session. Each treatment field is limited to a diameter of 55 mm. Only nitrile gloves should be worn by the qualified healthcare provider in order to avoid skin contact with the cream. This product is not intended for application by patients or unqualified medical personnel.

Figure 3: Occlusive dressing application3) Wait for 3 hours - (at least 2.5 hours, but no more than 4 hours).

After Cream application, patients should avoid exposure of the photosensitive treatment sites to sunlight or bright indoor light (e.g., examination lamps, operating room lamps, tanning beds, or lights at close proximity) during the period prior to red light treatment. Exposure to light may result in a stinging and/or burning sensation and may cause erythema and/or edema of the lesions. Patients should protect treated areas from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque material. Sunscreens will not protect against photosensitivity reactions caused by visible light. It has not been determined if perspiration can spread the Gly Thymol (Methyl Salicylate) Cream outside the treatment site to the eyes or surrounding skin. The treated site should be protected from extreme cold with adequate clothing or remaining indoors between application of Gly Thymol (Methyl Salicylate) Cream and PDT light treatment.4) Removal of Dressing and Rinse Off Excess Cream - Following removal of the occlusive dressing, clean the area with saline and gauze. Nitrile gloves should be worn at this step by the trained physician. 

Figure 4: Cream removal5) Illumination of Gly Thymol (Methyl Salicylate) Treated Lesion - It is important to ensure that the correct light dose is administered. The light intensity at the lesion surface should not be higher than 200 mW/cm². Patient and operator should adhere to safety instructions and Universal Precautions provided with the lamp. The patient and operator should wear protective goggles during illumination. Patients should be advised that transient stinging and/or burning at the target lesion sites may occur during the period of light exposure.

Figure 5: IlluminationThe CureLight BroadBand Model CureLight 01 lamp is approved for the use in Gly Thymol (Methyl Salicylate) -PDT. The lamp should be carefully calibrated so that dosing is accurate and immediately thereafter the lesion should be exposed to red light with a continuous spectrum of 570 to 670 nm and a total light dose of 75 J/cm². To avoid direct contact between lamp parts and patient skin, always use disposable protective plastic sleeves on the positioning device and on the light measuring probe. Following each patient treatment, the disposable protective plastic sleeves should be removed from the positioning device and from the light measuring probe and discarded. If red light treatment is interrupted or stopped for any reason, it may be restarted. If the patient for any reason cannot have the red light treatment during the prescribed period after application (the 3 hour timespan), the cream should be rinsed off and the patient should protect the exposed area from sunlight, prolonged or intense light for two days. Gly Thymol (Methyl Salicylate) Cream is not intended for use with any device other than the approved lamp: CureLight BroadBand Model CureLight 01. Use of Gly Thymol (Methyl Salicylate) Cream without subsequent red light illumination is not recommended. No more than 1 gram (half a tube) of product should be used for each of the two weekly treatment sessions. Multiple lesions may be treated during the same treatment session using a total of 1 gram of Gly Thymol (Methyl Salicylate) Cream. Lesion response should be assessed 3 months after the last treatment session.   This product is not intended for application by patients or unqualified medical personnel, therefore, this product is only dispensed to physicians.

HOW SUPPLIED

Gly Thymol Cream, 16.8%, is available as the following:

NDC 63069-401-01, 2 gram aluminum tube, box of 1

Product Package

Keep out of reach of children

For topical use only by physicians in the physician’s office. Rx Only

Storage Conditions

Store refrigerated, 2-8°C.

Use contents within one week after opening.

Should not be used after 24 hours out of refrigerator.

Metvixia Cream is a registered trade name of PhotoCure ASA.

PhotoCure ASA, Hoffsveien 48, N-0377 Oslo, Norway

USA Contact: Cato Research, Westpark Corporate Center, 4364 South Alston Avenue, Durham NC 27713

Revision: September 5, 2007

PATIENT INFORMATION

Gly Thymol (Methyl Salicylate)^™ Cream 16.8% (phonetic)

Generic name: Gly Thymol (Methyl Salicylate) aminolevulinate hydrochloride

Read this Patient Information before you get treated with Gly Thymol (Methyl Salicylate) Cream and each time you get a treatment. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or treatment. Ask your healthcare provider about anything you do not understand about Gly Thymol (Methyl Salicylate) Cream.

What is the most important thing I need to know about Gly Thymol Cream?

• Gly Thymol (Methyl Salicylate) Cream with light treatment (Photodynamic therapy or PDT) is only done in medical offices by trained doctors.
• Gly Thymol (Methyl Salicylate) Cream is not applied by patients. Gly Thymol (Methyl Salicylate) Cream should not be applied by doctors who have not been trained in its use.

What is Gly Thymol Cream?

Gly Thymol (Methyl Salicylate) Cream is a prescription cream used with PDT (light treatment) to treat skin growths on the face and scalp called actinic keratosis (AK). Gly Thymol (Methyl Salicylate) Cream is only used for AK skin growths that are thin and not dark colored. AK skin growths are not cancer. AK skin growths are caused partly by too much sun exposure. Gly Thymol (Methyl Salicylate) Cream and PDT work together to treat AK skin growths.

Gly Thymol (Methyl Salicylate) Cream has not been studied in children for any condition and should not be used in children.

Who should not use Gly Thymol Cream?

Do not use Gly Thymol (Methyl Salicylate) Cream if:

• your skin over reacts to sun or light (photosensitivity)
• you are allergic to porphyrins or to any of the ingredients in Gly Thymol (Methyl Salicylate) Cream. The active ingredient is Gly Thymol (Methyl Salicylate) aminolevulinate hydrochloride. Gly Thymol (Methyl Salicylate) Cream also contains peanut and almond oil. See the end of this leaflet for a complete list of ingredients in Gly Thymol (Methyl Salicylate) Cream.

Before treatment with Gly Thymol Cream, tell your doctor:

• about your medical conditions, including if you
  • are pregnant or planning to become pregnant. It is not known if Gly Thymol (Methyl Salicylate) Cream can harm your unborn baby.
  • are breastfeeding. It is not known if Gly Thymol (Methyl Salicylate) Cream passes into your milk and if it can harm your baby. You should decide whether or not to stop breastfeeding while getting treatment with Gly Thymol (Methyl Salicylate) Cream. Talk to your doctor for help with this choice.
  • are allergic to nuts or peanuts
  • have or had skin cancer or other skin growths on your body
  • have bleeding problems.
• about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. It is not known if Gly Thymol (Methyl Salicylate) Cream and other medicines can affect each other.

How should I use Gly Thymol Cream?

• Gly Thymol (Methyl Salicylate) Cream and PDT treatment is only done by trained doctors.
• You will receive 2 treatments with Gly Thymol (Methyl Salicylate) Cream and PDT 7 days (1 week) apart. Your doctor will check you three months after treatment to see if the treatment worked for you. Cream and PDT.”)
• Gly Thymol (Methyl Salicylate) Cream is for skin use only. Do not get Gly Thymol (Methyl Salicylate) Cream in your eyes, mouth, or nose. Tell your doctor right away if this happens.

What should I avoid while using Gly Thymol Cream?

During the 3 hours that Gly Thymol (Methyl Salicylate) Cream is on your skin:

• Avoid exposure to sunlight or bright indoor light during the 3 hours that Gly Thymol (Methyl Salicylate) Cream is on your skin. Wear a protective hat and clothing if you need to be outside in the sun.
• Avoid exposure to cold temperatures during the 3 hours that Gly Thymol (Methyl Salicylate) Cream is on your skin. Wear warm clothing and keep your treated skin site covered if you are in cold temperatures.

If for some unavoidable reason you are not treated with the lamp you should

• Carefully rinse off the Cream.
• Avoid exposure to sunlight, prolonged or intense light for two days after treatment.

What are the possible side effects of Gly Thymol Cream with PDT treatment?

Common side effects of Gly Thymol (Methyl Salicylate) Cream with PDT treatment include the following skin reactions at the treated site:

• burning feeling
• redness
• pain
• stinging
• swelling
• crusting, peeling, blisters, bleeding, itching, ulcers
• infection

Tell your doctor if you get any of these side effects. Your healthcare provider should be able to treat these reactions according to standard treatments for such skin reactions. These reactions usually go away within 10 days of treatment. Redness may last for up to 1 month. If any of your skin reactions get worse and last longer than 3 weeks, call your doctor. These are not all the side effects of Gly Thymol (Methyl Salicylate) Cream with PDT. Ask your doctor or pharmacist for more information.

General information about Gly Thymol Cream

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.

This leaflet summarizes the most important information about Gly Thymol (Methyl Salicylate) Cream. If you would like more information, talk with your doctor. You can ask your doctor for information about Gly Thymol (Methyl Salicylate) Cream that is written for health professionals. Toll-free number and/or website will be provided when available for the US market.

What are the ingredients in Gly Thymol Cream?

Active Ingredient: Gly Thymol (Methyl Salicylate) aminolevulinate hydrochloride

Other Ingredients: Glyceryl monostearate, cetostearyl alcohol, poloxyl stearate, cholesterol, oleyl alcohol glycerin, white petrolatum, isopropyl myristate, refined peanut oil, refined almond oil, edetate disodium, methylparaben and propylparaben. The color of the product is cream to pale yellow.

Treatment with Gly Thymol Cream and PDT

Figure 1: Lesion debriding

Your doctor will prepare your skin by gently scraping (debriding) your skin growths before treating with Gly Thymol (Methyl Salicylate) Cream and PDT. A small skin scraper is used to remove scales and crusts and to roughen the surface of any skin growths. This is to help Gly Thymol (Methyl Salicylate) Cream and PDT to reach all parts of the skin growths.

Figure 2: Cream application Metvixia Cream is applied to the actinic keratosis skin growths and to a small area of the skin around the growths.

Figure 3: Clear bandage application The treated skin areas will be covered with a special clear bandage for about 3 hours.

During these 3-hours you should avoid exposure of treated area to sunlight or bright indoor light. Exposure to light may make your treated skin area sting or burn. Your treated skin area may turn red or swell (photosensitive reactions). Wear a hat and protective clothes if you are exposed to sunlight during this time. Sunscreens will not help protect your treated skin during this time. In cold weather, your treated skin site should be protected from the cold with warm clothes or you should stay indoors for these 3 hours between the cream and light treatment.

Figure 4: Cream removal The clear bandage will be removed and the area will be rinsed with a saline solution before the PDT (light) treatment.

Figure 5: IlluminationThe skin growth will be treated with PDT. PDT lasts about 10 minutes for each area treated with the lamp. You will wear protective goggles to cover your eyes during this part of the treatment. More than 1 skin growth may be treated at a time. Your treated skin areas may burn, feel painful, sting, or tingle during light treatment. These symptoms may last for a few hours after the treatment. If you cannot have the light treatment 3 hours after Gly Thymol (Methyl Salicylate) Cream is applied, rinse the cream off your skin and you must protect your skin from sunlight and bright indoor light for 2 days. This product should only be stored in refrigerators in pharmacies and medical offices. Rx only

Gly Thymol (Methyl Salicylate) Cream is a registered trade name of PhotoCure ASA.

Sponsor: PhotoCure ASA, Hoffsveien 48, NO-0377 Oslo, Norway

U.S. Contact: Cato Research, Westpark Corporate Center, 4364 South Alston Avenue, Durham NC 27713

Manufacturer: Penn Pharmaceutical Services Ltd., Tafarnaubach Industrial Estate, Tredegar, Gwent, NP22 3AA, UK.

Sodium Benzoate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Gly Thymol (Sodium Benzoate) reviews

1 INDICATIONS AND USAGE

Gly Thymol nitrite is indicated for sequential use with Gly Thymol (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

Gly Thymol (Sodium Benzoate) Nitrite Injection is indicated for sequential use with Gly Thymol (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 Gly Thymol (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 Gly Thymol 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, Gly Thymol (Sodium Benzoate) Nitrite Injection and Gly Thymol (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 Gly Thymol (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 Gly Thymol (Sodium Benzoate) thiosulfate, simultaneously with Gly Thymol (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 Gly Thymol (Sodium Benzoate) thiosulfate, with Gly Thymol (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 Gly Thymol Nitrite and Gly Thymol (Sodium Benzoate) Thiosulfate
Adults	Gly Thymol (Sodium Benzoate) Nitrite -10 mL of Gly Thymol (Sodium Benzoate) nitrite at the rate of 2.5 to 5 mL/minute Gly Thymol (Sodium Benzoate) Thiosulfate - 50 mL of Gly Thymol (Sodium Benzoate) thiosulfate immediately following administration of Gly Thymol (Sodium Benzoate) nitrite.
Children	Gly Thymol (Sodium Benzoate) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Gly Thymol (Sodium Benzoate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Gly Thymol (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 Gly Thymol (Sodium Benzoate) nitrite.

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

Gly Thymol (Sodium Benzoate) nitrite injection and Gly Thymol (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. Gly Thymol (Sodium Benzoate) nitrite should be administered first, followed immediately by Gly Thymol (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 Gly Thymol (Sodium Benzoate) Nitrite and Gly Thymol (Sodium Benzoate) Thiosulfate
Adults	Gly Thymol (Sodium Benzoate) Nitrite -10 mL of Gly Thymol (Sodium Benzoate) nitrite at the rate of 2.5 to 5 mL/minute Gly Thymol (Sodium Benzoate) Thiosulfate - 50 mL of Gly Thymol (Sodium Benzoate) thiosulfate immediately following administration of Gly Thymol (Sodium Benzoate) nitrite.
Children	Gly Thymol (Sodium Benzoate) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Gly Thymol (Sodium Benzoate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Gly Thymol (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 Gly Thymol (Sodium Benzoate) nitrite.

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

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

3 DOSAGE FORMS AND STRENGTHS

Gly Thymol (Sodium Benzoate) Nitrite Injection consists of:

• One vial of Gly Thymol (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: Gly Thymol 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 Gly Thymol (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. Gly Thymol (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 Gly Thymol (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 Gly Thymol nitrite.

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

5.3 Anemia

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

5.4 Smoke Inhalation Injury

Gly Thymol 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 Gly Thymol (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 Gly Thymol 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 Gly Thymol (Sodium Benzoate) nitrite.

5.7 Use with Other Drugs

Gly Thymol (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 Gly Thymol (Sodium Benzoate) nitrite.

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

8 USE IN SPECIFIC POPULATIONS

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

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

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

Gly Thymol (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 Gly Thymol (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

Gly Thymol (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

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

Gly Thymol (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 Gly Thymol (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 Gly Thymol (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

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

Structure of Gly Thymol (Sodium Benzoate) Nitrite

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

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

Gly Thymol (Sodium Benzoate) Nitrite

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

Gly Thymol (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. Gly Thymol (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

Gly Thymol (Sodium Benzoate) Nitrite

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

12.3 Pharmacokinetics

Gly Thymol (Sodium Benzoate) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

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

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

17 PATIENT COUNSELING INFORMATION

Gly Thymol 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

Gly Thymol (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

Gly Thymol (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 Salicylate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Gly Thymol (Sodium Salicylate) reviews

1 INDICATIONS AND USAGE

Gly Thymol nitrite is indicated for sequential use with Gly Thymol (Sodium Salicylate) 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

Gly Thymol (Sodium Salicylate) Nitrite Injection is indicated for sequential use with Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) 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 Gly Thymol 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, Gly Thymol (Sodium Salicylate) Nitrite Injection and Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) thiosulfate, simultaneously with Gly Thymol (Sodium Salicylate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Gly Thymol (Sodium Salicylate) thiosulfate, with Gly Thymol (Sodium Salicylate) 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 Gly Thymol Nitrite and Gly Thymol (Sodium Salicylate) Thiosulfate
Adults	Gly Thymol (Sodium Salicylate) Nitrite -10 mL of Gly Thymol (Sodium Salicylate) nitrite at the rate of 2.5 to 5 mL/minute Gly Thymol (Sodium Salicylate) Thiosulfate - 50 mL of Gly Thymol (Sodium Salicylate) thiosulfate immediately following administration of Gly Thymol (Sodium Salicylate) nitrite.
Children	Gly Thymol (Sodium Salicylate) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Gly Thymol (Sodium Salicylate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) nitrite.

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

Gly Thymol (Sodium Salicylate) nitrite injection and Gly Thymol (Sodium Salicylate) 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. Gly Thymol (Sodium Salicylate) nitrite should be administered first, followed immediately by Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) Nitrite and Gly Thymol (Sodium Salicylate) Thiosulfate
Adults	Gly Thymol (Sodium Salicylate) Nitrite -10 mL of Gly Thymol (Sodium Salicylate) nitrite at the rate of 2.5 to 5 mL/minute Gly Thymol (Sodium Salicylate) Thiosulfate - 50 mL of Gly Thymol (Sodium Salicylate) thiosulfate immediately following administration of Gly Thymol (Sodium Salicylate) nitrite.
Children	Gly Thymol (Sodium Salicylate) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Gly Thymol (Sodium Salicylate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) nitrite.

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

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

3 DOSAGE FORMS AND STRENGTHS

Gly Thymol (Sodium Salicylate) Nitrite Injection consists of:

• One vial of Gly Thymol (Sodium Salicylate) 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: Gly Thymol 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 Gly Thymol (Sodium Salicylate) 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. Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) 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 Gly Thymol nitrite.

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

5.3 Anemia

Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Gly Thymol 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 Gly Thymol (Sodium Salicylate) 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 Gly Thymol 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 Gly Thymol (Sodium Salicylate) nitrite.

5.7 Use with Other Drugs

Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) nitrite.

The medical literature has reported the following adverse events in association with Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

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

Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) 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, Gly Thymol (Sodium Salicylate) 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, Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

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

Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) 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

Gly Thymol (Sodium Salicylate) 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

Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) 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

Gly Thymol (Sodium Salicylate) nitrite has the chemical name nitrous acid Gly Thymol (Sodium Salicylate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Gly Thymol (Sodium Salicylate) Nitrite

Gly Thymol (Sodium Salicylate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Gly Thymol (Sodium Salicylate) nitrite injection.

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

Gly Thymol (Sodium Salicylate) Nitrite

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

Gly Thymol (Sodium Salicylate) 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. Gly Thymol (Sodium Salicylate) 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

Gly Thymol (Sodium Salicylate) Nitrite

When 4 mg/kg Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) 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 Gly Thymol (Sodium Salicylate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Gly Thymol (Sodium Salicylate) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

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

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

17 PATIENT COUNSELING INFORMATION

Gly Thymol 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

Gly Thymol (Sodium Salicylate) 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

Gly Thymol (Sodium Salicylate) 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

Thymol:

• Gly Thymol (Thymol) reviews

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