Celepid MCT-LCT

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
• Celepid MCT-LCT (Glycerol) reviews

Celepid MCT-LCT (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. Celepid MCT-LCT (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:

• Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.

Celepid MCT-LCT (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. Celepid MCT-LCT (Glycerol) must be used with dietary protein restriction and, in some cases, dietary supplements. (1)

Limitations of Use:

• Celepid MCT-LCT (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

• Celepid MCT-LCT 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 Celepid MCT-LCT (Glycerol):

• Patients should receive the dosage of Celepid MCT-LCT (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

Celepid MCT-LCT (Glycerol) should be prescribed by a physician experienced in the management of UCDs.

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

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

Total daily dosage of Celepid MCT-LCT (Glycerol) (mL) = total daily dosage of sodium phenylbutyrate tablets (g) × 0.86

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

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

3 DOSAGE FORMS AND STRENGTHS

Oral liquid: colorless to pale yellow, 1.1 g/mL of Celepid MCT-LCT (Glycerol) phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate).

Oral liquid: 1.1 g/mL. (3)

4 CONTRAINDICATIONS

Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol), peak PAA concentrations after dosing with Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) dosage .

5.2 Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption

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

Other Adverse Reactions

Celepid MCT-LCT (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 Celepid MCT-LCT (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.

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

Probenecid

Probenecid may inhibit the renal excretion of metabolites of Celepid MCT-LCT (Glycerol) including PAGN and PAA.

7.3 Potential for Celepid MCT-LCT to Affect Other Drugs

Drugs with narrow therapeutic index that are substrates of CYP3A4

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

Risk Summary

Limited available data with Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT 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 Celepid MCT-LCT (Glycerol).

8.4 Pediatric Use

Safety and efficacy of Celepid MCT-LCT (Glycerol) have been established in pediatric patients 2 months of age and older with UCDs.

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

Patients 2 Months to Less Than 2 Years of Age

The safety and efficacy of Celepid MCT-LCT (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

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

Celepid MCT-LCT (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.

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

Cardiac Electrophysiology

The effect of multiple doses of Celepid MCT-LCT (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 Celepid MCT-LCT (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

Celepid MCT-LCT (Glycerol) is a pro-drug of PBA. Upon oral ingestion, PBA is released from the Celepid MCT-LCT (Glycerol) backbone in the gastrointestinal tract by lipases. PBA derived from Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol), peak plasma levels of PBA, PAA, and PAGN occurred at 2 hours, 4 hours, and 4 hours, respectively. Upon single-dose administration of Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) phenylbutyrate was detected in plasma. While the study was inconclusive, the incomplete hydrolysis of Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) (i.e., Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) phenylbutyrate was in the following decreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and pancreatic lipase–related protein 2. Further, Celepid MCT-LCT (Glycerol) phenylbutyrate was hydrolyzed in vitro by esterases in human plasma. In these in vitro studies, a complete disappearance of Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) twice daily for 7 days.

Plasma Celepid MCT-LCT (Glycerol) phenylbutyrate was not measured in patients with hepatic impairment.

After multiple doses of Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) on other drugs

Midazolam

In healthy subjects, when oral midazolam was administered after multiple doses of Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) did not significantly affect the pharmacokinetics of celecoxib, a substrate of CYP2C9. When 200 mg of celecoxib was orally administered with Celepid MCT-LCT (Glycerol) after multiple doses of Celepid MCT-LCT (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, Celepid MCT-LCT (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, Celepid MCT-LCT (Glycerol) phenylbutyrate was not tumorigenic at doses up to 1000 mg/kg/day.

Mutagenesis

Celepid MCT-LCT (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

Celepid MCT-LCT (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 Celepid MCT-LCT (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 → Celepid MCT-LCT (Glycerol) for 2 weeks; or
• Celepid MCT-LCT (Glycerol) for 2 weeks → sodium phenylbutyrate for 2 weeks.

Sodium phenylbutyrate or Celepid MCT-LCT (Glycerol) were administered three times daily with meals. The dose of Celepid MCT-LCT (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 Celepid MCT-LCT (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.

Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) and sodium phenylbutyrate, respectively. The ratio of geometric means was 0.91 [95% CI 0.8, 1.04].

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

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

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

Open-Label, Uncontrolled, Extension Study in Adults

A long-term (12-month), uncontrolled, open-label study (Study 2) was conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period. A total of 51 adults were in the study and all but 6 had been converted from sodium phenylbutyrate to Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) (range: 6 to 30 micromol/L). Of 51 adult patients participating in the 12-month, open-label treatment with Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) (range: 24.2 to 31.4 micromol/L). Of the 43 adult patients participating in the open-label treatment with Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) in pediatric patients 2 to 17 years of age with UCDs was evaluated in 2 fixed-sequence, open-label, sodium phenylbutyrate to Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol). Mean fasting venous ammonia values were within normal limits during long-term treatment with Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) (range: 15.4 to 25.1 micromol/L). Of the 45 pediatric patients participating in the open-label treatment with Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol). The dosage of Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol) was initiated. The dosage of Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (Glycerol). The dosage of Celepid MCT-LCT (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 Celepid MCT-LCT (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 Celepid MCT-LCT (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

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

Lactation

Advise patients that breastfeeding is not recommended during treatment with Celepid MCT-LCT (Glycerol) .

Administration

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

Celepid MCT-LCT (Glycerol) is a registered trademark of Horizon Therapeutics, LLC.

Soybean Oil:

• Warnings
• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdose section
• Dosage and administration
• How supplied
• Storage and handling
• Limited warranty
• References
• Celepid MCT-LCT (Soybean Oil) reviews

WARNINGS

This product is intended for use only by licensed medical personnel experienced in administering allergenic extracts and trained to provide immediate emergency treatment in the event of a life-threatening reaction. Allergenic extracts may potentially elicit a severe life-threatening systemic reaction, rarely resulting in death.1

Therefore, emergency measures and personnel trained in their use must be available immediately in the event of such a reaction.

Patients should be instructed to recognize adverse reaction symptoms, be observed in the office for at least 30 minutes after skin testing or treatment, and be cautioned to contact the physician's office if symptoms occur. See ADVERSE REACTION section of this package insert regarding adverse event reporting.

Standardized glycerinated extracts may be more potent than regular extracts and therefore are not directly interchangeable with non-standardized extracts, or other manufacturers' products.

Patients with cardiovascular diseases and/or pulmonary diseases such as symptomatic unstable, steroid dependent asthma, and/or those who are receiving cardiovascular drugs such as beta blockers, may be at higher risk for severe adverse reactions. These patients may also be more refractory to the normal allergy treatment regimen. Patients should be treated only if the benefit of treatment outweighs the risks.1

Patients on beta blockers may be more reactive to allergens given for testing or treatment and may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. 2

This product should never be injected intravenously.

Refer to the WARNINGS, PRECAUTIONS, ADVERSE REACTIONS and OVERDOSE Sections for further discussion.

DESCRIPTION

The allergenic extract in this vial is referred to as a "bulk" extract or stock concentrate since it is designed primarily for the physician equipped to prepare dilutions and mixtures as required. The extract is sterile and intended for subcutaneous injection for immunotherapy and scratch, prick or puncture for diagnosis. Unless specified otherwise, the concentration of extract supplied will in most cases be expressed in weight to volume (e.g., 1:10 or 1:20 w/v) and will be the strongest available. Where mixtures of pollens and non-pollens have been ordered, the mixed extract will be treated as a pollen mixture. To insure maximum potency for the entire dating period, all bulk concentrates will contain 50% volume to volume (v/v) glycerin unless otherwise requested. Dilutions will also be prepared with 50% (v/v) glycerin unless another diluent is specified.

Source materials utilized in allergenic extract products include pollens, molds, animal epidermals, insects, foods and environmental materials.

Pollens are collected using techniques such as waterset or vacuuming, cleaned and purified to greater than 99% single specie pollen (less than 1% foreign particle presence).

Molds are typically grown on synthetic nutrient medias and are derived from the surface growth (mycelia).

Animal source materials are collected from animals deemed to be healthy at the time of collection by a veterinarian or individual trained and certified by a veterinarian. Epidermals include feathers, hair and dander, or the whole epidermal (pelt) as described on product labeling.

Regular process epidermals are extractions of the source material without additional processing, except that certain materials are defatted. AP (acetone precipitated) epidermal source materials are derived from the precipitate formed when acetone is added to an aqueous extract. The resulting precipitate is dried, and becomes the source material for the AP product.

Insects are collected in whole body form. Extractions take place as whole body or ground insects.

Information on Foods and other Environmental source materials can be obtained by contacting our Customer Service Department.

The following is a brief summary of the six methods of describing allergenic product concentration.

1. Weight to volume (w/v). Weight to volume (w/v) describes the weight of allergenic source material added to a given volume of extracting fluid. A 1:10 w/v extract, e.g., indicates that the solution contains the extractable material from one gram of raw material added to each 10 mL Glycero-Coca's or 10 mL Coca's extracting fluid. The amount and composition of extracted materials will vary with the type of antigen, the extracting fluid, duration of extraction, pH, temperature, and other variables. Pollens are typically extracted at a 1:20 w/v ratio in Glycero-Coca's while Coca's extracts are 1:10 w/v. Epidermal, environmental, regular molds and insect products are typically extracted at 1:10 w/v. AP (acetone precipitated) epidermal products are prepared at a 1:50 w/v concentration (i.e., 1 gram of dried precipitate in 50 mL of reconstitution fluid). AP Dog Hair-Dander is prepared at 1:100 w/v concentration. (i.e., 1 gram of dried precipitate in 100 mL of reconstitution fluid.)

2. Protein Nitrogen Units per mL (PNU/mL). One protein nitrogen unit represents 0.00001 mg phosphotungstic acid precipitable protein nitrogen dissolved in one mL of antigen extract. The PNU content of extracts of the same antigen may vary according to the method of measuring the PNU. Thus, the PNU content of extracts from different manufacturers is not comparable unless the PNU method is known to be the same and is reproducible from lot to lot. The amount of protein nitrogen extracted from the source material is influenced by such factors as the type of antigen, the extracting fluid, duration of extraction, pH, temperature and other variables. Allergenic materials make up a variable proportion of the total protein of an extract. Most allergenic extracts are assayed for PNU. Specific PNU information is available upon request.

3. Amb a 1. Of the many allergens from Short Ragweed which have been purified and characterized [Amb a 1 3 (also known as Antigen E), Amb a 2 3 (also known as Antigen K), Ra3 4, Ra4 (BPA-R) 5, Ra5 6, Ra6, Ra7, Ra87, and cytochrome C 8], Amb a 1 is considered the most important and has been selected as the basis for standardization. Extracts of Short Ragweed containing Amb a 1 are diffused in agar against standard anti-serum to Amb a 1, and compared to the diffusion of standard Amb a 1 solutions. The amount of Amb a 1 is expressed as units of Amb a 1 per mL of extract. A Short Ragweed pollen extracted at 1:20 (w/v) usually assays within a range of 50,000 to 70,000 PNU/mL and 100 to 300 units of Amb a 1 per mL.

The Amb a 1 concentration of any Short Ragweed extract which is diluted with a diluent or other allergenic extracts is determined by calculation. The resulting Amb a 1 value does not reflect the total potency of the product if Short Ragweed extract is mixed with another allergenic extract.

4. Allergy Units per mL (AU/mL). The potency of extracts labeled in Allergy Units (AU)/mL is determined by in vitro comparison to a reference standard established by the Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration (FDA).

5. Bioequivalent Allergy Units per mL (BAU/mL). Other standardized allergenic extracts are labeled in Bioequivalent Allergy Units/mL (BAU/mL) based on their comparison (by in vitro assay or major allergen content) to CBER, FDA Reference Preparations. The FDA reference extracts have been assigned Bioequivalent Allergy Units based on the CBER ID₅₀EAL method.9 Briefly, highly sensitive patients are skin tested to the reference preparation using an intradermal technique employing 3-fold extract dilutions. Depending on the dilution which elicits a summation of erythema diameter of 50, Bioequivalent Allergy Units are assigned as follows:

References labeled 10,000 BAU/mL can be diluted one to a half million fold, and references labeled 100,000 BAU/mL can be diluted one to 5 million fold and produce a sum of erythema diameter of 50 mm when Intradermal testing highly reactive subjects.

6. Concentrate. Concentrate label terminology applies to allergenic extract mixtures, where the individual allergens being combined vary in strength or the designation of strength.

e.g. Concentrate

50% Short Ragweed 1:20 w/v

25% Std. Cat Pelt 10,000 BAU/mL

25% Mite D. farinae 10,000 AU/mL

Should the physician choose to calculate the actual strength of each component in the "Concentrate" mixture, the following formulation may be used:

Ingredients: Active ingredients are the allergen(s) noted on the vial label. Preservative is 50% (v/v) glycerin, or 0.4% phenol, as indicated on the vial label. Additional ingredients are 0.5% sodium chloride, and 0.275% sodium bicarbonate.

CLINICAL PHARMACOLOGY

The mechanism by which hyposensitization is achieved is not known completely. It has been shown that repeated injections of appropriate allergenic extracts will ameliorate the intensity of allergic symptoms upon contact with the allergen.11, 12, 13, 14 Clinical studies which address the efficacy of immunotherapy are available. The allergens which have been studied are cat, mite, and some pollen extracts.10, 15, 16, 17, 18, 19

IgE antibodies bound to receptors on mast cell membranes are required for the allergic reaction, and their level is probably related to serum IgE concentrations. Immunotherapy has been associated with decreased levels of IgE, and also with increases in allergen specific IgG "blocking" antibody.

The histamine release response of circulating basophils to a specific allergen is reduced in some patients by immunotherapy, but the mechanism of this change is not clear.

Further study and clarification of the relationships among changes in blocking antibody, reaginic antibody, and mediator-releasing cells, and between these three factors and successful immunotherapy, is needed.

INDICATIONS AND USAGE

Allergenic extracts are indicated for use in diagnosis and immunotherapy of patients presenting symptoms of allergy (hay fever, rhinitis, etc.) to specific environmental allergens. The selection of allergenic extracts to be used should be based on a thorough and carefully taken history of hypersensitivity, and confirmed by skin testing.

The use of mixed or unrelated antigens for skin testing is not recommended since, in the case of a positive reaction, it does not indicate which component of the mix is responsible for the reaction, while, in the case of a negative reaction, it fails to indicate whether the individual antigens at full concentration would give a positive reaction. Utilization of such mixes for compounding a treatment may result, in the former case, in administering unnecessary antigens and, in the latter case, in the omission of a needed antigen.

Avoidance of allergens is to be advocated if possible, but cannot always be attained, e.g., allergy to dog dander in kennel owners and employees, dog breeders, research workers, veterinarians, etc.

Allergens to which a patient is extremely sensitive should not be included in treatment mixes with allergens to which there is much less sensitivity, but should be administered separately. This allows individualized and better control of dosage increases, including adjustments in dosage becoming necessary after severe reactions which may occur with the highly reactive allergen.

CONTRAINDICATIONS

There are no known absolute contraindications to immunotherapy. See PRECAUTIONS and WARNINGS.

Patients with cardiovascular diseases and/or pulmonary diseases such as symptomatic unstable, steroid-dependent asthma, and/or those who are receiving cardiovascular drugs such as beta blockers, may be at higher risk for severe adverse reactions. These patients may also be more refractory to the normal allergy treatment regimen. Patients should be treated only if the benefit of treatment outweighs the risks.1

Treat patients only with allergens to which they are allergic by skin test reaction, have a history of symptoms on exposure, and are likely to be exposed to again.

Any injections, including immunotherapy, should be avoided in patients with a bleeding tendency. Patients on beta blockers may be more reactive to allergens given for testing or treatment and may be unresponsive to the usual doses of epinephrine used to treat systemic reactions.2

Since there are differences of opinion concerning the possibility of routine immunizations exacerbating autoimmune diseases, immunotherapy should be given cautiously to patients with other immunologic diseases and only if the risk from exposure is greater than the risk of exacerbating the underlying disorder.

WARNINGS

Allergenic extracts must be temporarily withheld from patients or the dose adjusted downward if any of the following conditions exist: (1) severe symptoms of rhinitis and/or asthma; (2) infection or flu accompanied by fever; (3) any evidence of an excessively large local or any generalized reaction during the initial stages of immunotherapy or during maintenance therapy, and/or (4) exposure to excessive amounts of clinically relevant allergen prior to a scheduled injection. Do not administer immunotherapy during a period of symptoms due to exposure. Since the individual components of the extract are those to which the patient is allergic, and to which s/he will be exposed, typical allergic symptoms may follow shortly after the injection, particularly when the antigen load from exposure plus the injected antigen exceeds the patient's antigen tolerance.

THE CONCENTRATE MUST NOT BE INJECTED AT ANY TIME UNLESS TOLERANCE HAS BEEN ESTABLISHED. DILUTE CONCENTRATED EXTRACTS WITH STERILE DILUENT FOR SKIN TESTING AND IMMUNOTHERAPY.

INJECTIONS MUST NEVER BE GIVEN INTRAVENOUSLY. Subcutaneous injection is recommended. Intracutaneous or intramuscular injection may produce large local reactions or be excessively painful.

AFTER INSERTING NEEDLE SUBCUTANEOUSLY, BUT BEFORE INJECTING, ALWAYS WITHDRAW THE PLUNGER SLIGHTLY. IF BLOOD APPEARS IN THE SYRINGE, CHANGE NEEDLE AND GIVE THE INJECTION IN ANOTHER SITE.

IF CHANGING TO A DIFFERENT LOT OF EXTRACT: All extracts lose potency over time, and a fresh extract could have an effective potency that is substantially greater than that of the old extract. Even though it is the same formula and concentration, the first dose from the new vial should not exceed 50% of the previous dose.

IF THE EXTRACT PREVIOUSLY USED WAS FROM ANOTHER MANUFACTURER: Since manufacturing processes and sources of raw materials differ among manufacturers, the interchangeability of extracts from different manufacturers cannot be insured. The starting dose of the extract therefore should be greatly decreased even though the extract is the same formula and dilution. In general, a dose reduction to 50% of the previous product dose should be adequate, but each situation must be evaluated separately considering the patient's history of sensitivity, tolerance of previous injections, and other factors. If the patient tolerates a 50% decrease, the next dose could be raised to the previous dose amount. If the decrease is greater than 50%, the next dose would need to be determined by the allergist, depending on the situation. Dose intervals should not exceed one week when rebuilding dose. See DOSAGE AND ADMINISTRATION.

IF A PROLONGED PERIOD OF TIME HAS ELAPSED SINCE THE LAST INJECTION: Patients may lose tolerance for allergen injections during prolonged periods between doses. The duration of tolerance is an individual characteristic and varies from patient to patient. In general, the longer the lapse in the injection schedule, the greater dose reduction required. If the interval since last dose is over four weeks, perform skin tests to determine starting dose. See DOSAGE AND ADMINISTRATION.

IF THE PREVIOUS EXTRACT WAS OUTDATED: The dating period for allergenic extracts indicates the time that they can be expected to remain potent under refrigerated storage conditions (2° - 8°C). During the storage of extracts, even under ideal conditions, some loss of potency occurs. For this reason, extracts should not be used beyond their expiration date. If a patient has been receiving injections of an outdated extract, s/he may experience excessive local or systemic reactions when changed to a new and possibly more potent extract. In general, the longer the material has been outdated, the greater the dose reduction necessary for the fresh extract.

IF CHANGING FROM ALUM-ADSORBED TO AQUEOUS OR GLYCERINATED EXTRACTS: When the patient was previously receiving alum-adsorbed or alum-precipitated extract, the safest course is to start over as though the patient had not been receiving immunotherapy. See DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS.

IF ANY OTHER CHANGES HAVE BEEN MADE IN THE EXTRACT CONCENTRATE FORMULA: Changes other than those listed above may include situations such as a redistribution of component parts or percentages, a difference in extracting fluid (i.e., change from non-glycerin extracts to 50% glycerin extracts), combining two or more stock concentrates, or any other change. It should be recognized that any change in formula can affect a patient's tolerance of the treatment. The usual 1/2 of the previous dose for a new extract may produce an adverse reaction; extra dilutions are recommended whenever starting a revised formula. The greater the change, the greater the number of dilutions required.

Proper selection of the dose and careful injection should prevent most systemic reactions. It must be remembered that allergenic extracts are highly potent in sensitive individuals, and that systemic reactions of varying degrees of severity may occur, including urticaria, rhinitis, conjunctivitis, wheezing, coughing, angioedema, hypotension, bradycardia, pallor, laryngeal edema, fainting, or even anaphylactic shock and death, as described under ADVERSE REACTIONS. Patients should be informed of this, and the precautions should be discussed prior to immunotherapy. Severe systemic reactions should be treated as indicated in ADVERSE REACTIONS. Refer to WARNINGS box.

PRECAUTIONS

1. General

The presence of asthmatic signs and symptoms appear to be an indicator for severe reactions following allergy injections. An assessment of airway obstruction either by measurement of peak flow or an alternate procedure may provide a useful indicator as to the advisability of administering an allergy injection.1, 24, 25, 26, 27

Concentrated extracts must not be injected unless tolerance has been established. Concentrated extracts must be diluted prior to use: See DOSAGE and ADMINISTRATION for detailed instructions on the dilution of allergenic extracts.

Any evidence of a local or generalized reaction requires a reduction in dosage during the initial stages of immunotherapy, as well as during maintenance therapy.

Allergenic extracts diluted with sterile Albumin Saline with Phenol may be more potent than extracts diluted with diluents which do not contain stabilizers. When switching from non-stabilized to stabilized diluent, consider weaker initial dilutions for both intradermal testing and immunotherapy.

Sterile solutions, vials, syringes, etc. should be used and aseptic precautions observed in making dilutions.

To avoid cross-contamination, do not use the same needle to withdraw materials from vials of more than one extract, or extract followed by diluent.

A sterile tuberculin syringe graduated in 0.01 mL units and with a needle at least 5/8" long should be used to measure each dose from the appropriate dilution.

Aseptic techniques should always be employed when injections of allergenic extracts are being administered. A separate sterile syringe should be used for each patient to prevent transmission of hepatitis and other infectious agents from one person to another.

Patient reactions to previous injections should be reviewed before each new injection, so that dosage can be adjusted accordingly. See ADVERSE REACTIONS and WARNINGS.

Rarely, a patient is encountered who develops systemic reactions to minute doses of allergen and does not demonstrate increasing tolerance to injections after several months of treatment. If systemic reactions or excessive local responses occur persistently at very small doses, efforts at immunotherapy should be stopped.

PATIENTS SHOULD BE OBSERVED IN THE OFFICE FOR AT LEAST 30 MINUTES AFTER SKIN TESTING AND EACH TREATMENT INJECTION. Most severe reactions will occur within this time period, and rapid treatment measures should be instituted. See ADVERSE REACTIONS for such treatment measures.

In order to avoid darkening and possible precipitation, do not dilute the following extracts with solutions containing phenol: Privet pollen and food extracts of White Potato, Corn, Oat, Rye, and Wheat. Injections of such extracts discolored by reaction with phenol may produce a lasting tattoo-like discoloration of the skin.

2. Information for Patients

Patients should be instructed in the recognition of adverse reactions to immunotherapy, and in particular, to the symptoms of shock. Patients should be made to understand the importance of a 30 minute observation period, and be cautioned to return to the office promptly if symptoms occur after leaving. Patients should be instructed to report any symptoms of exposure to the allergen, so the physician can adjust the dosage appropriately.

3. Drug Interactions

Patientswith cardiovascular diseases and/or pulmonary diseases such assymptomatic unstable, steroid-dependent asthma, and/or those who arereceiving cardiovascular drugs such as beta blockers, may be at higherrisk for severe adverse reactions. These patients may also be morerefractory to the normal allergy treatment regimen. Patients should betreated only if the benefit of treatment outweighs the risks.1

Patientson beta blockers may be more reactive to allergens given for testing ortreatment and may be unresponsive to the usual doses of epinephrineused to treat allergic reactions.2. Certain medications may lessen the skin test wheal anderythema responses elicited by allergens and histamine for varying timeperiods. Conventional antihistamines should be discontinued at least 5days before skin testing. Long acting antihistamines should bediscontinued for at least 3 weeks prior to skin testing. 28 Topical steroids should be discontinued at the skin test site for at least 2-3 weeks before skin testing.28, 29

Tricyclic antidepressants such as Doxepin should be withheld for at least 7 days before skin testing. 30 Topical local anesthetics may suppress the flare responses and should be avoided in skin test sites.31

4. Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been conducted with allergenic extracts to determine their potential for carcinogenicity, mutagenicity or impairment of fertility.

5. Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with allergenic extracts. It is also not known whether allergenic extracts can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Allergenic extracts should be given to a pregnant woman only if clearly needed. The physician must carefully consider the benefit-to-risk ratio to both patient and fetus, of performing skin testing or continuing immunotherapy during pregnancy. The recommended precautions for preventing adverse reactions are especially important in the pregnant patient. Based on the physician's discretion, immunotherapy maintenance doses may be continued during pregnancy if the patient has not experienced adverse side effects. Immunotherapy is generally not initiated during pregnancy due to the risks associated with systemic reactions and their treatment. 33

6. Nursing Mothers

There are no current studies on the secretion of allergenic extract components in human milk or their effect on the nursing infant. Because many drugs are excreted in human milk, caution should be exercised when allergenic extracts are administered to a nursing woman.

7. Pediatric Use

Since dosage for the pediatric population is the same as for adults 34, 35 larger volumes of solution may produce excessive discomfort. Therefore, in order to achieve the total dose required, the volume of the dose may need to be divided into more than one injection per visit.

8. Geriatric Use

The reactions from immunotherapy can be expected to be the same in elderly patients as in younger ones. Elderly patients may be more likely to be on medication that could block the effect of epinephrine which could be used to treat serious reactions, or they could be more sensitive to the cardiovascular side effect of epinephrine because of pre-existing cardiovascular disease. 36

ADVERSE REACTIONS

Physicians administering allergenic extract testing or treatment materials should be experienced in the treatment of severe systemic reactions. See WARNINGS box at the beginning of this package insert.

1. Local Reactions

Some erythema, swelling or pruritus at the site of injection are common, the extent varying with the patient. Such reactions should not be considered significant unless they persist for at least 24 hours. Local reactions (erythema or swelling) which exceed 4-5 cm in diameter are not only uncomfortable, but also indicate the possibility of a systemic reaction if dosage is increased. In such cases the dosage should be reduced to the last level not causing the reaction and maintained at this level for two or three treatments before cautiously increasing again. Large persistent local reactions may be treated by local cold, wet dressings and/or the use of oral antihistamines. They should be considered a warning of possible severe systemic reactions and an indication of the need for temporarily reduced dosages. A mild burning immediately after the injection is to be expected. This usually subsides in 10 to 20 seconds.

2. Systemic Reactions

With careful attention to dosage and administration, systemic reactions occur infrequently, but it cannot be overemphasized that in sensitive individuals, any injection could result in anaphylactic shock. Therefore, it is imperative that physicians administering allergenic extracts understand and be prepared for the treatment of severe reactions.

Most severe systemic reactions will begin within a 30 minute time period, but systemic reactions may occur at any time after skin tests or immunotherapy. Symptoms may range from mild to life-threatening (due to anaphylaxis)as described below.

Other possible systemic reactions which may occur in varying degrees of severity are laryngeal edema, fainting, pallor, bradycardia, hypotension, angioedema, cough, wheezing, conjunctivitis, rhinitis, and urticaria. Adverse reaction frequency data for allergenic extract administration for testing and treatment show that risk is low. 1, 37

If a systemic or anaphylactic reaction does occur, apply a tourniquet above the site of injection and inject 1:1,000 epinephrine-hydrochloride intramuscularly or subcutaneously into the opposite arm. Loosen the tourniquet at least every 10 minutes. Do not obstruct arterial blood flow with the tourniquet.

EPINEPHRINE

Dosage:

ADULT: 0.3 to 0.5 mL should be injected. Repeat in 5 to 10 minutes if necessary.

PEDIATRIC: The usual initial dose is 0.01 mg (mL) per kg body weight or 0.3 mg (mL) per square meter of body surface area. Suggested dosage for infants to 2 years of age is 0.05 mL to 0.1 mL; for children 2 to 6 years, 0.15 mL; and children 6 to 12 years, 0.2 mL. Single pediatric doses should not exceed 0.3 mg (mL). Doses may be repeated as frequently as every 20 minutes, depending on the severity of the condition and the response of the patient. After administration of epinephrine, profound shock or vasomotor collapse should be treated with intravenous fluids, and possibly vasoactive drugs. Airway patency should be insured. Oxygen should be given by mask. Intravenous antihistamine, inhaled bronchodilators, theophylline and/or adrenal corticosteroids may be used if necessary after adequate epinephrine and circulatory support has been given. Emergency resuscitation measures and personnel trained in their use must be available immediately in the event of a serious systemic or anaphylactic reaction not responsive to the above measures [Ref. J. Allergy and Clinical Immunology, 77(2):p. 271-273, 1986].

Rarely are all of the above measures necessary; the tourniquet and epinephrine usually produce prompt responses. However, the physician should be prepared in advance for all contingencies. Promptness in beginning emergency treatment measures is of utmost importance.

Severe systemic reactions mandate a decrease of at least 50% in the next dose, followed by cautious increases. Repeated systemic reactions, even of a mild nature, are sufficient reason for the cessation of further attempts to increase the reaction-causing dose.

3. Adverse Event Reporting

Report all adverse events to Jubilant HollisterStier LLC, Customer Technical Services Department at 1 (800) 992-1120. A voluntary adverse event reporting system for health professionals is available through the FDA MEDWATCH program. Preprinted forms (FDA Form 3500) are available from the FDA by calling 1 (800) FDA-1088. Completed forms should be mailed to MEDWATCH, 5600 Fisher Lane, Rockville, MD 20852-9787 or Fax to: 1 (800) FDA-0178.

OVERDOSE SECTION

See ADVERSE REACTIONS.

DOSAGE AND ADMINISTRATION

1. General

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

Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his clinical response, and tolerance to the extract administered during the early phases of an injection regimen.

Allergen extracts should be administered using a sterile syringe with 0.01 mL gradations and a 25-27 gauge x 1/2" to 5/8" needle. The injections are given subcutaneously. The most common sites of injection are the lateral aspect of the upper arm or thigh. Intracutaneous or intramuscular injections may produce large local reactions and may be very painful.

Sterile aqueous diluent containing human serum albumin [Albumin Saline with Phenol ] or diluent of 50% glycerin may be used when preparing dilutions of the concentrate for immunotherapy. Dilutions should be made accurately and aseptically, using sterile diluent, vials, syringes, etc. Mix thoroughly and gently by rocking or swirling. Maintain stock solutions and dilutions constantly at 2° - 8°C. To prepare dilutions for intradermal and therapeutic use, make a 1:10 dilution by adding 1.0 mL of the Concentrate to 9.0 mL of sterile aqueous diluent. Subsequent serial dilutions are made in a similar manner.

Following is a suggested schedule for average patients and will be satisfactory in most cases. However, the degree of sensitivity varies in many patients. The size of the dose should be adjusted according to the patient's tolerance and reaction. Decrease the size of the dose if the previous injection resulted in marked local or the slightest general reaction. Another dose should never be given until all reactions resulting from the previous dose have disappeared.

The starting dose should be based on skin tests of the extract to be used for immunotherapy. To determine the starting dose, begin intradermal testing with the most dilute extract preparation. Inject 0.02 mL and read the reaction after 15 minutes. Intradermal testing is continued with increasing concentrations of the extract until a reaction of 10-20 mm erythema ( ∑ E 0-40 mm) and/or a 5 mm wheal occurs. This concentration at a dose of 0.03 mL then can serve as a starting dose for immunotherapy. Subsequent doses can be increased by 0.03 mL to as high as 0.12 mL increments each time until 0.3 mL is reached, at which time a dilution 10 times as strong can be used, starting with 0.03 mL. Proceed in this way until a tolerance dose is reached or symptoms are controlled. Suggested maintenance dose for a pollen extract is 0.2 mL of the Concentrate, while for a non-pollen extract the maximum suggested dose is 0.5 mL of the Concentrate. Occasionally, higher doses are necessary to relieve symptoms. Special caution is required in administering doses greater than 0.2 mL. The interval between doses is normally 3 to 7 days during dose building regimen.

Normally immunotherapy can be started with a 1:100,000 dilution of extracts labeled in weight/volume. Certain therapeutic mixtures are labeled as Concentrate, (v/v) dilutions of Concentrate, Amb a 1, Allergy units/mL or Bioequivalent Allergy Units/mL. (See DESCRIPTION.) Strength of each antigen in the mixture is indicated in the product labeling. For beginning treatment, use at least a 1,000-fold dilution of the Concentrate extract for non-pollens, and at least a 10,000-fold dilution of the Concentrate extract for pollens.

In some patients, the dosage may be increased more rapidly than recommended above. In seasonal allergies, treatment should be started and the interval between doses regulated so that at least the first twenty doses will have been administered by the time symptoms are expected. Thus, the shorter the interval between the start of immunotherapy and the expected onset of symptoms, the shorter the interval between each dose. Some patients may even tolerate daily doses.

Should symptoms develop before the next injection is scheduled, the interval between doses should be decreased. Should allergic symptoms or local reactions develop shortly after the dose is administered, the size of the dose should be decreased. In seasonal allergies, it is often advisable to decrease the dose to one-half or one-quarter of the maximum dose previously attained if the patient has any seasonal symptoms.

A maintenance dose, the largest dose tolerated by the patient that relieves symptoms without producing undesirable local or general reactions, is recommended for most patients. The upper limits of dosage have not been established; however, doses larger than 0.2 mL of extract may be painful if glycerin is present. The dosage of allergenic extract does not vary significantly with the respiratory allergic disease under treatment. The size of this dose and the interval between doses will vary and can be adjusted as necessary.

The interval between maintenance doses can be increased gradually from one week to 10 days, to two weeks, to three weeks, or even to four weeks, if tolerated. Repeat the doses at a given interval three or four times to check for untoward reactions before further increasing the interval. Protection is lost rapidly if the interval between doses is more than four weeks. (See WARNINGS.)

The usual duration of treatment has not been established. A period of two or three years of injection therapy constitutes an average minimum course of treatment.

2. Pediatric Use

The dose for the pediatric population is the same as for adults.

3. Geriatric Use

The dose for elderly patients is the same as for adult patients under 65.36

HOW SUPPLIED

In 10 mL, 30 mL and 50 mL vials at the w/v, Concentrate, v/v dilution of Concentrate, AU/mL (Standardized Mite Extracts: D. farinae, D. pteronyssinus 10,000 and 30,000 AU/mL; Mite Mixtures: 5,000 AU/mL each species, or 15,000 AU/mL each species), BAU/mL (Standardized Cat Hair and Cat Pelt extracts: 10,000 BAU/mL; Standardized Grass extracts: 10,000 and 100,000 BAU/mL); Amb a 1 units/mL; or PNU/mL ordered by the physician. Please see the current Allergy Product Catalog.

STORAGE AND HANDLING

The expiration date is listed on the container label. To ensure the maximum potency, the extract and its dilutions should be stored at 2° - 8°C, and kept in this temperature range at all times, even during use. Dilutions are less stable than concentrates. If loss of potency is suspected, dilutions should be checked by skin testing with equal v/v dilutions of a freshly prepared dilution on individuals known to be allergic to the specific allergen.

LIMITED WARRANTY

A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use. No warranty, express or implied, including any warranty of merchantability or fitness, is made. Representatives of the Company are not authorized to vary the terms or the contents of any printed labeling, including the package insert, for this product except by printed notice from the Company's headquarters. The prescriber and user of this product must accept the terms hereof.

REFERENCES

1. Lockey, R.F., L.M. Benedict, P.C. Turkletaub, S.C. Bukantz. Fatalities from immunotherapy (IT) and skin testing (ST). J. Allergy Clin. Immunol., 79 (4): 660-677, 1987.

2. Jacobs, R.L., G.W. Rake, Jr., et al. Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade. J. Allergy Clin. Immunol., 68 (2): 125-127, August 1981.

3. Griffith, I.J., J. Pollock, D.G. Klapper, B.L. Rogers and A.K. Nault. Sequence Polymorphism of Amb a I and Amb a II, the Major Allergens in Ambrosia artemisiifolia (Short Ragweed). Int. Arch. Allergy Apply. Immunol., 96: 296-304, 1991.

4. Underdown, B. J. and L. Goodfriend. Isolation and characterization of an allergen from short ragweed pollen. Biochem. 8 (3): 980-989, 1969.

5. Griffiths, B. W and R. Brunet. Isolation of a basic protein antigen of low ragweed pollen. Can. J. Biochem. 49 (3): 396-400, 1971.

6. Lapkoff, C. B. and L. Goodfriend. Isolation of a low molecular weight ragweed allergen: Ra5. Int. Arch. Allergy Appl. Immunol. 46 (2): 215-229, 1974.

7. Hussain, R. and D. G. March. Characterization and allergenic activity of ragweed allergens Ra6, Ra7, Ra8. J. Allergy Clin. Immunol. 65 (3): 230, abstr. 218, 1980

8. Goodfriend, L., A. M. Choudhury, J. Del Carpio and T. P. King. Cytochrome C: New ragweed pollen allergen. Fed. Proc. 38 (3, part II): 1415, abstr. 6261, 1979.

9. Turkeltaub, P.C., MD, and S.C. Rastogi, PhD. Quantitative intradermal test procedure for evaluation of subject sensitivity to standardized allergenic extracts and for assignment of bioequivalent allergy units to reference preparations using the ID₅₀EAL method. Allergenics Products Testing Laboratory, Center for Biologics Evaluation and Research (CBER), FDA. Revised: November, 1994.

10. Norman, P. S. Postgraduate Course Presentation. An overview of immunotherapy, implications for the future. J. Allergy Clin. Immunol., 65 (2): 87-96, 1980.

11. Lowell, F. C. and W. Franklin. A "double-blind" study of treatment with aqueous allergenic extracts in cases of allergic rhinitis. J. Allergy, 34 (2):165-182, 1963.

12. Lowell, F. C. and W. Franklin. A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever. N. Eng. J. Med. 273 (13): 675-679, 1965.

13. Zavazal, V. and A. Stajner. Immunologic changes during specific treatment of the atopic state. II. Acta. Allergol. 25 (1): 11-17, 1970.

14. Reisman, R. E., J. I. Wypych, and E. E. Arbesman. Relationship of immunotherapy, seasonal pollen exposure and clinical response to serum concentrations of total IgE and ragweed-specific IgE. Int. Arch. Allergy Appl. Immunol. 48 (6): 721-730, 1975.

15. Taylor, W. W., J. L. Ohman, F. C. Lowell. Immunotherapy in cat-induced asthma; double-blind trial with evaluation of bronchial responses to cat allergen and histamine. J. Allergy Clin. Immunol., 61 (5): 283-287, 1978.

16. Smith, A. P. Hyposensitization with Dermatophagoides pteronyssinus antigen: Trial in asthma induced by house dust. Br. Med. J., 4: 204-206, 1971.

17. Chapman, M. D., T. A. E. Platts-Mills, M. Gabriel, H. K. Ng, W. G. L. Allen, L. E.Hill, A. J. Nunn. Antibody response following prolonged hyposensitization with Dermatophagoides pteronyssinus extract. Int. Arch. Allergy Appl. Immunol., 61:431-440, 1980.

18. Norman, P. S., W. L. Winkenwerder. Maintenance immunotherapy in ragweed hay fever. J. Allergy, 74: 273-282, 1971.

19. Norman, P. S., W. L. Winkenwerder, L. M. Lichtenstein. Immunotherapy of hay fever with ragweed Antigen E; comparisons with whole pollen extract and placebos. J. Allergy, 42: 93-108, 1968.

20. Middleton, E., C. E. Reed and E. F. Ellis, editors. Allergy Principles and Practice. C. V. Mosby Co., St. Louis, 1978, pp. 877-898.

21. Sheldon, J. M., R. G. Lovell and K. P. Mathews. A Manual of Clinical Allergy, Second Edition. W. B. Saunders. Philadelphia, 1967, pp. 107-112.

22. Sherman, W. B. Hypersensitivity Mechanisms and Management. W. B. Saunders. Philadelphia, 1968, pp. 169-172.

23. Swineford, O. Asthma and Hay Fever. Charles C. Thomas. Springfield, IL, 1971, pp. 148-155.

24. Reid, M.J., R.F. Lockey, P.C. Turkletaub, T.A.E., Platts-Mills. Survey of fatalities from skin testing and immunotherapy. J. 0 Clin. Immunol. 92 (1): 6-15, July 1993.

25. Reid, M.J., G. Gurka. Deaths associated with skin testing and immunotherapy. J. Allergy Clin. Immunol. 97(1) Part 3:231, Abstract 195, January 1996.

26. Thompson, R.A., et al, report of a WHO/IUIS working group. The current status of allergen immunotherapy (hyposensitization). Allergy. 44: 369-379, 1989.

27. Malling, H.J., B. Weeke, et al, The European Academy of Allergology and Clinical Immunology. Position Papers. Allergy. 48 (Supplement 14): 9-82, 1993.

28. Pipkorn, U. Pharmacological influence of anti-allergic medication on In Vivo allergen testing. Allergy. 43: 81-86,1988.

29. Andersson, M. and U. Pipkorn. Inhibition of the dermal immediate allergic reaction through prolonged treatment with topical glucocorticosteroids. J. Allergy Clin. Immunol. 79 (2): 345-349, February 1987.

30. Rao, K.S., et al. Duration of suppressive effect of tricyclic anti-depressants on histamine induced wheal and flare reactions on human skin. J. Allergy Clin. Immunol. 82: 752-757, November 1988.

31. Pipkorn, U., and M. Andersson. Topical dermal anesthesia inhibits the flare but not the wheal response to allergen and histamine in the skin prick test. Clinical Allergy. 17: 307-311, 1987.

32. DuBuske, L.M., C.J. Ling and A.L. Sheffer. Special problems regarding allergen immunotherapy. Immunol. Allergy Clin. North Am. (USA). 12(1): 145-175, 1992.

33. Li, J.T., R.F. Lockey, I.L. Bernstein, J.M. Ortnoy, R.A. Nicklas. Allergen Immunotherapy: A Practice Parameter. Ann. Allergy, Asthma and Immunotherapy 90 (1): 26, 2003.

34. Patterson, R., et al. Allergy Principles and Practice, 2nd ed. E. Middleton, Jr., C. E. Reed, E. F. Ellis, Ed., C. V. Mosby Co., 1983, St. Louis, MO, 1983, Chapter 52

35. Levy, D. A., L. M. Lichtenstein, E. O. Goldstein, and K. Ishizaka. Immunologic and cellular changes accompanying the therapy of pollen allergy. J. Clinical Investigation, 50:360, 1971.

36. Peebles, R.S., Jr., B. Bochner, Howard J. Zeitz, ed. Anaphylaxis in the elderly. Immunology and Allergy Clinics of North America. 13 (3): 627-646, August 1993.

37. Turkeltaub, P.C., MD, and P.J. Gergen, MD. The risk of adverse reactions from percutaneous prick-puncture allergen skin testing, venipuncture, and body measurements: Data from the second National Health and Nutrition Examination Survey 1976-80 (NHANES II). J. Allergy Clin. Immunol. 84(6): 886-890, Dec. 1989.

Water:

• Active ingredient
• Purpose
• Uses
• Warnings
• Directions
• Other information
• Inactive ingredients
• Questions?
• Celepid MCT-LCT (Water) reviews

Active ingredient

Celepid MCT-LCT (Water) 99.8%

Purpose

Emergency eyewash

Uses

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

Warnings

For external use only

Do not use

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

When using this product

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

When using this product

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

Stop use and consult a doctor if you have

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

Keep out of reach of children.

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

Directions

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

• if necessary, continue flushing with emergency eyewash or shower
  

• do not reuse
• once opened, discard
  

• obtain medical treatment
  

Other information

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

Inactive ingredients

Questions?

Sperian Eye and Face Protection, Inc.

(a Honeywell Company)

825 East Highway 151

Platteville, WI 53818 USA