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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
CARBAGLU (NDA-022562)
(CARGLUMIC ACID)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
01/19/2024 (SUPPL-14)
8 Use in Specific Populations
8.4 Geriatric Use
(Additions and/or revisions underlined)
Clinical studies of CARBAGLU did not include patients 65 years of age and older to determine whether they respond differently from younger patients.
08/05/2021 (SUPPL-13)
8 Use in Specific Populations
8.4 Renal Impairment
(Newly Added Subsection)
Plasma concentrations of carglumic acid increased in patients with renal impairment [see Clinical Pharmacology (12.3)]. Reduce the CARBAGLU dosage in patients with moderate or severe renal impairment [see Dosage and Administration (2.3)]. The pharmacokinetics of carglumic acid have not been evaluated in patients with end stage renal disease.
01/22/2021 (SUPPL-8)
6 Adverse Reactions
6.1 Clinical Trials Experience(Extensive changes; please refer to label)
(Newly added subsection)
The following adverse reactions have been identified during postapproval use of CARBAGLU. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.
Skin and subcutaneous tissue disorders: pruritus, rash including rash erythematous, rash maculopapular, rash pustular
8 Use in Specific Populations
8.1 Pregnancy(Additions and/or revisions underlined)
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women with NAGS deficiency exposed to CARBAGLU. If CARBAGLU is administered during pregnancy, health care providers should report CARBAGLU exposure by calling 1-888-575-8344.
Although rare case reports of CARBAGLU use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, untreated NAGS deficiency, PA and MMA can result in irreversible neurologic damage and death in pregnant women [see Clinical Considerations].
In an animal reproduction study, decreased survival and growth occurred in offspring born to rats that received carglumic acid at a dose approximately 38 times the maximum reported human maintenance dose.
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, miscarriage, 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.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Pregnant women with urea cycle disorders, PA, and MMA may experience an increase in catabolic stress which can trigger a hyperammonemic crisis both in the intrapartum and in the post-partum (3-14 days post-partum) periods. Maternal complications related to hyperammonemic crisis can include neurological impairment, coma and in some cases death.
Data
Animal Data
No effects on embryo-fetal development were observed in pregnant rats treated with up to 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC [area under the plasma concentration-time curve]) from two weeks prior to mating through organogenesis or in pregnant rabbits treated with up to 1000 mg/kg/day (approximately 6 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC) during organogenesis.
In a pre- and post-natal developmental study, female rats received oral carglumic acid from organogenesis through lactation at doses of 500 mg/kg/day and 2000 mg/kg/day. Decreased growth of offspring was observed at 500 mg/kg/day and higher (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC), and reduction in offspring survival during lactation was observed at 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC). No effects on physical and sexual development, learning and memory, or reproductive performance were observed through maturation of the surviving offspring at maternal doses up to 2000 mg/kg/day. The high dose (2000 mg/kg/day) produced maternal toxicity (impaired weight gain and approximately 10% mortality).
(Additions and/or revisions underlined)
The safety and effectiveness of CARBAGLU for the treatment of pediatric patients (birth to 17 years of age) with acute or chronic hyperammonemia due to NAGS deficiency and acute hyperammonemia due to PA or MMA have been established, and the information on these uses are discussed throughout the labeling. There are insufficient data to determine if there is a difference in clinical or biochemical responses between adult and pediatric patients treated with CARBAGLU.
(Additions and/or revisions underlined)
Clinical studies of CARBAGLU did not include patients 65 years of age and older.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(Additions and/or revisions underlined)
Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
Instruct the patient on the following:
Preparation and Administration [see Dosage and Administration (2.3)]
Disperse CARBAGLU tablets in water. Do not swallow whole or crushed.
Take CARBABLU immediately before meals or feedings.
- CARBAGLU tablets dispersed in water can be administered orally or via a nasogastric tube or gastrostomy tube as described in the Instructions for Use.
Storage [see How Supplied/Storage and Handling (16)]
Store UNOPENED container in a refrigerator at 2°C to 8°C (36°F to 46°F).
After first opening of the container: do not refrigerate, store at room temperature between 15°C and 30°C (59°F and 86°F). Keep the container tightly closed in order to protect from moisture. Write the date of opening on the tablet container.
- Discard one month after first opening. Do not use after the expiration date stated on the tablet container.
Pregnancy [see Use in Specific Populations (8.1)]
Advise women with NAGS deficiency who are exposed to CARBAGLU during pregnancy that there is a pregnancy surveillance program that monitors pregnancy outcomes.
01/22/2021 (SUPPL-9)
6 Adverse Reactions
6.1 Clinical Trials Experience(Extensive changes; please refer to label)
(Newly added subsection)
The following adverse reactions have been identified during postapproval use of CARBAGLU. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.
Skin and subcutaneous tissue disorders: pruritus, rash including rash erythematous, rash maculopapular, rash pustular
8 Use in Specific Populations
8.1 Pregnancy(Additions and/or revisions underlined)
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women with NAGS deficiency exposed to CARBAGLU. If CARBAGLU is administered during pregnancy, health care providers should report CARBAGLU exposure by calling 1-888-575-8344.
Although rare case reports of CARBAGLU use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, untreated NAGS deficiency, PA and MMA can result in irreversible neurologic damage and death in pregnant women [see Clinical Considerations].
In an animal reproduction study, decreased survival and growth occurred in offspring born to rats that received carglumic acid at a dose approximately 38 times the maximum reported human maintenance dose.
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, miscarriage, 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.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Pregnant women with urea cycle disorders, PA, and MMA may experience an increase in catabolic stress which can trigger a hyperammonemic crisis both in the intrapartum and in the post-partum (3-14 days post-partum) periods. Maternal complications related to hyperammonemic crisis can include neurological impairment, coma and in some cases death.
Data
Animal Data
No effects on embryo-fetal development were observed in pregnant rats treated with up to 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC [area under the plasma concentration-time curve]) from two weeks prior to mating through organogenesis or in pregnant rabbits treated with up to 1000 mg/kg/day (approximately 6 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC) during organogenesis.
In a pre- and post-natal developmental study, female rats received oral carglumic acid from organogenesis through lactation at doses of 500 mg/kg/day and 2000 mg/kg/day. Decreased growth of offspring was observed at 500 mg/kg/day and higher (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC), and reduction in offspring survival during lactation was observed at 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC). No effects on physical and sexual development, learning and memory, or reproductive performance were observed through maturation of the surviving offspring at maternal doses up to 2000 mg/kg/day. The high dose (2000 mg/kg/day) produced maternal toxicity (impaired weight gain and approximately 10% mortality).
(Additions and/or revisions underlined)
The safety and effectiveness of CARBAGLU for the treatment of pediatric patients (birth to 17 years of age) with acute or chronic hyperammonemia due to NAGS deficiency and acute hyperammonemia due to PA or MMA have been established, and the information on these uses are discussed throughout the labeling. There are insufficient data to determine if there is a difference in clinical or biochemical responses between adult and pediatric patients treated with CARBAGLU.
(Additions and/or revisions underlined)
Clinical studies of CARBAGLU did not include patients 65 years of age and older.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(Additions and/or revisions underlined)
Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
Instruct the patient on the following:
Preparation and Administration [see Dosage and Administration (2.3)]
Disperse CARBAGLU tablets in water. Do not swallow whole or crushed.
Take CARBABLU immediately before meals or feedings.
- CARBAGLU tablets dispersed in water can be administered orally or via a nasogastric tube or gastrostomy tube as described in the Instructions for Use.
Storage [see How Supplied/Storage and Handling (16)]
Store UNOPENED container in a refrigerator at 2°C to 8°C (36°F to 46°F).
After first opening of the container: do not refrigerate, store at room temperature between 15°C and 30°C (59°F and 86°F). Keep the container tightly closed in order to protect from moisture. Write the date of opening on the tablet container.
- Discard one month after first opening. Do not use after the expiration date stated on the tablet container.
Pregnancy [see Use in Specific Populations (8.1)]
Advise women with NAGS deficiency who are exposed to CARBAGLU during pregnancy that there is a pregnancy surveillance program that monitors pregnancy outcomes.
12/23/2019 (SUPPL-11)
8 Use in Specific Populations
Lactation(PLLR Conversion, as below)
Risk Summary
It is not known whether carglumic acid is present in human milk. There are no available data on the effects of carglumic acid on the breastfed infant or the effects on milk production. Carglumic acid is present in milk from treated rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CARBAGLU and any potential adverse effects on the breastfed child from CARBAGLU or from the underlying maternal condition.
(PLLR Conversion, as below)
Risk Summary
Although rare case reports of CARBAGLU use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, untreated NAGS deficiency can result in irreversible neurologic damage and death in pregnant women [see Warnings and Precautions (5.1) and Clinical Considerations].
In an animal reproduction study, decreased survival and growth occurred in offspring born to rats that received carglumic acid at a dose approximately 38 times the maximum reported human maintenance dose.
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, miscarriage, 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.
There is a pregnancy pharmacovigilance program for CARBAGLU. If CARBAGLU is administered during pregnancy, health care providers should report CARBAGLU exposure by calling 1-888-575-8344.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Pregnant women with urea cycle disorders may experience an increase in catabolic stress which can trigger a hyperammonemic crisis both in the intrapartum and in the post-partum (3-14 days post-partum) periods. Maternal complications related to hyperammonemic crisis can include neurological impairment, coma and in some cases death.
(Additions and/or revisions underlined)
Data
Animal Data
No effects on embryo-fetal development were observed in pregnant rats treated with up to 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC [area under the plasma concentration-time curve]) from two weeks prior to mating through organogenesis or in pregnant rabbits treated with up to 1000 mg/kg/day (approximately 6 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC) during organogenesis.
In a pre- and post-natal developmental study, female rats received oral carglumic acid from organogenesis through lactation at doses of 500 and 2000 mg/kg/day.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(Additions and/or revisions underlined)
· Advise women who are exposed to CARBAGLU during pregnancy that there is a pregnancy surveillance program that monitors pregnancy outcomes [see Use in Specific Populations (8.1)].
11/16/2017 (SUPPL-5)
5 Warnings and Precautions
5.1 Hyperammonemia(Additions and/or revisions are underlined)
Any episode of acute symptomatic hyperammonemia should be treated as a life-threatening emergency. Treatment of severe hyperammonemia may require dialysis, preferably hemodialysis and/or hemofiltration, to reduce plasma ammonia concentration. Untreated hyperammonemia can result in brain damage and death, and prompt use of all therapies necessary to reduce plasma ammonia level is essential.
Since hyperammonemia in NAGS deficiency is the result of imbalance between ammonia detoxification capacity and protein catabolism, complete protein restriction during an acute hyperammonemic episode is recommended for no longer than 12 to 36 hours while maximizing caloric supplementation to reverse catabolism. Protein should be reintroduced as early as possible, following improvement of metabolic and clinical abnormalities in this setting. During long-term management, dietary protein restriction should be instituted to maintain blood ammonia level within an acceptable range for age.
Ongoing monitoring of plasma ammonia level, neurological status, growth parameters, protein intake/nutritional status (both during acute hyperammonemic episodes and long-term), and relevant laboratory tests in patients receiving CARBAGLU should be part of evaluating the clinical response to treatment.
6 Adverse Reactions
6.1 Clinical Trials Experience(Additions and/or revisions are underlined)
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Table 1 summarizes adverse reactions occurring in 2 or more patients treated with CARBAGLU in the retrospective case series (greater than or equal to 9%).
Table 1: Adverse Reactions Reported in Greater than or Equal to 2 Patients in the Retrospective Case Series Treated with CARBAGLU (Table has been revised; please refer to label)
8 Use in Specific Populations
8.1 Pregnancy(Additions and/or revisions are underlined)
…Decreased survival and growth occurred in offspring born to animals that received carglumic acid at a dose approximately 38 times the maximum reported human maintenance dose…
No effects on embryo-fetal development were observed in pregnant rats treated with up to 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC [area under the plasma concentration-time curve]) from two weeks prior to mating through organogenesis or in pregnant rabbits treated with up to 1000 mg/kg/day (approximately 6 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC).
In a peri- and post-natal developmental study, female rats received oral carglumic acid from organogenesis through lactation at doses of 500 and 2000 mg/kg/day. Decreased growth of offspring was observed at 500 mg/kg/day and higher (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC) and reduction in offspring survival during lactation was observed at 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC). No effects on physical and sexual development, learning and memory, or reproductive performance were observed through maturation of the surviving offspring at maternal doses up to 2000 mg/kg/day. The high dose (2000 mg/kg/day) produced maternal toxicity (impaired weight gain and approximately 10% mortality).
(Additions and/or revisions are underlined)
…Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CARBAGLU, breast-feeding is not recommended…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
Preparation and Administration
- Disperse CARBAGLU tablets in water. Do not swallow whole or crushed.
- Take CARBABLU immediately before meals or feedings.
- CARBAGLU tablets dispersed in water can be administered orally or via a nasogastric tube, as described in the Instructions for Use.
Storage
- Store UNOPENED container in a refrigerator at 2 to 8 °C (36 to 46 °F). After first opening of the container: do not refrigerate, store at room temperature between 15 to 30°C (59 to 86°F)…
Lactation
- Advise women not to breast-feed during treatment with CARBAGLU.