What is CARBAGLU?

CARBAGLU is a medication that is structurally similar to N-acetylglutamate (NAG), a compound required by the body to start the urea cycle. NAGS deficiency may lead to the absence of NAG. The toxic substances that build up in PA and MMA may lead to less NAG production. CARBAGLU acts as a replacement for NAG to help activate the urea cycle, which may lower high ammonia levels.

CARBAGLU is the only FDA-approved therapy to supplement treatment of acute high blood ammonia levels (hyperammonemia) due to NAGS deficiency, propionic acidemia, and methylmalonic acidemia. CARBAGLU is also the only FDA-approved therapy to treat chronic high blood ammonia levels due to NAGS deficiency.

The right diagnosis made an incredible difference in my life.

Mary, a person living with NAGS Deficiency

This is an actual patient story, but the patient’s name has been changed and a stock photo has been used to protect her privacy.

A patient story

A community and a path to the future

Mary, like many other twenty-somethings, is a full-time student working toward a master’s degree and has two part-time jobs. Ten years ago, when she was in the hospital yet again with symptoms she had been experiencing periodically her entire life, she would not have thought this would be possible.

READ MARY'S STORY

HOW DOES CARBAGLU WORK IN PA and MMA?

Urea cycle blockage in PA and MMA

Propionic acidemia (PA) and methylmalonic acidemia (MMA) are disorders that may indirectly block or limit your body’s ability to remove excess ammonia (NH4+) through a process called the urea cycle. This can happen because of the underlying enzyme deficiency in PA or MMA that causes toxins to build up in your body, which, in turn, can impair your urea cycle. CARBAGLU can be the key to helping your body’s urea cycle function as it should.

Normal conditions

The job of NAGS is to produce the cofactor NAG, which is the “key” that activates (or “turns on”) CPS1, the enzyme that controls the first step of the urea cycle.

When you have acute high blood ammonia levels due to propionic acidemia (PA) or methylmalonic acidemia (MMA)

Your gene that causes PA or MMA does not instruct your body to produce any or enough enzyme to break down certain amino acids. Toxins begin to build up in your body, causing two things to happen that interfere with the urea cycle:

  • The level of acetyl-CoA, which is required for producing NAG, is lowered
  • Activity of the NAGS enzyme is blocked or limited.

This type of hyperammonemia is called secondary hyperammonemia since the impaired genes and enzyme deficiencies that cause PA or MMA are not part of the urea cycle.

As a result, your body lacks the cofactor NAG, which is the key to starting the urea cycle, and your blood ammonia level increases.

When you take CARBAGLU

The medication helps to replace the cofactor NAG that your body cannot produce on its own because your body has a partial or complete lack of NAGS enzyme function. CARBAGLU becomes the key that turns on CPS1 and starts the urea cycle. NAG is chemically very similar to CARBAGLU. Once your urea cycle is restored, your high ammonia level will decline to a normal level.

In people with PA or MMA, the most common side effects are: lower than normal white blood cells, reduced red cells in the blood, vomiting, abnormal levels of minerals in the body, decreased appetite, low blood sugar levels, lack of energy/unresponsiveness, brain disease that alters brain structure or function, and inflammation of the pancreas/increase in a type of protein made by the pancreas that helps the body digest fats.


Who should use CARBAGLU?

CARBAGLU may be used by people of all ages with acute high blood ammonia levels due to PA or MMA—from newborns to adults. CARBAGLU should be initiated as soon as a high blood ammonia level due to PA or MMA is suspected.


In a randomized, double blind, placebo-controlled, multi-center study of PA and MMA patients with acute high blood ammonia levels, each episode of high blood ammonia was treated with either standard treatment and a placebo or standard treatment and CARBAGLU. The following results were observed:

  • Ammonia levels were reduced more quickly in episodes of high blood ammonia that were treated with CARBAGLU compared to episodes that were treated with a placebo over a 7-day period.

  • During the first 3 days of treatment, more CARBAGLU-treated episodes of high blood ammonia reached a normal ammonia level than placebo-treated episodes.

What are the possible side effects of CARBAGLU in patients with PA or MMA?

The most common side effects of CARBAGLU are:

  • Lower than normal white blood cells

  • Reduced red cells in the blood

  • Vomiting

  • Abnormal levels of minerals in the body

  • Decreased appetite

  • Low blood sugar levels

  • Lack of energy/unresponsiveness

  • Brain disease that alters brain structure or function

  • Inflammation of the pancreas/increase in a type of protein made by the pancreas that helps the body digest fats

Talk to your doctor about any concerns about side effects before, or during, treatment with CARBAGLU.

HOW DOES CARBAGLU WORK IN NAGS DEFICIENCY?

Urea cycle blockage in NAGS deficiency

NAGS deficiency is a disorder that blocks or limits your body’s ability to remove excess ammonia (NH4+) through a process called the urea cycle. CARBAGLU can be the key to helping your body’s urea cycle function as it should.

Normal conditions

The NAGS gene provides instructions for making the NAGS enzyme. The job of NAGS is to produce the cofactor NAG, which is the “key” that activates (or “turns on”) CPS1, the enzyme that controls the first step of the urea cycle.

When you have high ammonia due to NAGS deficiency

Your body either produces NAGS enzyme that does not work properly or does not produce enough NAGS enzyme. As a result, your body lacks the cofactor NAG, which is the key to starting the urea cycle, and your blood ammonia level increases.

When you take CARBAGLU

The medication helps to replace the cofactor NAG that your body cannot produce on its own because your body partially or completely lacks NAGS enzyme function. CARBAGLU becomes the key that turns on CPS1 and starts the urea cycle. NAG is chemically very similar to CARBAGLU. Carbaglu can restore urea cycle function to help reduce ammonia levels to normal levels.

In people with NAGS deficiency, the most common side effects are: vomiting, abdominal pain, fever, inflammation of the tonsils, reduced red cells in the blood, diarrhea, ear infection, infections, inflammation of the throat and nasal passages, hemoglobin decreased in red blood cells, and headache.


Who should use CARBAGLU?

CARBAGLU may be used by people of all ages with high blood ammonia levels due to NAGS deficiency—from newborns to adults. CARBAGLU should be initiated as soon as the diagnosis of NAGS deficiency is suspected, which may be as soon as at birth, and managed by a physician and medical team experienced in metabolic disorders.


How well has CARBAGLU been shown to work in people with high blood ammonia levels due to NAGS deficiency?

In a clinical study, the effects of CARBAGLU in people with high blood ammonia levels due to NAGS deficiency has been shown to:

  • Reduce patients’ high blood ammonia levels within 24 hours.

  • Return patients’ ammonia levels to normal (based on the age of the patient) within 3 days.

  • Patients treated with CARBAGLU continued to maintain normal blood ammonia levels during the analyzed period of time over an average of 8 years.

What are the possible side effects of CARBAGLU in patients with NAGS deficiency?

The most common side effects of CARBAGLU are:

  • Infections

  • Vomiting

  • Abdominal Pain

  • Fever

  • Inflammation of the tonsils

  • Reduced red cells and protein molecules in red blood cells

  • Ear infection

  • Diarrhea

  • Inflammation of the throat & nasal passages

  • Headache

Talk to your doctor about any concerns about side effects before, or during, treatment with CARBAGLU.

Now I don’t have to wait days for my
ammonia level to get back down
to the level where I can function.

Linden, a person living with NAGS Deficiency
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Living to learn

Linden lives to learn. As a young girl and a successful student, Linden was happiest when she was growing and learning every day. Yet the simple act of going to school became a challenge because Linden has an extremely rare metabolic disease called NAGS (N-acetylglutamate synthase) deficiency. The disease partially or entirely blocks the body’s natural process to eliminate excess ammonia, which leads to high ammonia building up in the blood. This is dangerous because high blood ammonia can be extremely toxic to central nervous system.

A clue from Linden’s sister

Linden began having symptoms, including headaches, vomiting, and unusual behavior, off and on when she was 10 years old. “I was having a hard time responding to my parents’ questions,” she recalls. “I was dizzy and incredibly nauseated. I felt like I was looking at things through a tunnel; they seemed far away.”

Linden’s parents took her to the hospital where her condition began to get worse. Eventually a metabolic geneticist who had diagnosed Linden’s sister with high blood ammonia shortly after birth discovered that Linden had several times the normal level of ammonia in her blood. The diagnosis of NAGS deficiency meant that Linden had to drastically change her diet. Eating foods containing protein can trigger high blood ammonia levels in patients with certain inborn errors of metabolism such as urea cycle disorders. Other triggers include illness and intense exercise.

At the time there was no effective treatment for the symptoms of NAGS deficiency, so Linden continued to have periodic symptoms that affected what she loved most: learning. “I was a good student,” she says. “But because of frequent absences due to my health, I started falling behind.”

A clinical trial: help for Linden and others

Years later, Linden learned about a clinical trial for N-carbamylglutamate (which later became known as Carbaglu® or carglumic acid), a new treatment for symptoms of NAGS deficiency. Her doctor explained the potential risks and benefits of the medication. She was cautious because she had experienced difficulties with medications in the past, but after weighing the risks and benefits, she decided to participate in the study.

CARBAGLU (carglumic acid) treatment should be managed by a physician and medical team experienced in metabolic disorders.

Normally around lunchtime Linden would feel dizzy and nauseated, but within 24 hours of taking the medication, it’s what she didn’t feel—dizziness or nausea—that got her excited. “For me, the medication started working right away,” she says. Now that she’s on appropriate therapy, “I don’t have to wait days for my ammonia level to get back down to the point where I can function, go to work, and do what I need to do.” Linden continues to see her doctor for periodic monitoring to ensure that she’s on a maintenance dose of CARBAGLU that is right for her.

While Linden remains aware of the possible risks of taking CARBAGLU, she’s thankful for a treatment that has made “all the difference in the world” by stabilizing her ammonia levels. She explains: “Taking CARBAGLU every day means that I no longer have to adhere to a strictly regimented, low-protein diet, which outside of my struggles in school was one of my biggest challenges with NAGS deficiency.” Taking CARBAGLU daily also means that Linden no longer worries about developing high ammonia and ending up in the hospital.

Armed with a treatment for the symptoms caused by NAGS deficiency, Linden continued her educational pursuits. “I wouldn’t have been able to earn a master’s degree in special education without getting my NAGS deficiency under control,” she says. “That I’m sure of.” Her goal is to ensure educational opportunities for students with disabilities, which includes advocating for the inclusive-classroom model. “I want to make a positive difference with the next generation,” she says. Enabled and inspired, Linden is still learning—and she’s inspiring others to do the same.

Indications and Usage

Carbaglu® (carglumic acid) is a prescription drug used in all ages to help treat a rare inherited disorder called NAGS deficiency, a lack or shortage of NAGS enzyme activity, which leads to high blood ammonia levels (hyperammonemia).

  • CARBAGLU is used to supplement treatment of acute hyperammonemia due to the lack or shortage of the NAGS enzyme. Other ammonia lowering therapies such as other medications, hemodialysis and limiting protein in the diet are recommended during an acute episode.
  • CARBAGLU is used to maintain normal blood ammonia levels in children and adults with NAGS deficiency. During maintenance therapy, the use of other ammonia lowering therapies and limiting protein may be needed based on plasma ammonia levels.

Important Safety Information

  • Hyperammonemia: Monitor plasma ammonia level during treatment. Prolonged exposure to elevated plasma ammonia level can result in brain injury or death. Prompt use of all therapies necessary to reduce blood ammonia level is essential.
  • Most common side effects in >9% of patients are: vomiting, abdominal pain, fever, inflammation of the tonsils, reduced red cells in the blood, diarrhea, ear infection, infections, inflammation of the throat and nasal passages, protein molecules in red blood cells decreased, and headache.
  • To report SUSPECTED SIDE EFFECTS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1‑800-FDA-1088 or www.fda.gov/medwatch.
  • Pregnancy: The effects of CARBAGLU on pregnancy and an unborn baby are not known.
  • Nursing Mothers: Breastfeeding is not recommended while taking CARBAGLU.
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