Ravicti

Dosage Forms & Strengths

oral liquid

• 1.1 g/mL

Urea Cycle Disorders

Nitrogen-binding agent for chronic management of adults and children aged ≥2 months with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone

Adults: Give PO in 3 equally divided dosages, each rounded up to nearest 0.5 mL

Not to exceed 17.5 mL/day

Also see Administration section

Switching from sodium phenylbutyrate to glycerol phenylbutyrate

• Total daily dose of Ravicti (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86
• Total daily dose of Ravicti (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81

Phenylbutyrate-naïve

• 4.5-11.2 mL/m²/day (5-12.4 g/m²/day)
• Determine starting dose by patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence
• Dietary protein is ~15% nitrogen by weight
• ~47% of dietary nitrogen is excreted as waste and ~70% of phenylbutyrate dose is converted to urinary phenylacetylglutamine (U-PAGN), so an initial estimated dose is 0.6 mL/g dietary protein ingested per day

Dosage Modifications

Adjustment based on plasma ammonia: Adjust dose to produce fasting plasma ammonia level less than half ULN according to age

Adjustment based on urinary phenylacetylglutamine

• Each gram of U-PAGN excreted over 24 hr 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, adjusted dosage upward
• The amount of dose adjustment should factor in the amount of dietary protein that has not been covered (not to exceed 17.5 mL/day)
• Also consider concomitant medications (eg, probenecid) that may decrease urinary excretion of PAGN

Adjustment based on plasma phenylacetate (PPA)

• PAA levels may be useful to guide dosing if symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or intercurrent illness
• Ammonia levels must be monitored closely when changing the dose
• If a high PAA to PAGN ratio exists, a further dosage increase may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction
• The PAA to PAGN ratio has been observed to be generally <1 in patients without significant PAA accumulation

Hepatic impairment

• Moderate-to-severe hepatic impairment: Use starting dose at lower end of dosage range

Dosing Considerations

Must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements)

Monitor plasma ammonia levels

Dosage Forms & Strengths

oral liquid

• 1.1 g/mL

Urea Cycle Disorders

Nitrogen-binding agent for chronic management of adults and children aged ≥2 months with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone

<2 months: Safety and efficacy not established

2 months to <2 years: Give PO in 3 equally divided dosages, each rounded up to nearest 0.1 mL

≥2 years: Give PO in 3 equally divided dosages, each rounded up to nearest 0.5 mL

Not to exceed 17.5 mL/day

Also see Administration section

Switching from sodium phenylbutyrate to glycerol phenylbutyrate

• Total daily dose of Ravicti (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86
• Total daily dose of Ravicti (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81

Phenylbutyrate-naïve

• 4.5-11.2 mL/m²/day (5-12.4 g/m²/day)
• Determine starting dose by patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence
• Dietary protein is ~15% nitrogen by weight
• ~47% of dietary nitrogen is excreted as waste and ~70% of phenylbutyrate dose is converted to urinary phenylacetylglutamine (U-PAGN), so an initial estimated dose is 0.6 mL/g dietary protein ingested per day

Dosage Modifications

Adjustment based on plasma ammonia: Adjust dose to produce fasting plasma ammonia level less than half ULN according to age

Adjustment based on urinary phenylacetylglutamine

• Each gram of U-PAGN excreted over 24 hr 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, adjusted dosage upward
• The amount of dose adjustment should factor in the amount of dietary protein that has not been covered (not to exceed 17.5 mL/day)
• Also consider concomitant medications (eg, probenecid) that may decrease urinary excretion of PAGN

Adjustment based on plasma phenylacetate (PPA)

• PAA levels may be useful to guide dosing if symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or intercurrent illness
• Ammonia levels must be monitored closely when changing the dose
• If a high PAA to PAGN ratio exists, a further dosage increase may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction
• The PAA to PAGN ratio has been observed to be generally <1 in patients without significant PAA accumulation

Hepatic impairment

• Moderate-to-severe hepatic impairment: Use starting dose at lower end of dosage range
• Conversion of PAA to PAGN occurs in the liver, hepatic impairment may reduce conversion capability and result in higher plasma PAA and PAA to PAGN ratio

Renal impairment

• Efficacy and safety unknown in patients with renal impairment
• Monitor ammonia levels closely when initiating in patients with impaired renal function

Dosing Considerations

Must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements)

Monitor plasma ammonia levels

Ravicti is part of the drug class:

• Various alimentary tract and metabolism products

Take Ravicti exactly as your doctor tells you.

• Your doctor will tell you how much Ravicti to take and when to take it.
• Your doctor may change your dose if needed.
• Take Ravicti with food.
• Ravicti is an oral liquid that is taken by mouth using an oral syringe or measuring cup. Ask your pharmacist for an oral syringe or measuring cup if you do not have one.
• Stay on the diet that your doctor gives you.
• Talk to your doctor about participating in a UCD registry. The purpose of this registry is to collect information about people with UCD to improve care. For more information about the registry program call 1-855-823-2595 or visit www.ucdregistry.com.

For people who have a nasogastric or gastric tube in place, Ravicti should be given as follows:

• Use an oral syringe to withdraw the prescribed dose of Ravicti from the bottle.
• Place the tip of the syringe into the tip of the nasogastric or gastric tube and push the plunger of the syringe to give Ravicti into the tube.
• Flush the nasogastric or gastric tube with 30 mL of water and allow the flush to drain.
• Flush the nasogastric or gastric tube a second time with an additional 30 mL of water.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Get emergency medical help if you have signs of an allergic reaction: hives; cough, wheezing, difficult breathing; feeling like you might pass out; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any signs of high blood levels of ammonia (hyperammonemia):

• weakness, lack of energy;

• thinking problems, changes in behavior, feeling irritable;

• breathing problems;

• feeding problems; or

• seizure (convulsions).

Glycerol phenylbutyrate can affect your nervous system. Call your doctor at once if you have:

• drowsiness, unusual tiredness;

• memory problems;

• a light-headed feeling, like you might pass out;

• confusion, ongoing headache, vomiting;

• numbness, tingling, or burning pain in your hands or feet;

• altered sense of taste; or

• hearing problems.

Common side effects may include:

• occasional headache;

• nausea, vomiting, stomach pain;

• indigestion or heartburn, gas, diarrhea;

• loss of appetite;

• dizziness, tired feeling;

• rash; or

• (common in children younger than 2 years) fever, cold or flu symptoms, cough, small bumps on the skin.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

This medicine comes with a Medication Guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.

It is important that you or your child follow any special diet instructions from your doctor, such as using a low-protein diet. If you have any questions about this, check with your doctor.

Use an oral syringe or dosing cup to measure your dose. You may also give this medicine with a nasogastric tube or gastrostomy tube (g-tube).

To use the oral liquid with a nasogastric tube or g-tube:

• Use an oral syringe to measure your dose and place it on the tip of the nasogastric tube or g-tube.
• Inject the medicine into the tube.
• Flush the tube with 10 mL of water to rinse all of the medicine into the stomach.
• Rinse the tube again with additional 10 mL of water to clear the tube.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (liquid):
  • For treatment of urea cycle disorders:
    • For patients not on phenylbutyrate treatment:
      • Adults and children 2 years of age and older—Dose is based on body size and must be determined by your doctor. The dose is 4.5 to 11.2 milliliters (mL) per square meter (m[2]) per day and divided into 3 equal doses, each rounded up to the nearest 0.5 mL. Your doctor may adjust your dose as needed. However, the dose is usually not more than 17.5 mL per day.
      • Children 2 months up to 2 years of age—Dose is based on body size and must be determined by your doctor. The dose is 4.5 to 11.2 milliliters (mL) per square meter (m[2]) per day and divided into 3 or more equal doses, each rounded up to the nearest 0.1 mL. Your doctor may adjust your dose as needed. However, the dose is usually not more than 17.5 mL per day.
      • Children younger than 2 months of age—Use is not recommended.
    • For patients switching from sodium phenylbutyrate powder to Ravicti®:
      • Adults and children 2 years of age and older—The dose is the total daily dose of sodium phenylbutyrate that you are already taking multiplied by 0.81 and divided into 3 equal doses, each rounded up to the nearest 0.5 mL. Your doctor may adjust your dose as needed. However, the dose is usually not more than 17.5 milliliters (mL) per day.
      • Children 2 months up to 2 years of age—The dose is the total daily dose of sodium phenylbutyrate that you are already taking multiplied by 0.81 and divided into 3 or more equal doses, each rounded up to the nearest 0.1 mL. Your doctor may adjust your dose as needed. However, the dose is usually not more than 17.5 milliliters (mL) per day.
      • Children younger than 2 months of age—Use is not recommended.
    • For patients switching from sodium phenylbutyrate tablets to Ravicti®:
      • Adults and children 2 years of age and older—The dose is the total daily dose of sodium phenylbutyrate that you are already taking multiplied by 0.86 and divided into 3 equal doses, each rounded up to the nearest 0.5 mL. Your doctor may adjust your dose as needed. However, the dose is usually not more than 17.5 milliliters (mL) per day.
      • Children 2 months up to 2 years of age—The dose is the total daily dose of sodium phenylbutyrate that you are already taking multiplied by 0.86 and divided into 3 or more equal doses, each rounded up to the nearest 0.1 mL. Your doctor may adjust your dose as needed. However, the dose is usually not more than 17.5 milliliters (mL) per day.
      • Children younger than 2 months of age—Use is not recommended.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Loose stools (diarrhea).
• Not hungry.
• Gas.
• Belly pain or heartburn.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Ravicti can affect your nervous system. Call your doctor right away if you have: confusion, headaches, memory problems, hearing problems, vomiting, an altered sense of taste, numbness or tingling in your hands or feet, or if you feel unusually sleepy or light-headed.

Ravicti should not be given to a child under 2 months old.

Common side effects of Ravicti include: dizziness, fatigue, headache, nausea, and vomiting. See below for a comprehensive list of adverse effects.

Applies to glycerol phenylbutyrate: oral solution

Along with its needed effects, glycerol phenylbutyrate (the active ingredient contained in Ravicti) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking glycerol phenylbutyrate:

• Continuing nausea or vomiting
• increase in the frequency of seizures
• loss of appetite
• swelling of the face
• tiredness and weakness

Some side effects of glycerol phenylbutyrate may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bloated or full feeling
• diarrhea
• excess air or gas in the stomach or intestines
• headache
• nausea
• passing gas
• rash
• upper abdominal or stomach pain
• vomiting

• Acid or sour stomach
• belching
• heartburn
• indigestion
• stomach discomfort or upset