Kuvan

Sapropterin comes as a tablet to dissolve in water or apple juice and take by mouth. It is usually taken once a day with food. Take sapropterin at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take sapropterin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Place the number of sapropterin tablets you were told to take in a cup that contains 4 to 8 ounces (1/2 to 1 cup or 120 to 240 milliliters) of water or apple juice. Stir the mixture or crush the tablets with a spoon to dissolve the tablets. The tablets may not dissolve completely; there may still be small pieces of tablet floating at the top of the liquid. When the tablets are mostly dissolved, drink the entire mixture. If pieces of tablets remain in the cup after you drink the mixture, pour more water or apple juice into the cup and drink it to be sure you swallow all the medication. Be sure to drink the entire mixture within 15 minutes after you prepare it.

Even if sapropterin tablets are stored properly, the color of the tablets may change to light yellow over time. This is normal and it is safe to take tablets that have changed color.

Your doctor will start you on an average dose of sapropterin and will check your blood phenylalanine level regularly. If your phenylalanine level does not decrease, your doctor will increase your dose of sapropterin. If your phenylalanine level does not decrease after one month of treatment with the higher dose of sapropterin, you and your doctor will know that your condition does not respond to sapropterin. Your doctor will tell you to stop taking the medication.

Sapropterin may help to control blood phenylalanine levels, but it will not cure PKU. Continue to take sapropterin even if you feel well. Do not stop taking sapropterin without talking to your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient.

Kuvan can cause serious side effects, including:

• Severe allergic reactions. Stop taking Kuvan and get medical help right away if you develop any of these symptoms of a severe allergic reaction:
  • wheezing or trouble breathing
  • coughing
  • rash
  • feeling lightheaded or you faint
  • flushing
  • nausea
• Inflammation of the lining of the stomach (gastritis). Gastritis can happen with Kuvan and may be severe. Call your doctor right away if you have any of these signs or symptoms:
  • severe upper stomach-area (abdominal) discomfort or pain, nausea and vomiting
  • blood in your vomit or stool
  • black, tarry stools
• Phe levels that are too low.  Some children under the age of 7 who take high doses of Kuvan each day may experience low Phe levels. 
• Too much or constant activity (hyperactivity) can happen with Kuvan. Tell your doctor if you have any signs of hyperactivity, including:
  • fidgeting or moving around too much
  • talking too much

Tell your health care provider if you are breastfeeding or plan to breastfeed. It is not known if Kuvan passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take Kuvan.

Take Kuvan exactly as prescribed by your doctor.

The dose your physician recommends may be based on your age.

Patients 1 month to 6 years: The recommended starting dose of Kuvan is 10 mg/kg taken once daily.

Patients 7 years and older: The recommended starting dose of Kuvan is 10 to 20 mg/kg taken once daily.

Sapropterin is a synthetic form of a natural substance that activates an enzyme needed to break down phenylalanine in the body.

Phenylketonuria (PKU) is a disorder in which the body cannot break down phenylalanine. Elevated phenylalanine levels can cause problems with thinking and behavior.

Sapropterin is used to lower blood levels of phenylalanine in people with a certain type of PKU.

Sapropterin may also be used for purposes not listed in this medication guide.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Absorption

Onset

Phenylalanine concentrations decrease within 24 hours following a single dose; maximal reductions occur within 1 month with daily administration.1

Duration

Phenylalanine concentrations remain stable over a 24-hour period following a single daily dose.1

Food

Absorption comparable when tablets are dissolved in water or orange juice under fasted conditions.1 Phenylalanine concentrations do not substantially increase with food intake following a single dose.1

High-fat/high-calorie meal may increase absorption of sapropterin.1

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Elimination

Half-life

Approximately 6.7 hours.1

Special Populations

Pharmacokinetics unaffected by age within the range of 9–49 years of age; not studied outside this range.1

Hepatic damage may impair phenylalanine metabolism.1

• Cofactor for phenylalanine hydroxylase (PAH), the enzyme that hydroxylates phenylalanine through an oxidative reaction to form tyrosine.1 4 5

• Enhances activity of residual PAH in patients with PKU, which improves the normal oxidative metabolism of phenylalanine and thus decreases blood phenylalanine concentrations in some patients with PKU.1 4 5

None.

Based on in vitro study, there is potential for Kuvan to inhibit p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in the gut at the therapeutic doses. Co-administration of Kuvan may increase systemic exposure to drugs that are substrates for P-gp or BCRP [see Clinical Pharmacology (12.3)]. 

Kuvan (COO-van)

(sapropterin dihydrochloride)

tablets

Kuvan (COO-van)

(sapropterin dihydrochloride)

powder for oral solution

Read this Instructions for Use before you start taking Kuvan and each time you refill your prescription. There may be new information. This information does not take the place of talking with your healthcare provider about your treatment. Talk to your doctor if you have any questions about the right dose of Kuvan to take or how to mix it.

Important information:

• Kuvan comes as a tablet or in a packet containing powder.
• Take Kuvan exactly as your doctor tells you. Your doctor should tell you how much Kuvan to take and when to take it. 
• Your doctor may change your dose of Kuvan depending on how you respond to treatment, or based on your baby’s weight.
• If your baby weighs 22 pounds or less, follow the section called “Instructions for giving Kuvan powder for oral solution (Kuvan 100 mg packets) to babies who weigh 22 pounds or less”.
• Take Kuvan 1 time each day with a meal. It is best to take Kuvan at the same time each day.

Instructions for taking Kuvan tablets:

Kuvan tablets can be swallowed whole or dissolved in water or apple juice. You may also crush the tablets and mix in a small amount of soft food, such as apple sauce or pudding.

To dissolve Kuvan tablets:

• Mix Kuvan tablets in 4 ounces to 8 ounces (½ cup to 1 cup) of water or apple juice. It may take a few minutes for the tablets to dissolve. To make the tablets dissolve faster, you can stir or crush them.
• The tablets may not dissolve completely. You may see small pieces floating on top of the water or apple juice. This is normal and safe for you to swallow.
• Drink within 15 minutes.
• After drinking your medicine, if you still see small pieces of the tablet, add more water or apple juice and drink to make sure that you take all of your medicine.

Instructions for taking Kuvan powder for oral solution:

For babies who weigh 22 pounds or less, see the section below called “Instructions for giving Kuvan powder for oral solution (Kuvan 100 mg packets) to babies who weigh 22 pounds or less.”

Kuvan powder for oral solution should be dissolved in water or apple juice. The powder for oral solution may also be mixed in a small amount of soft foods, such as apple sauce or pudding. 

To dissolve Kuvan powder for oral solution:

• Be sure that you know what dose of Kuvan your doctor has prescribed and whether you should use Kuvan 100 mg packets, Kuvan 500 mg packets, or both types of packets to prepare your dose.

• Open the packet(s) of Kuvan powder for oral solution by folding and tearing, or cutting at the dotted line in the upper right corner of the packet. Open the packet(s) only when you are ready to use them.

• Empty the contents of the packet(s) into 4 ounces to 8 ounces (1/2 cup to 1 cup) of water or apple juice.

• Drink within 30 minutes. 

Instructions for giving Kuvan powder for oral solution (Kuvan 100 mg packets) to babies who weigh 22 pounds or less:

• The dose of Kuvan is based on body weight. This will change as your baby grows. Your doctor will tell you:
  • the number of Kuvan 100 mg packets needed for one dose
  • the amount of water or apple juice needed to mix one dose of Kuvan
  • the amount of the mixture (powder and water or apple juice) you will need to give your baby his or her prescribed dose of medicine.
• Give your baby the prescribed amount of mixture (powder and water or apple juice) within 30 minutes after mixing. If you are not able to give your baby’s dose within 30 minutes after mixing, pour the unused medicine into the trash. You will need to mix a new dose.

Supplies needed to mix and give your baby’s dose of Kuvan powder for oral solution:

• the number of Kuvan 100 mg packets needed for one dose
• a small cup of water or apple juice
• one 30 mL medicine cup for mixing
• small spoon or clean utensil for mixing
• 10 mL oral dosing syringe
• scissors (optional)

Ask your pharmacist for a 30 mL medicine cup for mixing and an oral dosing syringe if you do not have these supplies.

How should I store Kuvan?

• Store Kuvan at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep Kuvan tablets in the original bottle with the cap closed tightly.
• Protect from moisture.

Keep Kuvan and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

BioMarin Pharmaceutical Inc.

Novato, CA 94949

Revised: 07/2015

© BioMarin Pharmaceutical Inc. All rights reserved.

Kuvan is a registered trademark of BioMarin Pharmaceutical Inc.

v2/2015

NDC 68135-300-02

Kuvan®
(sapropterin dihydrochloride) Tablets

100 mg*

* Equivalent to 76.8 mg of sapropterin

Rx only

120 Tablets

BIOMARIN®

Manufactured for
BioMarin Pharmaceutical Inc.
Novato, CA 94949
by EXCELLA GmbH
Nürnberger Strasse 12,
90537 FEUCHT
Germany

Store at 20°C to 25°C (68°F-77°F); excursions allowed between 15°C to 30°C (59°F-86°F)
[See USP Controlled Room Temperature]

Keep container tightly closed
Protect from moisture

Usual Dosage:
See Physician Package Insert

75497011-2124

Dimensions 59x59x86mm


Lot:



Exp:

RX only

To open

Fold on the dotted line and tear or cut across top of packet

NDC 68135-301-11

Kuvan®
(sapropterin dihydrochloride) Powder for Oral solution

100 mg*

* Equivalent to 76.8 mg of sapropterin

Directions: Dissolve contents of packet as described in the package insert.

Usual Dosage: see package insert

Store at 20°C to 25°C (68°F-77°F); excursions allowed between 15°C to 30°C (59°F-86°F)
See USP Controlled Room Temperature

Protect from moisture

Keep out of reach of children

RX only

Note New Strength!!

To open

Fold on the dotted line and tear or cut across top of packet

NDC 68135-482-10

Kuvan®
(sapropterin dihydrochloride) Powder for Oral solution

500 mg* per single use packet

* Equivalent to 384 mg of sapropterin

Directions: Dissolve contents of packet as described in the Instructions for Use.

Usual Dosage: see package insert

Store at 20°C to 25°C (68°F-77°F)
See USP controlled room temperature.

Protect from moisture

Keep out of reach of children

BIOMARIN®

Manufactured for
BioMarin Pharmaceutical Inc.,
Novato, CA 94949

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

Common side effects of Kuvan include: headache and rhinorrhea. See below for a comprehensive list of adverse effects.

Applies to sapropterin: oral powder for reconstitution, oral tablet dispersible

General

In phenylketonuria (PKU) trials, the most common side effects were headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion.

In clinical trials for non-PKU indications, a different formulation was used in patients with disorders other than PKU; some had underlying neurologic disorders or cardiovascular disease. Common side effects were headache, peripheral edema, arthralgia, polyuria, agitation, dizziness, nausea, pharyngitis, abdominal pain, upper abdominal pain, and upper respiratory tract infection. Serious and severe side effects included convulsions, exacerbation of convulsions, dizziness, gastrointestinal bleeding, postprocedural bleeding, headache, irritability, myocardial infarction, overstimulation, and respiratory failure.[Ref]

Nervous system

Very common (10% or more): Headache (15%)
Common (1% to 10%): Dizziness
Frequency not reported: Convulsions, exacerbation of convulsions, overstimulation
Postmarketing reports: Hyperactivity[Ref]

Respiratory

Very common (10% or more): Rhinorrhea (11%), pharyngolaryngeal pain (10%)
Common (1% to 10%): Cough, nasal congestion, pharyngitis, upper respiratory tract infection
Frequency not reported: Respiratory failure
Postmarketing reports: Pharyngitis[Ref]

Metabolic

Very common (10% or more): Low phenylalanine levels
Common (1% to 10%): Hypophenylalaninemia[Ref]

Gastrointestinal

Common (1% to 10%): Diarrhea, vomiting, nausea, abdominal pain, upper abdominal pain
Frequency not reported: Gastrointestinal bleeding
Postmarketing reports: Oropharyngeal pain, esophageal pain, gastritis, dyspepsia, abdominal pain, nausea, vomiting[Ref]

Cardiovascular

Frequency not reported: Myocardial infarction[Ref]

Other

Common (1% to 10%): Peripheral edema
Frequency not reported: Contusion, postprocedural bleeding, pyrexia[Ref]

Psychiatric

Common (1% to 10%): Agitation
Frequency not reported: Irritability

Musculoskeletal

Common (1% to 10%): Arthralgia[Ref]

Genitourinary

Common (1% to 10%): Polyuria[Ref]

Hypersensitivity

Postmarketing reports: Hypersensitivity reactions (including serious allergic reactions, anaphylaxis, rash)[Ref]

Dermatologic

Frequency not reported: Rash[Ref]

Hepatic

Frequency not reported: Increased GGT[Ref]

Some side effects of Kuvan may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus; caution is recommended. AU TGA pregnancy category: B1 US FDA pregnancy category: C Comments: This drug should be considered only if dietary restriction of phenylalanine (Phe) is ineffective in reducing blood Phe levels.

Animal studies have failed to reveal clear evidence of teratogenic activity; however, in a rabbit study, an increase (not statistically significant) in the incidence of holoprosencephaly occurred with high doses. There are no controlled data in human pregnancy. Uncontrolled Phe levels above 600 mcmol/L in pregnant women were associated with very high rates of neurological, cardiac, facial dysmorphism, and growth anomalies in their infants. Dietary control of Phe levels during pregnancy is essential to reduce the rate of Phe-induced teratogenic effects. US: To monitor the outcomes of pregnant women exposed to this drug, a patient registry has been established. For additional information: 1-866-906-6100 AU TGA pregnancy category B1: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.