Sapropterin

Before taking sapropterin,

• tell your doctor and pharmacist if you are allergic to sapropterin or any other medications.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: levodopa (in Sinemet, in Stalevo); methotrexate (Trexall); and PDE5 inhibitors such as sildenafil (Revatio, Viagra), tadalafil (Cialis), and vardenafil (Levitra). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had anorexia (an eating disorder in which a person eats too little and/or exercises too much to maintain even the minimum body weight considered normal for his/her age and height) or any other condition that causes you to be poorly nourished, or liver or kidney disease.
• tell your doctor if you have a fever or if you get sick at any time during your treatment. Fever and illness may affect your phenylalanine level, so your doctor may need to adjust your dose of sapropterin.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking sapropterin, call your doctor.

>10%

Rhinorrhea (11%)

Headache (15%)

1-10%

Diarrhea (8%)

Pharyngolaryngeal pain (10%)

Cough (7%)

Nasal congestion (4%)

Vomiting (8%)

Nausea (8%)

<1%

Gastritis

Gastrointestinal bleeding

Thrombocytopenia

Spinal cord injury

Abdominal pain

Decreased appetite

Respiratory tract infection

Peripheral edema

Sapropterin is usually given once daily. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

This medicine comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

Sapropterin works best if you take it with food.

You may swallow the tablet whole or dissolve it in 4 to 8 ounces of water or apple juice.

• It will take a few minutes for the tablet to dissolve, and you may see small pieces in the liquid. These pieces are safe for you to swallow.
• Stir the mixture and then drink all of it within 15 minutes after the tablet dissolves.
• To get the entire dose, add a little more water to the same glass, swirl gently and drink right away.

Sapropterin can reduce your phenylalanine blood levels within 24 hours of when you take it. However, it may take up to 30 days of using this medicine before it reaches its fullest effect in your body. For best results, keep using the medication as directed.

Tell your doctor if you have any changes in weight. Sapropterin doses are based on weight (especially in children), and any changes may affect the dose.

Sapropterin is only part of a complete program of treatment that also includes a special diet. Follow the diet plan created for you by your doctor or nutrition counselor. Get familiar with the list of foods you must avoid to help control your condition.

While using sapropterin, you may need frequent blood tests.

Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.

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

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Do not take 2 doses on the same day.

This is not a complete list of Sapropterindrug interactions. Ask your doctor or pharmacist for more information.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Sapropterin falls into category C:

In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans, though. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

OR

There are no well-controlled studies that have been done in pregnant women. Sapropterin should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby.

OR

No studies have been done in animals, and no well-controlled studies have been done in pregnant women. Sapropterin should be given to a pregnant woman only if clearly needed.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

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

• Enzyme Cofactor

Hyperphenylalaninemia: Oral:

Initial: 10 to 20 mg/kg once daily

Maintenance: Adjust dose after 1 month based on blood phenylalanine levels (if phenylalanine levels do not decrease from baseline after initiating 10 mg/kg, increase dose to 20 mg/kg once daily); discontinue if phenylalanine levels do not decrease after 1 month of treatment at 20 mg/kg/day (nonresponder). Maintenance range: 5 to 20 mg/kg once daily

Missed dose: A missed dose should be taken as soon as possible, but 2 doses should not be taken on the same day.

Adverse events have been observed in some animal reproduction studies. High levels of maternal phenylalanine are associated with congenital heart disease, developmental delay, facial dysmorphism, learning difficulties, and microcephaly. Phenylalanine (PHE) concentrations should be normalized prior to conception. Fetal development is optimal when PHE concentrations <360 micromol/L are achieved prior to conception (Vockley, 2014). Dietary control with proper supplementation is recommended during pregnancy. Maternal PHE requirements may change throughout pregnancy; frequent testing and dietary modifications may be necessary (Vockley, 2014). Some clinicians recommend that dietary control be achieved for at least 4 weeks prior to conception; however, studies suggest that as long as control is achieved by 10 weeks of pregnancy, teratogenic effects of untreated maternal phenylketonuria can be decreased (Koch, 2003; Maillot, 2007). In addition to standard fetal monitoring, fetal echocardiography is recommended at 18-22 weeks gestation (Vockley, 2014). Pregnant women exposed to sapropterin are encouraged to enroll in the Kuvan pregnancy registry (866-906-6100).

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

Administration advice:
-Take with a meal to increase absorption, preferably same time each day.
-May swallow tablets whole or dissolved in water or apple juice; take dissolved tablets within 15 minutes of dissolution.
-Take dissolved powder for oral solution within 30 minutes of dissolution.
-Take a missed dose as soon as possible, but do not take 2 doses on the same day.

Storage requirements:
-Protect from moisture.

Reconstitution/preparation techniques:
Tablets:
-May be dissolved in 120 to 240 mL of water or apple juice; the manufacturer's product information should be consulted for further information.
-May be crushed and then mixed in a small amount of soft foods (e.g., apple sauce, pudding).
Powder for oral solution:
-Should be dissolved in 120 to 240 mL of water or apple juice
-May be stirred in a small amount of soft foods
-Packet contents should be emptied in water, apple juice, or soft foods and mixed thoroughly; it should dissolve completely.
-The manufacturer product information should be consulted regarding preparation for use in infants weighing 10 kg or less.

Monitoring:
-Gastrointestinal: Signs of gastritis
-Hepatic: Liver function tests in patients with liver dysfunction
-Metabolic: Blood Phe levels (during therapy; frequently in pediatric patients)
-Nervous system: For hyperactivity

Patient advice:
-Use this drug in addition to a Phe-restricted diet.