Sapropterin dihydrochloride, marketed under brand names such as Kuvan among others, is a medication used primarily to treat phenylketonuria (PKU), a genetic disorder in which the body is unable to properly metabolize phenylalanine, an amino acid present in many proteins. People with untreated PKU can accumulate high levels of phenylalanine in their body, leading to intellectual disabilities, behavioral problems, and mental disorders.

Sapropterin (Kuvan) is a co-factor in the synthesis of nitric oxide and three other aromatic amino acid hydroxylase enzymes. Along with restricted diet, it is used in children with phenylketonuria.

Sapropterin (Kuvan) Uses:

• Hyperphenylalaninemia:
  • It is used to reduce blood phenylalanine (PHE) levels in patients with hyperphenylalaninemia caused by tetrahydrobiopterin (BH4)-responsive phenylketonuria in conjunction with a PHE-restricted diet.

Sapropterin (Kuvan) Dose in Adults

Sapropterin (Kuvan) Dose in the treatment of Hyperphenylalaninemia: 

Starting Dose:

• The initial dose is usually between 10 to 20 milligrams per kilogram of body weight, taken once a day.

Maintenance Dose:

• After the first month, the dose might need to be adjusted based on blood tests that measure phenylalanine levels.
• If the initial dose is 10 mg/kg per day and doesn’t reduce phenylalanine levels, the dose may be increased to 20 mg/kg per day.
• If there's no improvement in phenylalanine levels after one month of taking 20 mg/kg per day, the treatment is usually stopped because it might not be effective (the person is a nonresponder).
• The maintenance dose can vary between 5 to 20 mg/kg once daily, depending on how the individual responds to the treatment.

If a Dose is Missed:

• If you forget to take a dose, take it as soon as you remember. However, if it's almost time for the next dose, skip the missed dose and go back to your regular schedule.
• Never take two doses at the same time.

Sapropterin (Kuvan) Dose in Childrens

Sapropterin (Kuvan) Dose in the adjunct treatment of Phenylalanine hydroxylase (PAH) deficiency disorders (eg, hyperphenylalaninemia, phenylketonuria [PKU]): 

For Infants and Children ≤6 years:

• Initial Dose: Start with 10 mg/kg once daily.
• Adjustments: After 1 month, check phenylalanine levels. If there is no decrease, increase the dose to 20 mg/kg once daily.
• Further Steps: If there is still no response after another month on 20 mg/kg/day, stop the treatment (the individual is a non-responder).
• Maintenance Dose: Typically ranges from 5 to 20 mg/kg once daily, tailored to the patient’s response. Doses in clinical trials were rounded to the nearest 100 mg, and sometimes up to 24 mg/kg/day was used.

For Children ≥7 years and Adolescents:

• Initial Dose: Start with 10 to 20 mg/kg once daily, based on individual factors.
• Adjustments: After 1 month, check phenylalanine levels.
  • If starting at 10 mg/kg: If there is no decrease, increase to 20 mg/kg once daily. If still no response after another month at this higher dose, discontinue sapropterin.
  • If starting at 20 mg/kg: Discontinue if there is no response after one month.
• Maintenance Dose: Ranges from 5 to 20 mg/kg once daily, tailored to patient response. In clinical trials, dosages up to 24 mg/kg/day were used.

General Notes:

• Dosage adjustments are based on the response of phenylalanine levels in the blood.
• Treatment continuation is contingent on effective phenylalanine reduction.
• Doses in clinical studies were often adjusted to the nearest 100 mg increment for practical dosing.

Pregnancy Risk Category: C

• There is limited information on the effects of using sapropterin during pregnancy, but high levels of phenylalanine (PHE) in pregnant women can lead to serious birth defects such as congenital heart disease, developmental delays, and microcephaly.
• It's important for women with phenylketonuria (PKU) to manage their PHE levels effectively before and during pregnancy to ensure healthy fetal development.
• Ideal PHE levels are below 360 micromol/L before conception.
• Sapropterin, combined with a low-PHE diet, may be safely used by pregnant women who respond to this treatment, helping them maintain these crucial low PHE levels.
• Ongoing studies continue to collect data on the outcomes of pregnancies exposed to sapropterin, and pregnant patients using this medication are encouraged to register their information for monitoring purposes.

Sapropterin use during breastfeeding:

• It's uncertain whether sapropterin transfers into breast milk.
• When deciding whether to continue breastfeeding while on sapropterin, it’s important to consider the potential for infant exposure, the benefits of breastfeeding for the baby, and the benefits of treatment for the mother.
• Mothers with phenylketonuria (PKU) have higher levels of phenylalanine in their breast milk.
• However, infants who do not have PKU are capable of metabolizing phenylalanine normally.
• Therefore, breastfeeding is generally supported for these mothers, even if they are being treated with sapropterin, as long as their infant does not have PKU.

Sapropterin (Kuvan) Dose in Kidney Disease:

• According to the manufacturer's labeling for sapropterin, there are no specific dosage adjustments recommended for patients with renal impairment.

Sapropterin (Kuvan) Dose in Liver disease:

• The manufacturer's labeling for sapropterin does not specify any dosage adjustments for patients with hepatic impairment.
• This indicates that the standard dosing regimen can be used in patients with liver issues.

Common Side Effects of Sapropterin (Kuvan):

• Central nervous system:
  • Headache
• Respiratory:
  • Rhinorrhea

Less Common Side Effects of Sapropterin (Kuvan):

• Gastrointestinal:
  • Diarrhea
  • Vomiting
• Respiratory:
  • Pharyngolaryngeal Pain
  • Cough
  • Rhinitis
  • Nasal Congestion

Contraindications to Sapropterin (Kuvan):

• In the United States, the manufacturer’s labeling for sapropterin does not list any specific contraindications. This suggests that, under U.S. guidelines, there are no explicit conditions or factors that would universally prevent someone from being prescribed this medication.
• However, the situation is different in Canada, where the labeling indicates a contraindication for patients with a known hypersensitivity to sapropterin or any component of its formulation. This means that in Canada, individuals who have had allergic reactions to sapropterin or any ingredients in the drug should not use it.

Warnings and precautions

Gastritis

• Reported instances of gastritis associated with sapropterin use suggest that patients should be monitored for this condition.
• Gastritis involves inflammation of the stomach lining and can cause symptoms such as abdominal pain, nausea, vomiting, and bloating.

Hyperactivity

• Observations of hyperactivity linked to sapropterin use indicate the need to monitor patients for this potential side effect.
• Hyperactivity involves increased levels of activity, restlessness, and difficulty in focusing or staying still.

Hypersensitivity

• Hypersensitivity reactions, such as anaphylaxis (a severe allergic reaction) and rash, have been reported with sapropterin use.
• Due to this risk, sapropterin is not recommended for individuals with a history of anaphylaxis to the medication.
• If a patient experiences anaphylaxis, treatment with sapropterin should be stopped immediately, and appropriate medical care should be initiated.
• Additionally, patients who experience anaphylaxis should continue following dietary restrictions for phenylalanine (PHE).
• This ensures comprehensive management of their condition and minimizes potential risks associated with phenylketonuria (PKU).

Hypophenylalaninemia:

• Some patients may experience low blood phenylalanine levels (hypophenylalaninemia) while taking sapropterin.
• It's noted that patients under 7 years of age treated at a dose of 20 mg/kg daily are at a higher risk of experiencing hypophenylalaninemia compared to those who are 7 years or older.
• This indicates the importance of monitoring phenylalanine levels regularly, especially in younger patients receiving higher doses of sapropterin, to prevent the risk of hypophenylalaninemia and ensure appropriate management of phenylketonuria (PKU).

Phenylketonuria:

• In managing phenylketonuria (PKU) with sapropterin treatment, it's crucial to monitor and maintain blood phenylalanine (PHE) levels within the target range.
• Upon diagnosis, it's important to lower PHE levels into the desired treatment range of 120 to 360 micromol/L as swiftly as possible.
• Infants with levels exceeding 600 micromol/L need treatment, though it may begin at 360 micromol/L or higher.
• Early intervention, especially in infancy, aims to lower PHE to 480 to 600 micromol/L initially.
• Prolonged high PHE levels can lead to severe neurological damage, while low levels can cause protein breakdown.
• Dietary control of phenylalanine intake is essential for nutritional balance and effective PHE control.
• Regular monitoring of blood PHE levels, especially in children, is necessary during treatment.
• It's worth noting that PHE blood level testing at doses below 20 mg/kg may underestimate treatment response.

Sapropterin: Drug Interaction

Monitoring parameters:

• Blood Phenylalanine Levels:
  • Baseline levels should be measured before starting treatment.
  • Check after 1 week of treatment, then periodically for the first month, and regularly thereafter.
  • Children may need more frequent monitoring.
• Blood Pressure:
  • Monitor blood pressure in patients taking medications like sildenafil, vardenafil, or tadalafil.
• Neurologic Status:
  • Watch for any changes in neurologic status in patients taking levodopa along with sapropterin.
• Gastritis Signs and Symptoms:
  • Be alert for signs and symptoms of gastritis, such as stomach pain or nausea.
• Hyperactivity:
  • Monitor for hyperactivity, which can involve increased activity levels or restlessness.

Guideline-Recommended Monitoring for Patients with Phenylalanine Hydroxylase Deficiency (Vockley 2014):

• Newly Diagnosed Infants:
  • Monitor phenylalanine (PHE) and tyrosine (TYR) frequently until PHE concentrations stabilize.
  • Then, monitor PHE weekly until age 1, increasing frequency during rapid growth or dietary transitions.
• Children (1 to 12 years):
  • Monitor PHE every 2 to 4 weeks.
• Adolescents and Stable Adults:
  • Monitor PHE monthly.
• Nutritional Assessment:
  • If a formal nutritional assessment indicates suboptimal dietary intake or overreliance on incomplete medical foods, consider additional monitoring including plasma amino acids, transthyretin, albumin, CBC, ferritin, vitamin D, vitamin B12, red blood cell essential fatty acids, trace minerals (copper, selenium, zinc), vitamin A, comprehensive metabolic panel, and folic acid.

How to administer Sapropterin (Kuvan)?

Powder for Oral Solution:

• Administration: Take with food, ideally at the same time daily.
• Preparation: Dissolve the powder in 120 to 240 mL (4 to 8 oz) of water, apple juice, or soft foods like applesauce or pudding. Mix thoroughly.
• Timing: Consume the solution within 30 minutes of dissolution.

Tablets:

• Administration: Also take with food, preferably at the same time each day.
• Swallowing Whole: Swallow the tablets whole or dissolve them in 120 to 240 mL (4 to 8 oz) of water or apple juice.
• Dissolving Tablets: Crush or stir the tablets to aid in dissolution. Take within 15 minutes of dissolving. Some residue may remain; rinse with more liquid and consume.
• Alternative Method: Crush tablets and mix in a small amount of soft food like applesauce or pudding.

Mechanism of action of Sapropterin (Kuvan):

• Sapropterin acts as a synthetic version of the cofactor BH4 (tetrahydrobiopterin), which is essential for the enzyme phenylalanine hydroxylase (PAH).
• PAH is responsible for converting phenylalanine into tyrosine.
• By supplying BH4, sapropterin helps activate any remaining PAH enzyme in individuals with PAH deficiency, improving the metabolism of phenylalanine and reducing its levels in those who respond to the treatment.
• It's estimated that approximately 25% to 50% of patients with PAH deficiency show a positive response to sapropterin therapy.

Onset of Action:

• Sapropterin typically starts working within 24 hours after administration, with its maximum effect being reached within about one month.

Duration:

• Its effects last for about 24 hours.

Absorption:

• Taking sapropterin with food, especially high-fat or high-calorie meals, enhances its absorption. Absorption is greater when the tablet is swallowed whole rather than dissolved.

Metabolism:

• Enzymes called dihydrofolate reductase and dihydropteridine reductase are responsible for the metabolism and recycling of the cofactor BH4.

Half-Life Elimination:

• Sapropterin has an elimination half-life of approximately 6.7 hours, with a range of 3.9 to 17 hours.

International Brands of Sapropterin:

• Kuvan

Sapropterin Brand Names in Pakistan:

No Brands Available in Pakistan.