Sapropterin PSK (Tablets) Instructions for Use

Marketing Authorization Holder

PSK Pharma, LLC (Russia)

ATC Code

A16AX07 (Sapropterin)

Active Substance

Sapropterin (USAN Mod.)

Dosage Form

Sapropterin PSK

Soluble tablets 100 mg: 30 or 120 pcs.

Dosage Form, Packaging, and Composition

Soluble tablets round, from almost white to light yellow in color with a marbled surface, the surface of the tablet is smooth.

Excipients : mannitol, crospovidone, sodium stearyl fumarate, calcium hydrogen phosphate, colloidal silicon dioxide, ascorbic acid, riboflavin.

30 pcs. – polyethylene jars (1) – cardboard packs.
120 pcs. – polyethylene jars (1) – cardboard packs.

The pack may be labeled with a first-opening control label.

Clinical-Pharmacological Group

Drug for the treatment of hereditary enzymatic deficiency

Pharmacotherapeutic Group

Other agents for the treatment of gastrointestinal diseases and metabolic disorders

Pharmacological Action

Sapropterin is an artificially synthesized equivalent of natural 6R-BH4, which is a co-factor for hydroxylases for phenylalanine, tyrosine, and tryptophan.

The rationale for its use in patients with phenylketonuria who are sensitive to tetrahydrobiopterin therapy is to restore the activity of the impaired phenylalanine hydroxylase and, consequently, to enhance or restore the oxidative metabolism of phenylalanine to a level sufficient to reduce or maintain its concentration in the blood, to prevent or mitigate further accumulation of phenylalanine, and to increase tolerance to dietary phenylalanine.

The rationale for prescribing sapropterin in patients with tetrahydrobiopterin metabolism disorders is to replenish the BH4 deficiency and thus restore the activity of phenylalanine hydroxylase, tryptophan hydroxylase, tyrosine hydroxylase, and nitric oxide synthase.

Pharmacokinetics

After oral administration, Sapropterin is absorbed from the gastrointestinal tract, with C_max in plasma on an empty stomach reached in 3-4 hours.

The rate and extent of absorption of sapropterin depend on the type of food taken with it. High-calorie, high-fat food enhances the absorption of sapropterin compared to taking it on an empty stomach, which leads to an average increase in its C_max by 40-85% after 4-5 hours.

Sapropterin was predominantly distributed in the kidneys, adrenal glands, and liver.

Sapropterin dihydrochloride is metabolized mainly in the liver to dihydrobiopterin and biopterin.

Since sapropterin dihydrochloride is an artificially synthesized analogue of 6R-BH4, it is reasonable to expect that it is metabolized by the same pathway as natural 6R-BH4. Folic acid and vitamin B₁₂ may increase BH4 levels.

After oral administration, most of the dose is excreted through the intestine, a smaller part – by the kidneys.

Indications

Hyperphenylalaninemia in adults and children with phenylketonuria or tetrahydrobiopterin metabolism disorder (in combination with diet).

ICD codes

Dosage Regimen

Individual, depending on the indications and body weight of the patient. Administered orally.

Treatment with sapropterin should be prescribed and monitored by a physician experienced in the treatment of phenylketonuria and tetrahydrobiopterin metabolism disorders.

Strict regulation of dietary phenylalanine and total protein intake while taking the drug is necessary to ensure adequate control of blood phenylalanine levels and nutritional balance.

Since hyperphenylalaninemia is a chronic condition in both phenylketonuria and tetrahydrobiopterin metabolism disorders, sapropterin is prescribed for long-term use if the response to treatment is positive. However, experience with its long-term use is limited.

Patients receiving Sapropterin should follow a phenylalanine-restricted diet and undergo regular clinical and laboratory examination (including monitoring of blood phenylalanine and tyrosine, assessment of nutrient intake and psychomotor development).

Adverse Reactions

Nervous system disorders very common – headache.

Respiratory system disorders very common – rhinorrhea; common – pharyngolaryngeal pain, nasal congestion, cough.

Gastrointestinal disorders common – diarrhea, vomiting, abdominal pain.

Metabolism and nutrition disorders common – hypophenylalaninemia.

Other in some cases, hypersensitivity reactions (including serious allergic reactions), rash were noted.

After discontinuation of sapropterin, a withdrawal syndrome may occur, which is manifested by an increase in blood phenylalanine concentration above the initial values.

Contraindications

Breastfeeding period; hypersensitivity to sapropterin.

With caution renal or hepatic impairment; predisposition to seizures; concomitant use with levodopa, dihydrofolate reductase inhibitors (including methotrexate, trimethoprim), vasodilators, including topical use (nitroglycerin, isosorbide dinitrate, sodium nitroprusside, molsidomine, PDE5 inhibitors, minoxidil); elderly age (over 65 years); pregnancy; children under 4 years of age.

Use in Pregnancy and Lactation

There are no confirmed data from clinical studies on the use of sapropterin during pregnancy. In experimental animal studies, no direct or indirect adverse effects on embryo-fetal development, as well as on labor and postnatal development, were found.

It is necessary to strictly control the concentration of phenylalanine in the blood of women planning pregnancy, both before pregnancy and throughout its entire duration. Otherwise, insufficiently strict control of phenylalanine concentration can lead to dangerous consequences for both the mother and the fetus. Physician-controlled restriction of dietary phenylalanine intake before and during pregnancy is the first-line treatment for these patients.

The issue of prescribing sapropterin to a pregnant woman should be considered only if strict adherence to the diet does not provide adequate reduction in blood phenylalanine concentration. Sapropterin should be prescribed to pregnant women with caution.

Contraindicated for use during breastfeeding.

Use in Hepatic Impairment

Sapropterin should be prescribed with caution in hepatic impairment.

Use in Renal Impairment

Sapropterin should be prescribed with caution in renal impairment.

Pediatric Use

Sapropterin should be prescribed with caution to children under 4 years of age.

Geriatric Use

Sapropterin should be prescribed with caution to elderly patients (over 65 years of age), as its safety and efficacy in this group of patients have not been established.

Special Precautions

Prolonged or intermittently repeated disruption of the phenylalanine – tyrosine – dihydroxy-L-phenylalanine (DOPA) metabolic chain may result in insufficient production of protein and neurotransmitters by the body.

Long-term reduction of phenylalanine and tyrosine concentrations in early childhood may lead to disorders of nervous system development.

Strict regulation of dietary phenylalanine and total protein intake while taking sapropterin is necessary to ensure adequate control of blood phenylalanine levels and nutritional balance.

Before prescribing sapropterin to patients with comorbidities, a doctor’s consultation is required, as in some diseases the concentration of phenylalanine in the blood may increase.

Data on the long-term use of sapropterin are limited.

Sapropterin should be used with caution in patients with a predisposition to seizures. Such patients may experience the appearance or exacerbation of seizure activity, especially at the beginning of therapy.

Use in pediatrics

When using sapropterin in children, especially under 1 year of age, frequent blood monitoring should be performed to maintain the recommended blood phenylalanine level.

Effect on ability to drive vehicles and operate machinery

No studies on the effect on the ability to drive vehicles and other mechanisms have been conducted. Nevertheless, due to the possible development of adverse reactions from the central nervous system (headache), caution should be exercised when driving and performing other activities that require increased attention and speed of psychomotor reactions.

Drug Interactions

Although concomitant use of drugs from the group of dihydrofolate reductase inhibitors (e.g., methotrexate, trimethoprim) has not been studied, such drugs may affect BH4 metabolism. These drugs should be prescribed with caution when used concomitantly with sapropterin.

BH4 is a co-factor for nitric oxide synthase (NO). Sapropterin should be used with caution simultaneously with drugs that have a vasodilatory effect, including topical agents, due to its influence on the metabolism or mechanism of action of NO. These include classical NO donors (e.g., nitroglycerin, isosorbide dinitrate, sodium nitroprusside, molsidomine), PDE5 inhibitors (such as sildenafil, vardenafil, tadalafil) and minoxidil.

Sapropterin must be used with caution in patients receiving levodopa, because combined therapy with levodopa and sapropterin in patients with BH4 deficiency may increase excitability and irritability, and also cause the appearance and increased frequency of seizures, especially at the beginning of therapy. In this case, adjustment of the levodopa dose may be required.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.