Sapropterin

Sapropterin is an Enzyme Cofactor belonging to Phenylketonuria.

Sapropterin is a cofactor used as an adjunct to phenylalanine restriction in the treatment of phenylketonuria (PKU).

The Time to peak plasma concentration of Sapropterin is approximately 3-4 hours. Sapropterin is distributed mainly to the kidneys, adrenal glands, spleen and liver. Sapropterin is extensively metabolised in the liver by dihydrofolate reductase and dihydropteridine reductase to dihydrobiopterin and dihydroxanthopterin as main metabolites. It is mainly excreted via faeces urine (small amount).

Sapropterin shows side effects like Diarrhea, nausea, vomiting, stomach pain, headache, cough, throat pain, or cold symptoms, fidgeting, moving around, or talking too much.

Sapropterin is available in the form of Oral Tablet and oral powder for reconstitution.

Sapropterin is available in India, US, Malaysia, Australia, Spain, Italy, France, Singapore, UK, Canada, China, and Japan.

Sapropterin belongs to the Phenylketonuria acts as an Enzyme Cofactor.

Sapropterin is a synthetic form of the cofactor BH4 (tetrahydrobiopterin) for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates phenylalanine to form tyrosine. BH4 activates residual PAH enzyme, improving normal phenylalanine metabolism and decreasing phenylalanine levels in Sapropterin responders.

The duration of action of Sapropterin is about 24 hours.

The Tmax of Sapropterin is about 3-4 hours.

Sapropterin is available in the form of Oral Tablet and oral powder for reconstitution.

Sapropterin tablet is taken orally, usually once daily.

Sapropterin is a cofactor used as an adjunct to phenylalanine restriction in the treatment of phenylketonuria (PKU).

Sapropterin is an Enzyme Cofactor belonging to Phenylketonuria.

Sapropterin is a synthetic form of the cofactor BH4 (tetrahydrobiopterin) for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates phenylalanine to form tyrosine. BH4 activates residual PAH enzyme, improving normal phenylalanine metabolism and decreasing phenylalanine levels in Sapropterin responders.

Sapropterin is approved for use in the following clinical indications

• Hyperphenylalaninemia

Sapropterin is a cofactor used as an adjunct to phenylalanine restriction in the treatment of phenylketonuria (PKU).

• Hyperphenylalaninemia

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.

Sapropterin is available in various strengths as 500mg and 100mg.

A low phenylalanine diet should be followed while taking sapropterin.

• Hypersensitivity Reactions Including Anaphylaxis

sapropterin is not recommended in patients with a history of anaphylaxis to sapropterin. Hypersensitivity reactions, including anaphylaxis and rash, have occurred [see Adverse Reactions (6.2)]. Signs of anaphylaxis include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash. Discontinue treatment with sapropterin in patients who experience anaphylaxis and initiate appropriate medical treatment. Continue dietary phenylalanine restrictions in patients who experience anaphylaxis.

• Gastritis

During clinical studies, gastritis was reported as a serious adverse reaction. Monitor patients for signs and symptoms of gastritis.

• Hypophenylalaninemia

In clinical trials, some patients have experienced low blood phenylalanine levels. Children younger than 7 years treated with sapropterin doses of 20 mg/kg per day are at increased risk for low levels of blood phenylalanine compared with patients 7 years and older.

• Monitor Blood phenylalanine Levels During Treatment

Treatment with sapropterin should be directed by physicians knowledgeable in the management of PKU. Prolonged elevations in blood phenylalanine levels in patients with PKU can result in severe neurologic damage, including severe mental retardation, microcephaly, delayed speech, seizures, and behavioral abnormalities. Conversely, prolonged levels of blood phenylalanine that are too low have been associated with catabolism and protein breakdown. Active management of dietary phenylalanine intake while taking sapropterin is required to ensure adequate phenylalanine control and nutritional balance. Monitor blood phenylalanine levels during treatment to ensure adequate blood phenylalanine level control. Frequent blood monitoring is recommended in the pediatric population

• Identify Non-Responders to sapropterin Treatment

Not all patients with PKU respond to treatment with sapropterin. In two clinical trials at a dose of 20 mg/kg per day, 56% to 75% of pediatric PKU patients responded to treatment with sapropterin, and in one clinical trial at a dose of 10 mg/kg per day, 20% of adult and pediatric PKU patients responded to treatment with sapropterin [see Clinical Studies (14.1)]. Response to treatment cannot be pre-determined by laboratory testing (e.g., molecular testing), and can only be determined by a therapeutic trial of sapropterin

• Treat All Patients with a phenylalanine-restricted Diet

All patients with PKU who are being treated with sapropterin should also be treated with a phenylalaninerestricted diet.

• Monitor Patients with Hepatic Impairment

Patients with liver impairment have not been evaluated in clinical trials with sapropterin. Monitor liver function tests in patients with liver impairment who are receiving sapropterin because hepatic damage has been associated with impaired phenylalanine metabolism.

• Monitor Patients when Co-administering sapropterin and Medications Known to Inhibit Folate Metabolism

Co-administering sapropterin with drugs known to affect folate metabolism (e.g., methotrexate) and their derivatives may require more frequent monitoring of blood phenylalanine levels because these drugs can decrease endogenous BH4 levels by inhibiting the enzyme dihydropteridine reductase (DHPR).

• Monitor Patients for Hypotension when Co-administering sapropterin and Drugs Known to Affect Nitric Oxide-Mediated Vasorelaxation

Monitor blood pressure when administering sapropterin with drugs that affect nitric oxide-mediated vasorelaxation (e.g., PDE-5 inhibitors such as sildenafil, vardenafil, or tadalafil), because both sapropterin dihydrochloride and PDE-5 inhibitors may induce vasorelaxation. The additive effect of sapropterin and PDE-5 inhibitor co-administration could lead to a reduction in blood pressure; however, the combined use of these medications has not been evaluated in humans. In animal studies, orally administered sapropterin in combination with a PDE-5 inhibitor had no effect on blood pressure.

• Monitor Patients when Co-administering sapropterin and Levodopa

Caution should be used with the administration of sapropterin to patients who are receiving levodopa. In a 10-year post-marketing safety surveillance program for a non-PKU indication using another formulation of the same active ingredient (sapropterin), 3 patients with underlying neurologic disorders experienced convulsions, exacerbation of convulsions, over-stimulation, or irritability during co-administration of levodopa and sapropterin. Monitor for change in neurologic status.

• Monitor Patients for Hyperactivity

In the post-marketing safety surveillance program for PKU, 2 patients experienced hyperactivity with administration of sapropterin. Monitor patients for hyperactivity.

It is not known whether sapropterin is present in human milk. Sapropterin is present in the milk of intravenously, but not orally, treated lactating rats. The developmental and health benefits of human milk feeding should be considered along with the mother’s clinical need for sapropterin and any potential adverse effects on the human milk-fed child from the drug or from the underlying maternal condition. Exercise caution when sapropterin is administered to a nursing woman.

There are no adequate and well-controlled studies with sapropterin in pregnant women. An embryofetal development study with sapropterin dihydrochloride in rats using oral doses up to 3 times the maximum recommended human dose (MRHD) given during the period of organogenesis showed no effects. In a rabbit study using oral administration of sapropterin dihydrochloride during the period of organogenesis, a rare defect, holoprosencephaly, was noted at 10 times the MRHD. sapropterin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

A low phenylalanine diet should be followed while taking sapropterin.

Common

• Headache, Rhinorrhea, Diarrhea, vomiting, Pharyngolaryngeal pain, cough, nasal congestion.

Rare

• Abdominal pain, anaphylaxis, dyspepsia, esophageal pain, esophagitis, gastritis, gastrointestinal inflammation, hyperactive behavior, hypersensitivity reaction, nausea, oropharyngeal pain, pharyngitis, skin rash

• Levodopa-Containing Products

Sapropterin may enhance the adverse/toxic effect of Levodopa-Containing Products.

• Methotrexate

May decrease the serum concentration of Sapropterin. Specifically, methotrexate may decrease tissue concentrations of tetrahydrobiopterin

• Phenobarbital

May decrease the serum concentration of Sapropterin. Specifically, phenobarbital may decrease tissue concentrations of tetrahydrobiopterin.

• Phosphodiesterase 5 Inhibitors

Sapropterin may enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors.

• Pralatrexate

May decrease the serum concentration of Sapropterin. Specifically, pralatrexate may decrease tissue concentrations of tetrahydrobiopterin.

• Primidone

May decrease the serum concentration of Sapropterin

• Trimethoprim

May decrease the serum concentration of Sapropterin. Specifically, trimethoprim may decrease tissue concentrations of tetrahydrobiopterin.

• Valproate Products

May decrease the serum concentration of Sapropterin. Specifically, valproate products may decrease tissue concentrations of tetrahydrobiopterin.

The common side effects of Sapropterin include the following

• Common side effects

Diarrhea, nausea, vomiting, stomach pain, headache, cough, throat pain, or cold symptoms, fidgeting, moving around, or talking too much.

• Rare side effects

Wheezing, Shortness of breath, Cough, flushing, Nausea, Rash, Pain in the upper abdominal area, Nausea, Vomiting, Black, Tarry or bloody stool, Vomiting blood

• Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies with sapropterin in pregnant women. An embryofetal development study with sapropterin dihydrochloride in rats using oral doses up to 3 times the maximum recommended human dose (MRHD) given during the period of organogenesis showed no effects. In a rabbit study using oral administration of sapropterin dihydrochloride during the period of organogenesis, a rare defect, holoprosencephaly, was noted at 10 times the MRHD. sapropterin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

It is not known whether sapropterin is present in human milk. Sapropterin is present in the milk of intravenously, but not orally, treated lactating rats. The developmental and health benefits of human milk feeding should be considered along with the mother’s clinical need for sapropterin and any potential adverse effects on the human milk-fed child from the drug or from the underlying maternal condition. Exercise caution when sapropterin is administered to a nursing woman.

• Pediatric Use

Children <7 years of age treated with doses of 20 mg/kg/day are at increased risk for low levels of blood PHE (hypophenylalaninemia).

• Geriatric Use

Clinical studies of sapropterin in patients with PKU did not include patients aged 65 years and older. It is not known whether these patients respond differently than younger patients.

Symptoms: Headache and dizziness.

Management: Symptomatic treatment.

Pharmacodynamic

Tetrahydrobiopterin (BH4) is used to convert several amino acids, including phenylalanine, to other essential molecules in the body including neurotransmitters. Tetrahydrobiopterin deficiency can be caused by mutations in GTP cyclohydrolase 1 (GCH1), 6-pyruvoyl-tetrahydropterin synthase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (PCBD1), 6-pyruvoyltetrahydropterin synthase (PTS), and quinoid dihydropteridine reductase (QDPR) genes. These genes make the enzymes that are critical for producing and recycling tetrahydrobiopterin. If one of the enzymes fails to function correctly because of a gene mutation, little or no tetrahydrobiopterin is produced. As a result, phenylalanine from the diet builds up in the bloodstream and other tissues and can damage nerve cells in the brain. High levels of phenylalanine can result in signs and symptoms ranging from temporary low muscle tone to mental retardation, movement disorders, difficulty swallowing, seizures, behavioral problems, progressive problems with development, and an inability to control body temperature

Pharmacokinetics

• Absorption

The Time to peak plasma concentration of Sapropterin is approximately 3-4 hours.

• Distribution

Sapropterin is distributed mainly to the kidneys, adrenal glands, spleen and liver.

• Metabolism and Excretion

Sapropterin is extensively metabolized in the liver by dihydrofolate reductase and dihydropteridine reductase to dihydrobiopterin and dihydroxanthopterin as main metabolites. It is mainly excreted via faeces urine (small amount).

• https://www.uptodate.com/contents/sapropterin-drug-information#F5568650
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf
• https://www.mims.com/philippines/drug/info/sapropterin?mtype=generic
• https://go.drugbank.com/drugs/DB00360
• https://www.drugs.com/mtm/sapropterin.html