Sapropterin Dihydrochloride - Indications, Dosage, and Side Effects

Overview

Sapropterin is a medicine used to lower blood phenylalanine (Phe) levels in adults and children aged one month and older who have phenylketonuria (PKU). This genetic disorder causes increased phenylalanine levels in the blood. It is taken in conjunction with a restricted diet. PKU can cause irreparable brain damage in newborns and children and impair adult brain function. Sapropterin increases the amount of BH4, a coenzyme that activates the PAH enzyme, which processes and regulates blood phenylalanine levels. The goal of Sapropterin medication with a protein-limited diet is to keep blood phenylalanine levels stable, minimize PKU symptoms and problems, and possibly facilitate a less restricted diet. In 2007, the US Food and Drug Administration (FDA) approved Sapropterin dihydrochloride for the treatment of phenylketonuria (PKU) and hyperphenylalaninemia (HPA). BH4 in the form of Sapropterin dihydrochloride facilitates the breakdown of phenylalanine. It works together with a Phe-restricted diet to lower blood phenylalanine levels.

Drug Group

Sapropterin dihydrochloride is a cofactor that aids phenylalanine restriction in treating phenylketonuria. It is also referred to as a phenylalanine hydroxylase activator. Tyrosine is produced when the enzyme phenylalanine hydroxylase hydroxylates the phenylalanine aromatic side chain. By attaching itself to an enzyme's activation site and blocking hydroxylation, phenylalanine functions as an activator.

Indications

Sapropterin dihydrochloride is a phenylalanine hydroxylase activator used to treat hyperphenylalaninemia (HPA) caused by tetrahydrobiopterin- (BH4)-responsive phenylketonuria (PKU) in adults and children aged one month and older. Sapropterin dihydrochloride should be combined with a Phe-restricted diet.

Contraindications

None.

Dosage Forms and Available Strengths

There are two forms of Sapropterin dihydrochloride available: tablets and powder. Each tablet contains 100 mg (milligrams) of Sapropterin dihydrochloride, while the powdered form for oral solution includes 100 mg and 500 mg.

Warnings and Precautions

• Hypersensitivity Reactions: Due to the risk of hypersensitivity events, including anaphylaxis (a severe, potentially fatal allergic reaction that can rapidly occur following exposure to an allergen), Sapropterin dihydrochloride is not indicated for individuals with a history of anaphylaxis. Wheezing, dyspnea (difficulty breathing), coughing, low blood pressure, flushing, nausea, and rash are all signs of anaphylaxis. Patients experiencing anaphylaxis should stop using Sapropterin dihydrochloride and continue to limit their protein and Phe intake.

• Upper Gastrointestinal Mucosal Inflammation: Sapropterin dihydrochloride has been associated with GI side effects such as esophagitis (the inflammation in the throat-to-gastric tube (esophagus)) and gastritis (a condition characterized by inflammation of the stomach's lining.). If not addressed, these can lead to serious problems such as esophageal stricture, esophageal ulcer, stomach ulcer, and hemorrhage (the sudden release of blood from a ruptured blood vessel, either within or outside the body). It is critical to look for signs and symptoms of upper gastrointestinal mucosal inflammation in patients.

• Hyperphenylalaninemia: Clinical trials using Sapropterin dihydrochloride have revealed that some PKU patients, particularly children under seven years old, may have hyperphenylalaninemia as compared with older individuals who received 20 mg/kg (milligrams per kilogram) per day.

• Monitoring Blood Phe Levels During Treatment: Prolonged Phe levels in the blood can cause significant brain damage in PKU patients, including intellectual impairment, developmental delay, and behavioral problems. Low levels, on the other hand, might cause catabolism and endogenous protein breakdown, resulting in negative developmental effects. For appropriate control and nutritional balance when taking Sapropterin dihydrochloride, active management of dietary Phe intake is required. Frequent blood testing is advised, particularly in the pediatric group.

• Lack of Biochemical Response: Some PKU patients do not respond biochemically to Sapropterin dihydrochloride treatment. In two clinical trials, 56 to 75 percent of pediatric PKU patients demonstrated a biochemical response, whereas 20 percent of adult and pediatric PKU patients showed a response in one experiment. The biochemical response of Sapropterin dihydrochloride therapy cannot be determined in the laboratory and must be studied in a clinical study.

• Interaction with Levodopa: Three patients with neurological diseases reported seizures, aggravation, over-stimulation, and irritability with co-administration of Levodopa and Sapropterin during a 10-year safety surveillance program. It is suggested that patients using Levodopa be monitored for changes in the neurological state during Sapropterin dihydrochloride treatment.

• Hyperactivity: Two individuals with PKU exhibited hyperactivity while taking Sapropterin dihydrochloride, emphasizing the importance of monitoring and treating side effects.

For Patients

What Is Phenylketonuria?

Phenylketonuria (PKU) is an uncommon genetic disorder in which the body accumulates phenylalanine due to a mutation in the phenylalanine hydroxylase (PAH) gene. If the individual with PKU consumes protein-rich foods or aspartame, this can cause major health concerns. People with PKU must limit the intake of phenylalanine, which is abundant in protein-rich foods. PKU, if left untreated, can produce mild to severe symptoms such as a musty odor, neurological issues, skin rashes, and intellectual impairment.

How Does Sapropterin Dihydrochloride Work?

The synthetic version of 6R-tetrahydrobiopterin (6R-BH4), the cofactor for phenylalanine hydroxylase, is Sapropterin dihydrochloride. This enzyme is in charge of converting the amino acid phenylalanine into tyrosine. This enzyme is defective or missing in people with phenylketonuria (PKU), resulting in excessive levels of phenylalanine in the blood. Sapropterin dihydrochloride works by increasing BH4, boosting the phenylalanine hydroxylase enzyme, lowering phenylalanine concentration, and treating PKU symptoms.

What Are the Clinical Uses of Sapropterin Dihydrochloride?

Sapropterin dihydrochloride is a prescription medicine used to treat phenylketonuria (PKU) and hyperphenylalaninemia (HPA) caused by tetrahydrobiopterin- (BH4)-responsive phenylketonuria (PKU) in adults and children one month of age and older. It is used along with a low-Phe diet. However, treatment does not eliminate the need for continuous nutritional monitoring.

What Is the Dosage of Sapropterin Dihydrochloride?

• Patients with PKU who are using Sapropterin dihydrochloride should also adhere to a Phe-restricted diet, which includes dietary protein and Phe restriction.

• A daily dose of 10 mg/kg is advised for pediatric patients aged one month to six years. The suggested dose for individuals aged seven and up is 10 to 20 mg/kg administered daily. Dosage modifications are possible between five and 20 mg/kg.

• Blood Phe levels should be checked regularly, especially in pediatric patients. Sapropterin dihydrochloride should be consumed with a meal and can be consumed whole or blended with soft foods or liquids.

What Are the Side Effects of Sapropterin Dihydrochloride?

Sapropterin may induce negative effects. Inform the doctor if any of the following problems are severe or fail to go away:

• Diarrhea.

• Nausea.

• Vomiting.

• Stomach ache.

• Headache.

• Cough, throat soreness, or cold symptoms.

• Fidgeting, moving around, or excessive talking.

Certain negative consequences can be severe. If patients experience any of the following symptoms, contact the doctor right away:

• Wheezing, shortness of breath, coughing, flushing, nausea, and rash.

• Upper abdominal area ache, nausea, vomiting, black, tarry, or bloody feces, vomiting blood.

Other negative effects of Sapropterin may occur. If patients have any odd side effects while taking this medicine, contact the doctor immediately.

What Are the Things to Inform the Doctor Before Taking Sapropterin Dihydrochloride?

• Tell the doctor and pharmacist if patients have been allergic to Sapropterin or any other medications before using it.

• Inform the pharmacist and doctor about any prescription or over-the-counter (OTC) drugs, vitamins, nutritional supplements, and herbal products patients take or plan to use. Mention Levodopa, Methotrexate, and PDE5 inhibitors like Sildenafil, Tadalafil, and Vardenafil, as well as Proguanil, Pyrimethamine, and Trimethoprim. The physician might need to constantly check for Sapropterin dihydrochloride adverse effects or modify the dosages of medications.

• Inform the doctor if patients are currently or previously suffering from anorexia (an eating illness in which people eat too little and or exercise too much to keep up even the bare minimum body weight regarded as normal for the individual's age and height) or any other condition that causes malnutrition or liver or kidney disease.

• Inform the doctor if patients develop a fever or become ill at any point throughout their treatment. Because fever and illness might impact the phenylalanine level, the doctor might have to adjust the Sapropterin dose.

• Inform the doctor if the patient is pregnant, intends to become pregnant, or is currently breastfeeding. Call the doctor if patients get pregnant while taking Sapropterin.

Dietary Considerations

Follow a low-phenylalanine diet while taking Sapropterin, and carefully follow the doctor's and nutritionist's advice. Before making any dietary changes, consult with the doctor.

Missed Dose

If a patient remembers missing a dosage, it is better to take it immediately. Patients should omit the missed dose and continue with the regular dosing schedule the next day if they forget. Take up to one or two doses daily to make up for a missed one.

Overdose

In the event of a Sapropterin overdose, call the poison control helpline. If the person collapses, experiences a seizure, has difficulty breathing, or cannot be awakened, contact emergency services urgently.

Storage and Handling

Keep medication tightly covered, out of children's access, and in a cool, dry location away from heat and moisture. To absorb moisture, do not remove the material from its package. Dispose of unused prescriptions in certain ways to keep pets, children, and others from eating drugs. Dispose of medications through a drug take-back program, which people may find by talking with the pharmacist or the nearby garbage or recycling department. Keep medication out of children's sight and reach, as many packages are not child-resistant and can be readily opened by little children. Always lock the safety caps and keep the medication up, out of sight, and out of reach of children.

For Doctors

Pharmacodynamics

Blood Phe levels in PKU patients who respond to BH4 treatment decline within 24 hours of a single dose of Sapropterin dihydrochloride. A daily dose of Sapropterin dihydrochloride keeps blood Phe levels steady for 24 hours. Twelve patients with blood Phe levels of 516 to 986 µmol/L were monitored for 24 hours after receiving a daily morning dose of 10 mg/kg. Throughout the 24 hours, no significant increases in blood Phe levels were found. The dose of Sapropterin dihydrochloride and average blood Phe levels were inversely related in an open-label, forced titration research. A dose-related shortening of the QT interval was seen in a cardiac electrophysiological study of 56 healthy people, exhibiting a maximum placebo-subtracted average variation from baseline of the QTc interval of -3.69 and -8.32 ms (milliseconds) at 20 and 100 mg/kg, respectively.

Chemical Taxonomy

Sapropterin, also known as Tetrahydrobiopterin or BH4, is an important cofactor in nitric oxide synthesis. It is required for phenylalanine-4-hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase conversions, such as phenylalanine to tyrosine, tyrosine to L-dopa, and tryptophan to 5-hydroxytryptophan.

Mechanism of Action

Tetrahydrobiopterin (BH4) is a naturally found cofactor or coenzyme for the enzymes phenylalanine-4-hydroxylase (PAH), tetrahydrobiopterin, and tryptophan-5-hydroxylase. It is required to metabolize phenylalanine to tyrosine, produce epinephrine, and form monoamine neurotransmitters such as serotonin, dopamine, and norepinephrine. BH4 also regulates apoptosis and other cellular activities mediated by nitric oxide generation. It interacts with molecular oxygen to generate an active oxygen intermediate capable of hydroxylation. BH4 aids in the reduction of phenylalanine levels in the bloodstream, thereby lowering its harmful effects. Normal serum phenylalanine values are 100 micromolars, but excessive levels are frequently greater than 1200 micromolars. Individuals who are deficient in tetrahydrobiopterin have difficulty converting phenylalanine to tyrosine. Excessive BH4 supplementation enhances enzyme efficiency. As an essential cofactor for tyrosine hydroxylase, BH4 allows tyrosine to be converted to L-dopa. Still, as a cofactor for tryptophan hydroxylase, BH4 allows tryptophan to be converted to 5-hydroxytryptophan, which is then turned into serotonin.

Pharmacokinetics

• Absorption: When paired with high-fat and calorie foods, Sapropterin dihydrochloride has increased absorption, while when consumed intact, it has increased absorption.

• Metabolism: Dihydrofolate reductase and dihydro pteridine reductase are involved in the metabolism and recycling of BH4, the active form of Sapropterin. The half-life elimination time is approximately 6.7 hours, ranging from 3.9 to 17 hours.

Toxicity

Sapropterin can induce headaches, diarrhea, vomiting, a runny nose, a sore throat, and a cough. It can cause serious side effects such as behavioral changes, seizures, speech problems, fever, loss of appetite, difficulty swallowing, throat soreness, stomach discomfort, nausea, vomiting, bloody stools, coughing up blood or vomit, and hyperactivity in some cases. These adverse effects can differ between people and may be influenced by age, weight, and overall health. It is critical to seek medical assistance if patients encounter any odd symptoms or side effects and consult healthcare experts for advice customized to their circumstances.

Drug Interactions

• Levodopa: In individuals getting Sapropterin dihydrochloride concurrently for a non-PKU condition, Sapropterin dihydrochloride can raise the level of tyrosine, a precursor of Levodopa, which might trigger neurologic complications.

• Inhibitors of Folate Synthesis: For example, Methotrexate, Valproic Acid, Phenobarbital, Trimethoprim, or the drugs that impede folate production may reduce endogenous BH4 bioavailability by blocking the enzyme dihydrofolate reductase, which plays a role in BH4 regeneration. Phe levels may rise due to this drop in net BH4 levels. Testing blood Phe levels more frequently while administering medication might be necessary.

• Drugs Affecting Nitric Oxide-Mediated Vasorelaxation: For example, PDE-5 Inhibitors Such as Sildenafil, Vardenafil, or Tadalafil or PDE-5 inhibitors and Sapropterin dihydrochloride both can promote vasorelaxation, which lowers blood pressure. However, the combined use of these drugs in people has yet to be studied. It is critical to keep a check on the level of blood pressure.

Clinical Studies

The study examined five clinical studies involving PKU patients to see how effective Sapropterin dihydrochloride was.

• The first trial included 489 patients aged eight to 48 years with baseline blood Phe levels above or above 450 mol/L. Each patient was administered Sapropterin dihydrochloride (10 mg/kg daily) for eight days. A response was defined as a decrease of thirty percent in blood Phe, and on day eight, 20 percent of patients were designated as responders.

• A study was done with 88 individuals suffering from PKU who reacted to Sapropterin dihydrochloride in Study 1. Patients were randomized to receive Sapropterin dihydrochloride (10 mg/kg per day) or a placebo for six weeks after a washout period. The efficacy of the Sapropterin dihydrochloride treatment was assessed by comparing the average change in blood Phe levels between the treatment group and the placebo group from baseline to week six. The mean Phe level at baseline was 843 mol/L (moles/liter) in the group treated with Sapropterin dihydrochloride and 888 mol/L in the placebo group. Week 6 Phe levels were 607 mol/L in the group treated with Sapropterin dihydrochloride and 891 mol/L in the placebo group. A statistically significant difference existed between the groups (p 0.001).

• The trial included 80 patients who completed Trial 2 after responding to the Sapropterin dihydrochloride treatment in Study 1. Six weeks of forced dose titration with three distinct dosages of Sapropterin dihydrochloride were followed by three two-week courses at various doses. After two weeks of treatment, blood Phe levels were measured at each dose level. The mean blood Phe levels were 844 mol/L at the initial phase of treatment and 744 mol/L at the end.

• Ninety juvenile PKU patients, ages 4 to 12, who were on Phe-restricted diets and exhibited blood Phe levels of 480 mol/L at screening were involved in a multicenter study. Patients received eight days of open-label treatment with Sapropterin dihydrochloride (20 mg/kg daily). A 30 percent drop in blood Phe from baseline was seen on Day 8 as a reaction to Sapropterin dihydrochloride.

• Ninety-three pediatric PKU patients with Phe levels greater than or equal to 360 mol/L at screening were enrolled in Study 5, ranging in age from one month to six years. Every patient received a daily dosage of 20 mg/kg of Sapropterin dihydrochloride and was maintained on a Phe-restricted diet. Sixty-one percent of patients had been classified as responders by week four.

Use in Specific Populations

• Pregnancy: A pregnancy exposure register has been set up to track the results of pregnancies in women exposed to Sapropterin dihydrochloride. Sapropterin dihydrochloride has not been linked to any significant birth abnormalities, miscarriages, or unfavorable outcomes for either the mother or the fetus. However, Sapropterin dihydrochloride did not influence embryo-fetal development in research conducted on rats. Holoprosencephaly, an uncommon abnormality, was observed in rabbit research at ten times the maximum recommended human dose (MRHD). Pregnancy loss, severe birth abnormalities, and other unfavorable pregnancy outcomes are inherent risks of every pregnancy. Uncontrolled blood levels of phenylalanine, both before and during pregnancy, are linked to a higher risk of unfavorable outcomes for the fetus. Reducing the likelihood of Phe-induced teratogenic consequences during pregnancy requires strict control of blood phenylalanine levels.

• Breastfeeding: Human milk does not contain enough sapropterin, and there have been no reports of lactation-related safety issues with newborns whose mothers were receiving Sapropterin dihydrochloride therapy. The mother's clinical requirements and any possible negative effects should be considered, in addition to the benefits of breastfeeding for development and health.

• Pediatric Use: In clinical studies, pediatric PKU patients between one month and sixteen are treated with Sapropterin dihydrochloride. Its safety and effectiveness for newborns are unknown. Through up to three years of testing, safety of Sapropterin dihydrochloride has been proven safe in children under four. According to a multicenter, open-label, single-arm study, Sapropterin dihydrochloride alone is ineffective for lowering blood Phe levels for longer than four weeks.

• Geriatric Use: Patients 65 years of age and older were not included in clinical trials on Sapropterin dihydrochloride in PKU patients, and it is unknown if these people react differently.