Sapropterin Dihydrochloride

SAPROPTERIN DIHYDROCHLORIDE- sapropterin dihydrochloride tablet
Par Pharmaceutical, Inc.

1 INDICATIONS AND USAGE

Sapropterin dihydrochloride tablets are indicated to reduce blood phenylalanine (Phe) levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). Sapropterin dihydrochloride tablets are to be used in conjunction with a Phe-restricted diet.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

Treatment with sapropterin dihydrochloride tablets should be directed by physicians knowledgeable in the management of PKU.

All patients with PKU who are being treated with sapropterin dihydrochloride tablets should also be treated with a Phe­ restricted diet.

Starting Dosage

Patients 1 month to 6 years: The recommended starting dose of sapropterin dihydrochloride tablets is 10 mg/kg taken once daily.

Patients 7 years and older: The recommended starting dose of sapropterin dihydrochloride tablets is 10 to 20 mg/kg taken once daily.

Dosage Adjustment

If a 10 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 10 mg/kg per day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg per day, the dose may be increased to 20 mg/kg per day. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg per day are non-responders and treatment with sapropterin dihydrochloride tablets should be discontinued in these patients.

If a 20 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 20 mg/kg per day for a period of 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride treatment and periodically during the first month. Treatment should be discontinued in patients who do not respond to sapropterin dihydrochloride tablets.

Once responsiveness to sapropterin dihydrochloride tablets has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg per day according to response to therapy. Periodic blood Phe monitoring is recommended to assess blood Phe control [see Warnings and Precautions (5.3)].

2.2 Preparation and Administration Instructions

Take Sapropterin dihydrochloride tablets orally with a meal to increase absorption, preferably at the same time each day. A missed dose should be taken as soon as possible, but two doses should not be taken on the same day.

Sapropterin Dihydrochloride Tablets

Sapropterin dihydrochloride tablets may be swallowed either as whole tablets or dissolved in 120 to 240 mL of water or apple juice and taken orally within 15 minutes of dissolution. It may take a few minutes for the tablets to dissolve. To make the tablets dissolve faster, tablets may be stirred or crushed. The tablets may not dissolve completely. Patients may see small pieces floating on top of the water or apple juice. This is normal and safe for patients to swallow. If after drinking the medicine patients still see pieces of the tablet in the container, more water or apple juice can be added to make sure all of the medicine is consumed. Sapropterin dihydrochloride tablets may also be crushed and then mixed in a small amount of soft foods such as apple sauce or pudding.

3 DOSAGE FORMS AND STRENGTHS

Sapropterin dihydrochloride tablets are for oral use. Each tablet contains 100 mg of sapropterin dihydrochloride (equivalent to 76.8 mg of sapropterin base). Tablets are off-white to light yellow, mottled, uncoated, round shaped tablets debossed with ‘P’ on one side and ‘720’ on other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions Including Anaphylaxis

Sapropterin dihydrochloride is not recommended in patients with a history of anaphylaxis to sapropterin dihydrochloride. 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 dihydrochloride in patients who experience anaphylaxis and initiate appropriate medical treatment. Continue dietary Phe restrictions in patients who experience anaphylaxis.

5.2 Gastritis

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

5.3 Hypophenylalaninemia

In clinical trials, some patients have experienced low blood Phe levels. Children younger than 7 years treated with sapropterin dihydrochloride doses of 20 mg/kg per day are at increased risk for low levels of blood Phe compared with patients 7 years and older [see Adverse Reactions (6.1)].

5.4 Monitor Blood Phe Levels During Treatment

Prolonged elevations in blood Phe 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 Phe that are too low have been associated with catabolism and protein breakdown. Active management of dietary Phe intake while taking sapropterin dihydrochloride is required to ensure adequate Phe control and nutritional balance. Monitor blood Phe levels during treatment to ensure adequate blood Phe level control. Frequent blood monitoring is recommended in the pediatric population [see Dosage and Administration (2.1)].

5.5 Identify Non-Responders to Sapropterin Dihydrochloride Treatment

Not all patients with PKU respond to treatment with sapropterin dihydrochloride. 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 dihydrochloride, 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 dihydrochloride [see Clinical Studies (14)].

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 dihydrochloride [see Dosage and Administration (2.1)].

5.6 Interaction with 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 patients who are receiving levodopa for change in neurologic status during treatment with sapropterin dihydrochloride [see Drug Interactions (7)].

5.7 Hyperactivity

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

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

PKU Clinical Studies

The safety of sapropterin dihydrochloride was evaluated in 7 clinical studies in patients with PKU (aged 1 month to 50 years) [see Clinical Studies (14)].

In Studies 1-4 (controlled and uncontrolled studies), 579 patients with PKU aged 4 to 49 years received sapropterin dihydrochloride in doses ranging from 5 to 20 mg/kg per day for lengths of treatment ranging from 1 to 164 weeks. The patient population was evenly distributed in gender, and approximately 95% of patients were Caucasian. The most common adverse reactions (≥4% of patients) were headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion.

The data described in Table 3 reflect exposure of 74 patients with PKU to sapropterin dihydrochloride at doses of 10 to 20 mg/kg per day for 6 to 10 weeks in two double-blind, placebo-controlled clinical trials (Studies 2 and 4).

Table 3 enumerates adverse reactions occurring in at least 4% of patients treated with sapropterin dihydrochloride in the double-blind, placebo-controlled clinical trials described above.

T able 3: Summary of Adverse Reactions Occurring in ≥4% of Patients in Placebo-Controlled Clinical Studies with Sapropterin Dihydrochloride

Me d DRA Preferred Term

T re atment

Sapropterin Dihydrochloride (N=74)

P lacebo

( N=59)

No. Patients (%)

No. Patients (%)

Headache

11 (15)

8 (14)

Rhinorrhea

8 (11)

0

Pharyngolaryngeal pain

7 (10)

1 (2)

Diarrhea

6 (8)

3 (5)

Vomiting

6 (8)

4 (7)

Cough

5 (7)

3 (5)

Nasal congestion

3 (4)

0

In open-label, uncontrolled clinical trials (Studies 1 and 3) all patients received sapropterin dihydrochloride in doses of 5 to 20 mg/kg per day, and adverse reactions were similar in type and frequency to those reported in the double-blind, placebo-controlled clinical trials [see Clinical Studies (14)].

In Study 5, 65 pediatric patients with PKU aged 1 month to 6 years received sapropterin dihydrochloride 20 mg/kg per day for 6 months. Adverse reactions in these patients were similar in frequency and type as those seen in other sapropterin dihydrochloride clinical trials except for an increased incidence of low Phe levels.

Twenty-five percent (16 out of 65) of patients developed Phe levels below normal for age [see Warnings and Precautions (5.3), Pediatric Use (8.4), and Clinical Studies (14)].

In Study 6, a long term, open-label, extension study of 111 patients aged 4 to 50 years, receiving Sapropterin dihydrochloride in doses ranging from 5 to 20 mg/kg per day, adverse reactions were similar in type and frequency to those reported in the previous clinical studies. Fifty-five patients received Sapropterin dihydrochloride both as dissolved and intact tablets. There were no notable differences in the incidence or severity of adverse reactions between the two methods of administration. The mean (± SD) exposure to sapropterin for the entire study population was 659 ± 221 days (maximum 953 days).

In Study 7, 27 pediatric patients with PKU aged 0 to 4 years received sapropterin dihydrochloride 10 mg/kg per day or 20 mg/kg per day. Adverse reactions were similar in type and frequency to those observed in other clinical trials, with the addition of rhinitis, which was reported in 2 subjects (7.4%).

Safety Experience from Clinical Studies for Non-PKU Indications

Approximately 800 healthy volunteers and patients with disorders other than PKU, some of whom had underlying neurologic disorders or cardiovascular disease, have been administered a different formulation of the same active ingredient (sapropterin) in approximately 19 controlled and uncontrolled clinical trials. In these clinical trials, subjects were administered sapropterin at doses ranging from 1 to 100 mg/kg per day for lengths of exposure from 1 day to 2 years.

Serious and severe adverse reactions (regardless of causality) during sapropterin administration were convulsions, exacerbation of convulsions [see Warnings and Precautions (5.6)] , dizziness, gastrointestinal bleeding, post-procedural bleeding, headache, irritability, myocardial infarction, overstimulation, and respiratory failure. Common adverse reactions were headache, peripheral edema, arthralgia, polyuria, agitation, dizziness, nausea, pharyngitis, abdominal pain, upper abdominal pain, and upper respiratory tract infection.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2020. All Rights Reserved.