Active Ingredient: Pegvaliase
Pegvaliase is indicated for the treatment of patients with phenylketonuria (PKU) aged 16 years and older who have inadequate blood phenylalanine control (blood phenylalanine levels greater than 600 micromol/l) despite prior management with available treatment options.
For this indication, competent medicine agencies globally authorize below treatments:
For:
In case that patient age in years is ≥ 16, subcutaneous, 2.5 milligrams pegvaliase, once weekly, over the duration of 4 weeks. Afterwards, in case that patient age in years is ≥ 16, subcutaneous, 2.5 milligrams pegvaliase, 2 times weekly, over the duration of 1 week. Afterwards, in case that patient age in years is ≥ 16, subcutaneous, 10 milligrams pegvaliase, once weekly, over the duration of 1 week. Afterwards, in case that patient age in years is ≥ 16, subcutaneous, 10 milligrams pegvaliase, 2 times weekly, over the duration of 1 week. Afterwards, in case that patient age in years is ≥ 16, subcutaneous, 10 milligrams pegvaliase, 4 times weekly, over the duration of 1 week. Afterwards, in case that patient age in years is ≥ 16, subcutaneous, 10 milligrams pegvaliase, once daily, over the duration of 1 week. Afterwards, in case that patient age in years is ≥ 16, subcutaneous, 20 milligrams pegvaliase, once daily, over the duration of 12 to 24 weeks. Afterwards, in case that patient age in years is ≥ 16, subcutaneous, 40 milligrams pegvaliase, once daily, over the duration of 16 weeks. Afterwards, in case that patient age in years is ≥ 16, subcutaneous, 60 milligrams pegvaliase, once daily. The maximum allowed total dose is 60 milligrams pegvaliase daily.
Before initiating treatment, blood phenylalanine level must be obtained. Monitoring of blood phenylalanine level is recommended once a month.
Dietary phenylalanine intake should remain consistent until a maintenance dose is established.
The recommended starting dose of pegvaliase is 2.5 mg administered once per week for 4 weeks.
The dose should be escalated gradually based on tolerability to the daily maintenance dose required to achieve blood phenylalanine level of 120 to 600 micromol/l according to Table 1.
The maintenance dose is individualised to achieve patient’s blood phenylalanine control (i.e. a phenylalanine level between 120 to 600 micromol/l) taking into account patient tolerability to pegvaliase and dietary protein intake (see Table 1).
Table 1. Recommended dosing regimen:
| Dose1 administered subcutaneously | Duration prior to next dose increase | |
|---|---|---|
| Induction | 2.5 mg once weekly | 4 weeks2 |
| Titration | 2.5 mg twice weekly | 1 week2 |
| 10 mg once weekly | 1 week2 | |
| 10 mg twice weekly | 1 week2 | |
| 10 mg four times a week | 1 week2 | |
| 10 mg daily | 1 week2 | |
| Maintenance3 | 20 mg daily | 12 weeks to 24 weeks2 |
| 40 mg daily4 | 16 weeks2 | |
| 60 mg daily4 | Maximum recommended dose |
1 If blood phenylalanine levels are below 30 micromol/l, dietary protein intake should be increased to appropriate levels, and then, if needed, the dose of pegvaliase should be reduced.
2 Additional time may be required prior to each dose escalation based on patient tolerability with pegvaliase.
3 The maintenance dose is individualised to achieve blood phenylalanine levels between 120 to 600 micromol/l.
4 If multiple injections are needed for a single dose, injections should be administered at the same time of day and injection sites should be at least 5 cm away from each other. Doses should not be divided over the course of the day.
During titration and maintenance of pegvaliase treatment, patients may develop blood phenylalanine levels below 30 micromol/l. To manage hypophenylalaninaemia, dietary protein intake should be increased to appropriate levels, and then, if needed, the dose of pegvaliase should be reduced. In patients experiencing hypophenylalaninaemia despite appropriate levels of protein intake, dose reductions are expected to be most effective in managing hypophenylalaninaemia. Patients should be monitored every 2 weeks until blood phenylalanine levels are within a clinically acceptable range.
If hypophenylalaninaemia develops prior to reaching daily dosing, the dose may be reduced to the previous titration dose. If hypophenylalaninaemia develops once daily dosing is reached, the dose may be reduced by at least 10 mg decrements to achieve and maintain blood phenylalanine levels in the clinically acceptable range. In patients experiencing hypophenylalaninaemia on 10 mg/day, the dose may be reduced to 5 mg/day.
Subcutaneous use.
Due to the potential for an acute systemic hypersensitivity reaction, premedication prior to each dose is required during induction and titration (time prior to reaching blood phenylalanine levels less than 600 micromol/l while on a stable dose). Patients should be instructed to pre-medicate with an H1-receptor antagonist, H2-receptor antagonist, and antipyretic. During maintenance, premedication may be reconsidered for subsequent injections based on patient tolerability to pegvaliase.
Initial administration(s) should be performed under supervision of a healthcare professional and patients should be closely observed for at least 60 minutes following each of these initial injection(s).
Prior to first dose of pegvaliase, the patient should be trained on the signs and symptoms of an acute systemic hypersensitivity reaction and to seek immediate medical care if a reaction occurs, and how to properly administer adrenaline injection device (auto-injector or pre-filled syringe/pen).
Patients should be instructed to carry an adrenaline injection device with them at all times during pegvaliase treatment.
For at least the first 6 months of treatment when the patient is self-injecting (i.e. when administration is not under healthcare professional supervision), an observer must be present during and for at least 60 minutes after each administration.
After 6 months of pegvaliase treatment, the need for an observer may be reconsidered.
Re-administration following mild to moderate acute systemic hypersensitivity reactions: The prescribing physician should consider the risks and benefits of re-administering the medicinal product following resolution of the first mild to moderate acute systemic hypersensitivity reaction. Re-administration for the first dose must be done under supervision of a healthcare professional with the ability to manage acute systemic hypersensitivity reactions.
The recommended injection sites on the body are: the front middle of the thighs and the lower part of the abdomen except for 5 cm directly around the navel. If a caregiver is giving the injection, the top of the buttocks and the back of the upper arms are also appropriate injection sites.
Pegvaliase should not be injected into moles, scars, birthmarks, bruises, rashes, or areas where the skin is hard, tender, red, damaged, burned, inflamed, or tattooed. The injection site should be checked for redness, swelling, or tenderness.
Patients or a caregiver should be advised to rotate sites for subcutaneous injections. If more than one injection is needed for a single dose, each injection site should be at least 5 cm away from another injection site.
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