Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

all patients

1st line – dietary therapy

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1st line – 

dietary therapy

Involves restriction of dietary protein and phenylalanine (phe) intake, and supplementation of all other amino acids in the form of specialized formulas or other dietary products. In infancy, this is achieved by providing the infant with a special phe-free formula supplemented with either breast milk or standard infant formula to supply the daily phe requirement. Phe-free formula is readily available by prescription, and is typically only prescribed by metabolic physicians.

Older children continue to drink a special phe-free product to provide their protein and calorie requirements, but obtain their limited prescribed daily phe requirement from food, including measured amounts of fruits and vegetables.

All meats, dairy products, rice, pasta, and commercial baked goods are restricted from the diet of patients with classical PKU. Patients with milder forms of the disorder require a less restrictive diet. The diets of patients with PKU should be carefully monitored by assessment of diet diaries, measurements of growth parameters, and laboratory studies, when indicated, to assure that patients are receiving adequate calories, protein, and trace minerals.

Consider – sapropterin

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sapropterin

Treatment recommended for SOME patients in selected patient group

Prevalence of response to BH4 treatment in patients with PKU has been variable, depending on the study. Most of the patients who respond have mild to moderate PKU. Sapropterin may increase tolerance to phenylalanine (phe) and reduces phe blood concentrations, allowing a less restrictive diet in some people.[19]

As a result of improved blood phe control, treatment with BH4 can lead to improvement in neurocognitive outcome. In well-controlled patients started on BH4, diet liberalization is often possible.

Some patients with mild forms of PKU may be completely controlled with BH4 therapy alone, without the need for any dietary protein or phe restriction. Adverse effects are generally mild and self-limited.

Primary options

sapropterin: children and adults: 5-20 mg/kg/day orally

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Consider – pegvaliase

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pegvaliase

Treatment recommended for SOME patients in selected patient group

Pegvaliase (injectable pegylated phenylalanine ammonia lyase) is an enzyme present in plants and bacteria but not in humans or other mammals. It converts phenylalanine (phe) to ammonia and trans-cinnamic acid, which are easily excreted. It has been developed as enzyme substitution therapy for patients with PKU to provide an alternative mechanism for phe metabolism.[15]​

Pegvaliase is indicated for adolescent and adult patients, and allows many treated individuals to achieve normal or near normal blood phenylalanine levels, even on an unrestricted diet. Pegvaliase is indicated to reduce blood phe levels in patients who have uncontrolled blood phe levels >10 mg/dL on existing management. It is approved for use in adults in the US and in adolescents ≥16 years of age, and adults in Europe.

Patients previously treated with sapropterin are required to discontinue its use at least 14 days prior to the first dose of pegvaliase.

Hypersensitivity reactions, including anaphylaxis, occur commonly, probably because antibodies to the product are produced. Because of the serious risk of anaphylaxis, the labeling includes a warning and the product is available only through a restricted Risk Evaluation and Mitigation Strategy program, which includes certification and training of prescribers, certification of pharmacies, and certification and education of patients. Consider premedication with an antihistamine and/or antipyretic for hypersensitivity reactions. Administer the first dose under medical supervision and observe the patient for 60 minutes after injection. Auto-injectable epinephrine (adrenaline) must be prescribed and be available at all times for patients taking pegvaliase.[16]

Primary options

pegvaliase: adults: 2.5 mg subcutaneously once weekly for 4 weeks, followed by 2.5 mg twice weekly for 1 week, then 10 mg once weekly for 1 week, then 10 mg twice weekly for 1 week, then 10 mg four times weekly for 1 week, then 10 mg once daily for 1 week, then 20 mg once daily for at least 24 weeks, may increase to 40 mg once daily for at least 16 weeks, maximum 60 mg/day

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Consider – large neutral amino acids (LNAA)

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Consider – 

large neutral amino acids (LNAA)

Treatment recommended for SOME patients in selected patient group

LNAA share a common transporter with phe at the level of the blood-brain barrier. It has been suggested that treatment with LNAA could reduce brain phe levels and ameliorate symptoms in patients with PKU, without altering blood phe levels.[17]​ A different LNAA mixture may compete with phe for absorption at the intestinal level, leading to a reduction in the blood phe level.[18]​ Further data are needed to address the efficacy and safety of these products. It seems prudent to restrict their use to adolescent and adult patients whose disorder cannot be adequately controlled by dietary therapy or by tetrahydrobiopterin.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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