Table 4 Recommended drugs and doses for BH4 disorders
From: Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies
| Â | Disorder | Starting dose | Doses | Target dose | Maximum dose | Management suggestion | Comment |
|---|---|---|---|---|---|---|---|
First line treatment | |||||||
Phe-reduced diet | All BH4D with HPA | Â | Â | Â | Â | Titrate Phe restriction according to Phe levels in DBS or plasma | Follow PKU national treatment recommendations Use either Phe reduced diet or Sapropterin dihydrochloride to control Phe levels |
Sapropterin dihydrochloride | All BH4D with HPA apart from DHPRD | 2-5 mg/kg BW/day | Divided in 1–3 doses/ day | 5–10 mg/kg BW/day | 20 mg/kg BW/day | Titrate dose according to Phe levels in DBS or plasma | Follow PKU national treatment recommendations Use either Phe reduced diet or Sapropterin dihydrochloride to control Phe levels |
L-Dopa/DC inhibitor (carbidopa/benserazide) 4:1 | All BH4D apart from PCDD | 0.5 mg–1 mg/kg BW/day Dose recommendation relates to L-Dopa component! | Divided in 2–6 doses/ day | AD-GTPCHD: 3–7 mg/kg BW/day All other BH4D: 10 mg/kg BW/day or maximally tolerated dosage Dose recommendation relates to L-Dopa component! | Depending on clinical symptoms. Some patients need more than 10 mg/kg BW/day for resolving clinical symptoms | Increase 0.5–1 mg/kg BW/day per week Follow BW adaption until the BW of 40 kg. After 40 kg adjust depending on clinical symptoms Consider analysis of CSF HVA for dose adjustment | In young infants at least as many dosages as meals would be ideal (usually 5–6 /day) |
5-Hydroxytryptophan (5-HTP) | All BH4D apart from AD-GTPCHD and PCDD | 1–2 mg/kg BW/day | Divided in 3–6 doses/day | Published target dose recommendations are highly variable 5-HTP doses are usually lower than L-Dopa doses |  | Titrate slowly (1–2 mg/kg BW/day per week) depending on clinical picture and side effects Consider analysis of CSF 5HIAA for dose finding | 5-HTP should follow L-Dopa/DCI treatment initiation Always in combination with a peripheral decarboxylase inhibitor (for example by simultaneous application with L-Dopa/DC inhibitor) |
Folinic acid | In DHPRD and all BH4D with low 5-MTHF in CSF |  | Divided in 1–2 doses/day | 10–20 mg/day |  | No titration needed Consider analysis of CSF 5MTHF for dose finding |  |
Second line treatment | |||||||
Pramipexolea (Dopamine agonist) | All BH4D apart from PCDD | 3.5–7 μg/kg/BW/day (base) 5–10 μg/kgBW/day (salt) Note: Distinction in salt and base content! (see product insert) | Divided in 3 equal doses/day | Titrate to clinical Symptoms | 75 μg/kg BW/day (3.3 mg/d base / 4 mg/d salt) | Increase every 7 days by 5 μg/kg BW/d |  |
Bromocriptinea (Dopamine agonist) | All BH4D apart from PCDD | 0.1 mg/kg BW/day | Divided in 2–3 doses/day | Titrate to clinical Symptoms | 0.5 mg/kg/d (or 30 mg/d) | Increase every 7 days by 0.1 mg/kg BW/d |  |
Rotigotinea (transdermal dopamine agonist) | All BH4D apart from PCDD | 2 mg/day |  | Titrate to clinical Symptoms | 8 mg/day | Increase weekly by 1 mg | Children > 12 years Exchange patch every 24 h |
Selegilinea (MAO B inhibitor) | All BH4D apart from PCDD | 0.1 mg/kg BW/day ATTENTION: orally disintegrating preparation needs much less dosage because of missing first-pass effect in the liver | Divided in 2 (−3) doses/day | Titrate to clinical Symptoms | 0.3 mg/kg/d (or 10 mg/d) | Increase every 2 weeks by 0.1 mg/kg BW/d | Can cause sleep disturbances – morning and afternoon or lunchtime dosage is possible ATTENTION: orally disintegrating preparation needs much less dosage because the first-pass effect of the liver is avoided |
Third line treatment | |||||||
Trihexyphenidyla (Anticholinergic drugs) | All BH4D apart from PCDD | < 15 kg: start 0.5–1 mg/day > 15 kg: start 2 mg/day | < 15 kg: in 1 dose > 15 kg: in 2 doses | Effective dose highly variable (6–60 mg) Titrate to clinical Symptoms | Maximum dose: < 15 kg BW 30 mg/day > 15 kg BW 60 mg/d | Increase every 7 days by 1–2 mg/d in 2–4 doses/d | Consider side effects: like dry mouth, dry eyes, blurred vision (mydriasis), urine retention, constipation. |
Entacaponea (COMT inhibitor) | All BH4D apart from PCDD | 200 mg (adult) |  |  | Up to 2.000 mg |  | In many countries licensed only for adults. Comedication with L-Dopa/DC inhibitor Consider reduction of concomitant L-Dopa supplementation (10–30%) |
Sertalinea (SSRI) | All BH4D apart from PCDD | 6–12 years: 25 mg/day in 1 dose > 12 years: 50 mg/day in 1 dose | 6–12 years: in 1 dose > 12 years: in 1 dose | Children 50 mg/day | 50 mg/day < 12 years 200 mg/day > 12 years | 6–12 years: increase after 7 days to 50 mg/day in 1 dose > 12 years 50 mg/day in 1 dose | Don’t stop treatment suddenly Note: Elevated risk of serotonin syndrome (SS) or malignant neuroleptic syndrome (MNS) when used with drugs impacting serotonergic pathway (e.g. 5-HTP, MAO inhibitors) |
Melatonina | All BH4D apart from PCDD | 0.01–0.03 mg/kg/day |  |  | 5–8 mg/day |  | Slow release preparation for sleep-maintenance insomnia available in some countries |