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Table 4 Recommended drugs and doses for BH4 disorders

From: Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies

  Disorder Starting dose Doses Target dose Maximum dose Management suggestion Comment
First line treatment
Phe-reduced diet All BH4D with HPA      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
  1. Please note: The doses given are in a range typically used and have been published. In individual patients, some adjustment may be necessary depending on symptom response and side effects
  2. aThe evaluated literature did not provide BH4D specific treatment dose recommendations for this drug. The listed doses, therefore, indicate treatment recommendations from Summary of Product Characteristics (SmPC) or neurotransmitter related publications (e.g. [119])
  3. Abbreviations: 5-HIAA 5-hydroxyindoleacetic acid, 5-HTP 5-hydroxytryptophan, 5-MTHF 5- methyltetrahydrofolate, HVA Homovanillic acid, AD-GTPCHD Autosomal-dominant GTPCHD: guanosine triphosphate cyclohydrolase I deficiency, BH4D Tetrahydrobiopterin deficiency, BW Body weight, COMT Catechol-O-methyl transferase, CSF Cerebrospinal fluid, DBS Dry blood spot, DC Decarboxylase, DCI Decarboxylase inhibitor, DHPRD Dihydropterin reductase deficiency, L-Dopa L-3,4-dihydroxyphenylalanine, MAO B Monoamine oxidase B, PCDD Pterin-4-alpha-carbinolamine dehydratase deficiency, Phe Phenylalanine, PKU Phenylketonuria, SSRI Selective serotonin reuptake inhibitor