Appendix A: Medications Used in the Treatment of Inborn Errors JH Walter and JE Wraith J.-M. Saudubray et. al (Eds.), Inborn Metabolic Diseases, DOI 10.1007/978-3-642-15720-2, © Springer- Verlag Berlin Heidelberg 2012 626 Appendix A · Medications Used in the Treatment of Inborn Errors Medication Mode of action Disorders Recommended dose Route Remarks Chapters Agalsidase Recombinant analogue of Fabry disease 0.2 mg/kg alt weeks IV 40 alfa (Repla- human α-galactosidase gal) A manufactured by gene activation in human fibro- blast cell line Agalsidase Recombinant analogue of Fabry disease 1.0 mg/kg alt weeks IV 40 beta (Fabra- human α-galactosidase A zyme) manufactured in Chinese Hamster Ovary (CHO) cell line Aglucosi- Recombinant analogue Pompe disease 20 mg/kg alt weeks IV 6 dase alfa of human α-glucosidase (Myozyme®) manufactured in Chinese Hamster Ovary (CHO) cell line AllopurinolXanthine-oxidase inhibitor Disorders leading Initial dosage 10-20 Oral36 to hyperuricaemia mg/kg per day in chil- (PRPP synthetase dren and 2-10 mg/kg superactivity; HGPRT per day in adults deficiency) and APRT deficiency Ammonium Chelating agent Wilson’s disease 160 mg/d in 6 divided Oral38 tetrathiomo- doses lybdate Betaine Remethylates hct to meth Classic homocysti- 100-150 mg/kg/day in Oral21 nuria two to three divided Remethylation de- doses, max. dose 6-9 fects g/d Biotin Co-factor for carboxylases Biotinidase defi- 5-20 mg/d Oral or 27 Treatment of presumed ciency, IV 2 transporter defect Multiple carboxylase deficiency Biotin-responsive basal ganglia disease Chenode- Inhibits cholesterol 7a- 3β-Dehydrogenase 3β-D: 12-18 mg/kg/d Oral34 oxycholic hydroxylase (rate-limiting def (3β-D); for first 2 months then acid enzyme in bile acid biosyn- Δ4-3-Oxosteroid 5β- 9-12 mg/kg/d; 3-ORD thesis) reductase deficiency :8 mg/kg/day; CTX: 750 (3-ORD); Cerebroten- mg/day (adults) dinous xanthomato- sis (CTX) CholesterolReplenishes cholesterolSmith-Lemli-Opitz 20-40 mg/kg/d in 3-4 Oral33 (SLO) syndrome divided doses Cholesty- Bile acid sequestrant Familial hypercholes- Adults: 12-24 g /d OralPossible 32 ramine terolaemia children: (wt in kg/70 vitamin A, D, x adult dose ) in four and K defi- divided doses ciency with prolonged treatment. Other bile acid resins include colestipol & colesevalam 627 Appendix A · Medications Used in the Treatment of Inborn Errors Medication Mode of action Disorders Recommended dose Route Remarks Chapters Cholic acidΔ4-3-Oxosteroid 5β- 8 mg/kg/day Oral33 reductase deficiency (3-ORD) Copper Increases intracellular Menkes disease 100-200 μg Cu/d (new- SC 38 histidine copper born) 1 mg Cu/d in older children Creatine Replenishes creatine Guanidinoacetate 300-400 mg/kg/d in Oral16 monohy- methyltransferase three to six divided drate (GAMT) deficiency doses arginine:glycine amidinotransferase (AGAT) deficiency Cyclic pyra- Replenishes deficient prod- Molybdenum co- 80-160 mg/kg/d IV 36 nopterin uct to allow production of factor deficiency monophos- molybdenum co-factor type A phate (cPMP) Cysteamine/ Depletes lysosomal cystine Cystinosis 1.3 g/m2/day of free- Oral Phospho- 43 phospho- base), given every 6 h and eye cysteamine cysteamine drops more palat- able Dextro- NMDA channel antagonist NKH 5-7 mg/kg/d in four Oral Doses up to 24 methorphan divided doses 35/mg/d have been used Diazoxide Inhibits insulin secretion Persistent hyperinsu- 15 mg/kg/d (newborn); Oral10 linism 10 mg/kg/d (infants), in three divided doses Dichloroac- Stimulates PDH activity by Primary lactic aci- 50 mg/kg/d in 3-4 di- Oral May cause 12 etate inhibiting PDH kinase dosis vided doses polyneurop- athy with prolonged use Entacapone Prevents the peripheral Disorders of BH4 15mg/kg/d in two to Oral17 breakdown of l-dopa synthesis three divided doses Ezetimibe Inhibits cholesterol absorp- Familial hypercholes- 10 mg/d Oral32 tion terolaemia Folinic acidProvides accessible source DHPR deficiency, 5-15 mg/d Oral, IV 17, 28 of folate for CNS UMP synthase defi- ciency (hereditary orotic aciduria), Methylene synthase deficiency, Methionine synthase deficiency, Hereditary folate ma- labsorption, Some disorders of cobalamin metabo- lism, Cerebral folate trans- porter 628 Appendix A · Medications Used in the Treatment of Inborn Errors Medication Mode of action Disorders Recommended dose Route Remarks Chapters Galsulfase Recombinant analogue Mucopolysacchari- 1.0 mg/kg per weekIV 40 (Naglazyme) of human N-acetylga- dosis type VI lactosamine 4 sulfatase manufactured in Chinese Hamster Ovary (CHO) cell line GemfibrozilFibrates decrease TG levels; Mixed or combined Adult dose: 1.2 g daily, OralCan cause a 32 other fibrates include beza- hyperlipidaemia usually in two divided myositis-like fibrate and fenofibrate doses; range 0.9–1.5 g syndrome, daily especially with impaired renal function; combination with a statin increases risk of rhabdomy- olysis G-CSF Stimulates granulocyte Neutropenia in GSD 5 μg/kg once daily SC 6 production Ib, Ic Glycine Forms isovalerylglycine Isovaleric acidaemia 150 mg/kg/d in three OralUp to 600 mg/ 19 with high renal clearance divided doses kg/d during decompensa- tion Haem Inhibits 5-aminolevulinic Acute porphyrias 3-4 mg/kg once daily IV 37 arginate acid synthase for 4 days Hydroxoco- Co-factor for methylmalo- Disorders of cobala- 1 mg IM daily; oral IM or Dose may 19, 28 balamin nyl mutase min metabolism dose 10 mg once or oral be reduced (vitamin B12) twice daily to once or twice weekly according to response 5-Hydroxy- Neurotransmitter replace- Disorders of neu- 1-2 mg/kg, increasing Oral Monitor CSF 17,29 tryptophan ment rotransmitter syn- gradually to 8-10 mg/ 5HIAA levels thesis kg in 4 divided doses Idursulfase Recombinant iduronate- MPS II 0.5 mg per kg by IV IV 40 (Elaprase®) 2-sulfatase produced in infusion weekly human cell line Imiglucerase Recombinant Gaucher disease Various regimens: IV 40 (Cerezyme) analogue of human 2.5 U/kg 3X per week β-glucocerebrosidase to manufactured in Chinese 60 U/kg per 2 weeks Hamster Ovary (CHO) line For type III Gaucher disease some clinicians recommend higher dosages: 120 U/kg per 2 weeks Ketamine N-Methyl-d-aspartate NKH 1-30 mg/kg/d in four Oral or 24 (NDMA) channel antago- divided doses IV nist l–Arginine Replenishes arginine; sub- Urea cycle disorders; 50-170 mg/kg (OCT Oral or IV loading 20 strate of nitrous oxide MELAS and CPS def) IV dose: (200 Up to 700 mg/kg in AL mg/kg) over & AS def 90 min 629 Appendix A · Medications Used in the Treatment of Inborn Errors Medication Mode of action Disorders Recommended dose Route Remarks Chapters Laronidase Recombinant ana- Mucopolysacchari- 100 U/kg per weekIV 40 (Aldura- logue of human α-l- dosis type I zyme) iduronidase manufac- tured in Chinese Ham- ster Ovary (CHO) line l-Carnitine Replenishes body stores; Primary and second- 100-200 mg/kg/d Oral or Do not use ra- 13, 19, ,23 Removes toxic acyl-CoA ary carnitine defi- IV cemix mixture intermediates from within ciencies the mitochondria l-Citrulline Replenishes citrulline and Used as an alterna- CPS & OCT def: 170 Oral 20, 26 arginine tive to arginine in mg/kg/day or 3.8 gm/ CPS def and OCT m2/day in divided dos- def; LPI es, LPI: 100 mg/kg/d in 3-5 doses l-Dopa Replacement of neu- Disorders of l-dopa 1-2 mg/kg increasing OralGive as l-do- 17,29 rotransmitters synthesis slowly to 10-12 mg/kg pa/carbidopa in four divided doses (1:10 or 1:5) Monitor CSF HVA levels l-Lysine-HCl Allows lysine absorption Lysinuric protein 20-30 mg/kg/day in Oral26 Intolerance three divided doses l-Serine Replenishes serine 3-Phosphoglycerate up to 600 mg/d in sic Oral25 dehydrogenase de- divided doses ficiency l-Tryptophan Increases kynurenic acid NKH 100 mg/kg/d in three Oral24 which is an endogenous divided doses antagonist of the NMDA receptor Magnesium Replenishes Mg Primary hypomagne- 0.5-1.5 ml/kg/d MgSO4 IV / oral38 saemia with second- 10% solution IV; oral ary hypocalcaemia maintenance 0.7-3.5 mmol/kg/d elemental Mg in three to five di- vided doses Mannose Improves glycosylation CDG Ib (PMI defi- 1 g /kg/d in five di- Oral Not of benefit 42 ciency) vided doses in CDG Ia Mercap- Chelating agent Cystinuria 15-20 mg/kg/d, up to Oral 26 topropio- max of 1,000 mg/d in nylglycine three divided doses (tiopronin) Metranida- Reduces propionate pro- Propionic and meth- 7.5-20 mg/kg once Oral19 zole duction by gut bacteria ylmalonic acidaemia daily Miglustat Inhibitor of glucosylcer- Gaucher disease; 100 mg TDSOralOnly recom- 39, 40 (Zavesca) amide synthase, the first neurological mani- mended for enzyme responsible for festations of NPC patients with glycosphingolipid (GSL) mild to mod- synthesis erate Gaucher disease who are unsuitable for enzyme replacement therapy. 630 Appendix A · Medications Used in the Treatment of Inborn Errors Medication Mode of action Disorders Recommended dose Route Remarks Chapters N-Carbam- Stimulates N-acetylgluta- N-Acetylglutamate 100-300 mg/kg/day in Oral 19, 20 oylgluta- mate synthase synthase deficiency, four divided doses mate Carbamoylphos- phate synthase defi- ciency Hyperammonaemia associated with or- ganic acidaemias Nicotin- Replenishes deficiency Hartnup disease 50-300 mg/day Oral26 amide state Nicotinic Inhibits the release of free Hyperlipidaemia (see Adult dose: 100– Oral32 acid (niacin) fatty acids from adipose Chapter 32 for indica- 200 mg 3 times daily, tissue; increases HDL- tions) gradually increased cholesterol over 2–4 weeks to 1–2 g three times daily NTBC (2-[2- Inhibits 4-hydroxyphe- Tyrosinaemia type I1 mg/kg in one to two OralCombine with 18 nitro-4-triflu- nylpyruvate