1-07-a de 003 - protirelin - art 45 public ar

Protirelin DE/W/063/pdWS/001 /39

Public Assessment Report

for paediatric studies submitted in accordance with Article 45 of Regulation (EC) No1901/2006, as

amended

Protirelin/ synthetic TRH

Antepan

DE/W/063/pdWS/001

Rapporteur: Germany

Finalisation procedure (Day 120): 27.11.2013

Date of finalisation of PAR: 17.12.2013


TABLE OF CONTENTS

I. Executive Summary ....................................................................................................... 4

II. Recommendation ........................................................................................................... 4

III. INTRODUCTION .............................................................................................................. 4

IV. SCIENTIFIC DISCUSSION .............................................................................................. 5

IV.1 Information on the pharmaceutical formulation used in the clinical study(ies) ......... 5

IV.2 Non-clinical aspects .................................................................................................................... 5

IV.3 Clinical aspects .............................................................................................................. 7

V. Rapporteur’s Overall Conclusion AND RECOMMENDATION .................................... 29

VI. Assessment of response to questions ....................................................................... 31

VII. Final Rapporteur’s Overall Conclusion AND RECOMMENDATION .......................... 37

VIII. List of Medicincal products and marketing authorisation holders involved ............ 38


ADMINISTRATIVE INFORMATION

Invented name of the medicinal product(s):

Antepan

INN (or common name) of the active substance(s):

Protirelin

MAH (s): See section VIII

Pharmaco-therapeutic group (ATC Code):

V04CJ02

Pharmaceutical form(s) and strength(s):

See section VIII


I. EXECUTIVE SUMMARY SmPC and PL changes are proposed in sections 4.2 and the corresponding section of PL. Summary of outcome

No change X Change

New study data: <section(s) xxxx, xxxx>

New safety information: <section(s) xxxx, xxxx>

X Paediatric information clarified: section 4.2

New indication: <section(s) xxxx, xxxx>

II. RECOMMENDATION See section VII.

III. INTRODUCTION Sanofi-Aventis did not conduct any paediatric study(ies) for protirelin concerned by article 45 of the paediatric regulation. In order to respond to the request in relation to Article 45 of the Regulation (EC)No 1901/2006, as amended on medicinal products for paediatric use, the MAH conducted a literature search in DIMIDI (German search engine). The search terms were : protirelin, TRH, in juvenile, young or newborn animals, or in children or adolescents. 9 non-clinical and 72 clinical publications for the diagnostic use of protirelin /TRH were discovered. Publications on its use for therapeutic purposes were left out. A short critical expert overview has also been provided.

The MAH stated that the submitted paediatric publications do not influence the benefit risk for Antepan and that there is no consequential regulatory action. In addition, the following documentation has been included as per the procedural guidance:

- A line listing - A SPC wording

Assessor’s comment: The MAH’s effort to provide the requested information is acknowledged. However, the intention of article 45 is to conduct a complete review of the available paediatric information. Therefore publications on the therapeutic use of protirelin in the paediatric population should also be provided.


IV. SCIENTIFIC DISCUSSION

IV.1 Information on the pharmaceutical formulation used in the clinical study(ies) Antepan is licensed in children of all age groups as well as in adults as solution for injection (200 µg/ 1 ml) and as nasal spray (1mg/spray).

Assessor’s comment: Please note that protirelin and TRH are used synonymously in this report.

IV.2 Non-clinical aspects

1. Introduction

The applicant did not conduct non-clinical studies for protirelin concerned by article 45 of the paediatric regulation. A literature search, conducted by the applicant, for animal studies revealed 8 publications describing the in vivo TSH response to TRH in newborn or juvenile animals, of which 5 reported on rats and 3 on sheep and one in vitro study. List of references:

Gyves PW, Gesundheit N, Taylor T, Butler JB, Weintraub BD. Changes in thyrotropin (TSH) carbohydrate structure and response to TSH-releasing hormone during postnatal ontogeny: analysis by concanavalin-A chromatography. Endocrinology 1987 Jul;121(1):133-40. Macho L, Štrbák V. Comparison of the effect of TRH on plasma TSH level in young and adult rats. Endocrinol Exp 1979 Sep;13(3):139-44. Walker P, Coulombe P, Dussault JH. Effects of triiodothyronine on thyrotropinreleasing hormone-induced thyrotropin release in the neonatal rat. Endocrinology 1980 Dec;107(6):1731-7. Sowers JR, Resch G, Walker S, Sollars E. Developmental patterns of the hypothalamic-pituitary axis in the euthyroid and hypothyroid male rat. Neuroendocrinology 1980 May;30(5):257-61. Štrbák V, Greer MA. Thyrotropin secretory response to thyrotropin-releasing hormone in the hypothyroid perinatal rat: further evidence of thyrotroph independence of the hypothalamus during early ontogenesis. Endocrinology 1981 Apr;108(4):1403-6. Oliver C, Giraud P, Lissitzky JC, Contye-Devolx B, Gillioz P. Influence of thyrotropin-releasing hormone on the secretion of thyrotropin in neonatal rats. Endocrinology 1981 Jan;108(1):179-82. Sack J, Fisher DA, Grajwer LA, Lam RW, Wang CC. The response of newborn sheep to TRH with and without somatostatin. Endocrinology 1977 Jun;100(6):1533-8. Klein AH, Fisher DA. Thyrotropin-releasing hormone stimulated pituitary and thyroid gland responsiveness and 3,5,3'-triiodothyronine suppression in fetal and neonatal lambs. Endocrinology 1980 Mar;106(3):697-701. Peeters R, Buys N, Vanmontfort D, Van Isterdael J, Decuypere E, Kuhn ER. Preferential release of tri-iodothyronine following stimulation by thyrotrophin or thyrotrophin-releasing hormone in sheep of different ages. J Endocrinol 1992 Jan;132(1):93-100.


2. Non clinical studies The non-clincal studies are summarised in Table 1, in chronological order and grouped by species. The results of these studies are somewhat contradictory, but overall an age-dependent TSH-response to TRH-administration was observed, at least in rats. An in vitro study on the TSH-response to TRH-incubation of pituitaries from 5-day and 56-day old male Sprague-Dawley rats showed that in addition to the differential response to TRH between these ages, there are also differences in the TSH carbohydrate structure and secretion [2]. Table 1: Animal studies investigating the TSH-response to TRH administration in newborn or juveniles

Assessor’s comment: The applicant submitted 8 publications describing the in vivo TSH response to TRH in newborn or juvenile rats and sheep. These studies are only suitable to support the pharmacodynamic activity of the TRH-test in paediatrics. No non-clinical studies have been submitted which described the safety of protrelin in juvenile animals. However, since TRH tests have widely been used in the paediatric population there are sufficient data on the safety of proterelin in paediatric patients.

3. Discussion on non clinical aspects and conclusion


Considering the human paediatric data available (see chapter IV.3), the animal data do not appear to be clinically relevant, although they may have supported the paediatric use of the TRH-test at the time. From the clinical publications it is clear that TRH tests have widely been used in the paediatric population. Therefore, the animal studies are of minor relevance for this application.

IV.3 Clinical aspects

1. Introduction

Antepan solution for injection and Antepan nasal spray are licensed in Germany and Austria.

Data from table 2 of the expert overview

Antepan is indicated to perform TRH tests in the diagnosis of thyroid and pituitary dysfunction in all age groups. The MAH submitted 72 publications (see list of references below). These publications are discussed in the clinical studies section.

Assessor’s comment: The applicant’s efforts to comply with article 45 of the paediatric regulation and provide the available information is acknowledged. Some of the publications submitted in this regard date from the early days of TRH testing, some constitute a collection of case reports or deal with very special issues which will most likely not result in amendments to the SPC. Therefore and due to the higher number of publications, only short summaries are given here. Please feel free to contact us, if further information will be required.

List of references

Borkenstein M, Stoffler G, Stogmann W, Fueger G, Falk W. [Normal values for circulating thyroid hormones, T3 uptake and thyrotropin before and after TRH. Radioimmunoassay determinations on 182 euthyroid children (author's transl)]. Monatsschr Kinderheilkd 1980 Jun;128(6):422-7. Foley TP, Jr., Owings J, Hayford JT, Blizzard RM. Serum thyrotropin responses to synthetic thyrotropin-releasing hormone in normal children and hypopituitary patients. A new test to distinguish primary releasing hormone deficiency from primary pituitary hormone deficiency. J Clin Invest 1972 Feb;51(2):431-7. Zabransky S, Cunow E, Lengle D. [Optimal TRH-testdose in children: 1 microgram TRH/kg (i. v.) (author's transl)]. Padiatr Padol 1981;16(3):335-41. Delitala G, Meloni T, Masala A, Corti R. Thyrotropin, prolactin and growth hormone


response to synthetic thyrotropin-releasing hormone in newborn infants. Biol Neonate 1978;33(5-6):236-9. Jacobsen BB, Andersen H, Dige-Petersen H, Hummer L. Pituitary-thyroid responsiveness to thyrotropin-releasing hormone in preterm and small-for-gestational age newborns. Acta Paediatr Scand 1977 Sep;66(5):541-8. Zabransky S. TRH test dose in children. Lancet 1980 Oct 18;2(8199):864. Jacobsen BB, Andersen H, ge-Petersen H, Hummer L. Thyrotropin response to thyrotropin-releasing hormone in fullterm, euthyroid and hypothyroid newborns. Acta Paediatr Scand 1976 Jul;65(4):433-8. Rose SR, Nisula BC. Circadian variation of thyrotropin in childhood. J Clin Endocrinol Metab 1989 Jun;68(6):1086-90. Ruppert F, Adonyi M, Ertl T, Sulyok E, Zámbó K, Csaba IF, et al. Thyrotropin and prolactin response to thyrotropin-releasing hormone in healthy and asphyxiated fullterm neonates. Acta Paediatr Hung 1983;24(2):111-8. Cavagnini F, Maraschini C, Dubini A, Ramella G, Danesi L, Fossati R. Inhibition by phospholipid liposomes of the prolactin and cortisol response to insulin hypoglycemia in man. Psychopharmacology (Berl) 1984;82(3):157-60. Van den Berghe G, de Zegher F, Vlasselaers D, Schetz M, Verwaest C, Ferdinande P, et al. Thyrotropin-releasing hormone in critical illness: from a dopamine-dependent test to a strategy for increasing low serum triiodothyronine, prolactin, and growth hormone concentrations. Crit Care Med 1996 Apr;24(4):590-5. Westwood ME, Butler GE, McLellan AC, Barth JH. The combined pituitary function test in children: an evaluation of the clinical usefulness of TRH and LHRH stimulation tests through a retrospective analysis of one hundred and twenty six cases. Clin Endocrinol (Oxf) 2000 Jun;52(6):727-33. Girard J, Staub JJ, Baumann JB, Nars PW. Assessment of Hypothalamo-Anterior Pituitary Secreting Capacity in Children on the Basis of A Single Test. Pediatric Research 1975;9(8). Ning C, Jiang Q, Wei H, Wang S, Wang MT. Hypothalamic-pituitary function assessment in children by a combined stimulation test. J Tongji Med Univ 1992;12(4):219-22. Savage DC, Swift PG, Johnston PG, Goldie DJ, Murphy D. Combined test of anterior pituitary function in children. Arch Dis Child 1978 Apr;53(4):301-4. Okada Y, Onishi T, Tanaka K, Morimoto S, Tsuji M, Watanabe K, et al. Prolactin and TSH responses to TRH, chlorpromazine and L-dopa in children with human growth hormone deficiency. Acta Endocrinol (Copenh) 1978 Jun;88(2):217-26. Zabransky S. Der TRH (Thyreotropin-Releasing-Hormon)-Stimulationstest. Pädiat Prax 1974;14:379-81. Costom BH, Grumbach MM, Kaplan SL. Effect of thyrotropin-releasing factor on serum thyroid-stimulating hormone. An approach to distinguishing hypothalamic from pituitary forms of idiopathic hypopituitary dwarfism. J Clin Invest 1971 Oct;50(10):2219-25.


Milhaud G, Rivaille P, Moukhtar MS, Binet E, Job JC. Response of normal, hypothyroid and hypothalamo-pituitary insufficient children to synthetic thyrotrophinreleasing hormone. J Endocrinol 1971 Nov;51(3):483-8. Kaplan SL, Grumbach MM, Friesen HG, Costom BH. Thyrotropin releasing factor (TRF) effect on secretion of human pituitary prolactin and thyrotropin in children and in idiopathic hypopituitary dwarfism: further evidence for hypophysiotropic hormone deficiencies. J Clin Endocrinol Metab 1972 Dec;35(6):825-30. Girard J, Staub JJ, Nars PW, Bühler U, Studer P, Baumann JB. Experience with thyrotropin releasing hormone (TRH): test in suspected thyroid disorders in childhood. Recent Progress in Pediatric Endocrinology 1977;12:197-211. Gruñeiro de Papendieck L, Iorcansky S, Rivarola MA, Heinrich JJ, Bergada C. Patterns of TSH response to TRH in children with hypopituitarism. J Pediatr 1982 Mar;100(3):387-92. Milner RD, Herber SM. Response to TRH in suspected hypopituitarism. Arch Dis Child 1983 Mar;58(3):195-7. Malvaux P, Beckers C. Serum thyrotrophin response to thyrotrophin-releasing hormone in normal children and in patients with short stature and various endocrine or genetic diseases. Clin Endocrinol (Oxf) 1973 Jul;2(3):219-25. Illig R, Krawczynska H, Torresani T, Prader A. Elevated plasma TSH and hypothyroidism in children with hypothalamic hypopituitarism. J Clin Endocrinol Metab 1975 Oct;41(4):722-8. Cacciari E, Bernardi F, Salardi S, Tassoni P, Cicognani A, Pirazzoli P, et al. The thyrotropin releasing hormone test in idiopathic pituitary dwarfism. Helv Paediatr Acta 1974 Nov;29(5):481-7. Crofton PM, Tepper LA, Kelnar CJ. An evaluation of the thyrotrophin-releasing hormone stimulation test in paediatric clinical practice. Horm Res 2008;69(1):53-9. Foley TP, Jr., Jacobs LS, Hoffman W, Daughaday WH, Blizzard RM. Human prolactin and thyrotropin concentrations in the serums of normal and hypopituitary children before and after the administration of synthetic thyrotropin-releasing hormone. J Clin Invest 1972 Aug;51(8):2143-50. Parks JS, Snyder PJ, Utiger RD, Moshang T, Jr., Bongiovanni AM. Thyrotropin and thyroidal responses to consecutive doses of thyrotropin-releasing hormone. J Clin Endocrinol Metab 1973 Sep;37(3):466-8. Zabransky S. [What significance has the plasma TSH determination (thyrotropin) for the diagnosis and course control of thyroid function?]. Monatsschr Kinderheilkd 1974 Jul;122(7):617-8. Mizukami Y, Michigishi T, Kawato M, Sato T, Nonomura A, Hashimoto T, et al. Chronic thyroiditis: thyroid function and histologic correlations in 601 cases. Hum Pathol 1992 Sep;23(9):980-8. Suter SN, Kaplan SL, Aubert ML, Grumbach MM. Plasma prolactin and thyrotropin and the response to thyrotropin-releasing factor in children with primary and hypothalamic hypothyroidism. J Clin Endocrinol Metab 1978 Nov;47(5):1015-20. Sheth JJ, Thakore PB, Trivedi BB, Shah NN, Vaidya RA. Sub-biochemical


hypothyroidism: an exaggerated thyroid stimulating hormone response to thyrotrophin releasing hormone. J Assoc Physicians India 1999 Mar;47(3):275-9. Tan SH, Lee BW, Uma R, Aw SE, Tay SH. TRH stimulation in non-toxic goitres in children and adolescence. J Singapore Paediatr Soc 1990;32(1-2):27-31. Gruñeiro-Papendieck L, Chiesa A, Martínez A, Heinrich JJ, Bergadá C. Nocturnal TSH surge and TRH test response in the evaluation of thyroid axis in hypothalamic pituitary disorders in childhood. Horm Res 1998;50(5):252-7. Mehta A, Hindmarsh PC, Stanhope RG, Brain CE, Preece MA, Dattani MT. Is the thyrotropin-releasing hormone test necessary in the diagnosis of central hypothyroidism in children. J Clin Endocrinol Metab 2003 Dec;88(12):5696-703. Rapaport R, Sills I, Patel U, Oppenheimer E, Skuza K, Horlick M, et al. Thyrotropinreleasing hormone stimulation tests in infants. J Clin Endocrinol Metab 1993 Oct;77(4):889-94. Rapaport R, Sills I, Patel U, Oppenheimer E, Skuza K, Horlick M, et al. Thyrotropinreleasing hormone stimulation tests in infants. J Clin Endocrinol Metab 1993 Oct;77(4):889-94 Rose SR, Manasco PK, Pearce S, Nisula BC. Hypothyroidism and deficiency of the nocturnal thyrotropin surge in children with hypothalamic-pituitary disorders. J Clin Endocrinol Metab 1990 Jun;70(6):1750-5. Sack J, Shafrir Y, Urbach D, Amado O. Thyroid-stimulating hormone, prolactin, and growth hormone response to thyrotropin-releasing hormone in treated children with congenital hypothyroidism. Pediatr Res 1985 Oct;19(10):1037-9. Beyer J, Happ J, Kollmann F, Menzel H, Grabs V, Althoff P, et al. [The TRH-test in children with hyperthyroidism, primary and secondary hypothyroidism, and clinically euthyroid goitre (author's transl)]. Dtsch Med Wochenschr 1974 Sep 27;99(39):1901- 6. Cuestas RA. Thyroid function in healthy premature infants. J Pediatr 1978 Jun;92(6):963-7. van Tijn DA, de Vijlder JJ, Vulsma T. Role of the thyrotropin-releasing hormone stimulation test in diagnosis of congenital central hypothyroidism in infants. J Clin Endocrinol Metab 2008 Feb;93(2):410-9. Hadeed AJ, Asay LD, Klein AH, Fisher DA. Significance of transient postnatal hypothyroxinemia in premature infants with and without respiratory distress syndrome. Pediatrics 1981 Oct;68(4):494-8. Patel YC, Burger HG. Serum thyrotropin (TSH) in pituitary and-or hypothalamic hypothyroidism: normal or elevated basal levels and paradoxical responses to thyrotropin-releasing hormone. J Clin Endocrinol Metab 1973 Aug;37(2):190-6. Zabransky S, Cunow E. [The optimal TRH test dosage in children. Discussional comment]. Monatsschr Kinderheilkd 1978 May;126(5):345-7. Borkenstein M. Intranasal application of TRH in children. Acta Endocrinologica 1982 Apr 1;99(3 Supplement):69-70. Borkenstein MH. The effects of intranasally sprayed synthetic TRH on TSH and on PRL secretion in children. Eur J Pediatr 1983 Mar;140(1):17-8.


Henderson JM, Brodsky DA, Fisher DM, Brett CM, Hertzka RE. Pre-induction of anesthesia in pediatric patients with nasally administered sufentanil. Anesthesiology 1988 May;68(5):671-5. Karl HW, Keifer AT, Rosenberger JL, Larach MG, Ruffle JM. Comparison of the safety and efficacy of intranasal midazolam or sufentanil for preinduction of anesthesia in pediatric patients. Anesthesiology 1992 Feb;76(2):209-15. Sato T, Suzuki Y, Taketani T, Ishiguro K, Nakajima H. Age-related change in pituitary threshold for TSH release during thyroxine replacement therapy for cretinism. J Clin Endocrinol Metab 1977 Mar;44(3):553-9. Huang TS, Huang SC, Hsu MM. A prospective study of hypothalamus pituitary function after cranial irradiation with or without radiosensitizing chemotherapy. J Endocrinol Invest 1994 Sep;17(8):615-23. Battelino T, Krzisnik C, Gottschalk ME, Zeller WP. Testing for thyroid function recovery in children and adolescents with Hashimoto thyroiditis. Ann Clin Lab Sci 1994 Nov;24(6):489-94. Schopohl J, Mojto J, Losa M, Mehltretter G, Müller OA, von WK. Changes in anterior pituitary response in patients with idiopathic hypothalamic hypogonadism caused by pulsatile GnRH therapy and testosterone replacement. Exp Clin Endocrinol Diabetes 1995;103(3):184-90. Rose SR, Leong GM, Yanovski JA, Blum D, Heavner G, Barnes KM, et al. Thyroid function in non-growth hormone-deficient short children during a placebo-controlled double blind trial of recombinant growth hormone therapy. J Clin Endocrinol Metab 1995 Jan;80(1):320-4. Wyatt DT, Gesundheit N, Sherman B. Changes in thyroid hormone levels during growth hormone therapy in initially euthyroid patients: lack of need for thyroxine supplementation. J Clin Endocrinol Metab 1998 Oct;83(10):3493-7. Sharma VK, Sialy R, Kumar B, Gupta S. Evaluation of thyroid function in north Indians with alopecia areata: response to intravenous injection of 100 micrograms thyrotropin releasing hormone (TRH). J Dermatol 1999 Jun;26(6):339-42. Radetti G, Bernasconi S, Bozzola M, Volta C, Tonini G, Gentili L, et al. Pyridostigmine and metoclopramide do not restore the TSH response to TRH inhibited by L-thyroxine treatment in children with goiter. J Endocrinol Invest 2000 Dec;23(11):744-7. Pasqualini T, Zantleifer D, Balzaretti M, Granillo E, Fainstein-Day P, Ramirez J, et al. Evidence of hypothalamic-pituitary thyroid abnormalities in children with end-stage renal disease. J Pediatr 1991 Jun;118(6):873-8. Pasqualini T, Ferraris J, Fainstein-Day P, Balzaretti M, Ramirez J, Ruiz S, et al. Hypothalamic-pituitary thyroid abnormalities in children after renal transplantation. Pediatr Nephrol 1996 Oct;10(5):621-4. Wilson JH, Lamberts SW. The effect of obesity and drastic caloric restriction on serum prolactin and thyroid stimulating hormone. Int J Obes 1981;5(3):275-8. Guzzaloni G, Grugni G, Moro D, Calò G, Tonelli E, Ardizzi A, et al. Thyroidstimulating


hormone and prolactin responses to thyrotropin-releasing hormone in juvenile obesity before and after hypocaloric diet. J Endocrinol Invest 1995 Sep;18(8):621-9. Campbell M, Hollander CS, Ferris S, Greene LW. Response to thyrotropin-releasing hormone stimulation in young psychotic children: a pilot study. Psychoneuroendocrinology 1978 Apr;3(2):195-201. Khan AU. Sensitivity and specificity of TRH stimulation test in depressed and nondepressed adolescents. Psychiatry Res 1988 Jul;25(1):11-7. Caston JC, Baber CB. The relationship between plasma amino acid ratios, the dexamethasone suppression test, the thyrotropin-releasing hormone test, and clinical response in affective disorders in children and adolescents: case reports. Advances In Therapy 1991;8(6):297-304. Caston JC, Baber CB, Petty LK. TRH test blunting changes and clinical response in adolescents with affective disorders treated with valproate: case reports. Advances In Therapy 1992;9(4):222-32. Conran MJ, Kearney PJ, Callaghan MN, Murphy D, Goggin T. Hypothalamic pituitary function testing on children receiving carbamazepine or sodium valproate. Epilepsia 1985 Nov;26(6):585-8. Yüksel A, Yalçin E, Cenani A. Influence of long-term carbamazepine treatment on thyroid function. Acta Paediatr Jpn 1993 Jun;35(3):229-32. Cansu A, Serdaroglu A, Çamurdan O, Hirfanoglu T, Bideci A, Gücüyener K. The evaluation of thyroid functions, thyroid antibodies, and thyroid volumes in children with epilepsy during short-term administration of oxcarbazepine and valproate. Epilepsia 2006 Nov;47(11):1855-9. Hirfanoglu T, Serdaroglu A, Camurdan O, Cansu A, Bideci A, Cinaz P, et al. Thyroid function and volume in epileptic children using carbamazepine, oxcarbazepine and valproate. Pediatr Int 2007 Dec;49(6):822-6. Verrotti A, Laus M, Scardapane A, Franzoni E, Chiarelli F. Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate. Eur J Endocrinol 2009 Jan;160(1):81-6. McFarland KF, Strickland AL, Metzger WT, Smith JS. Thyrotrophin-releasing hormone test: an adverse reaction. Arch Intern Med 1982 Jan;142(1):132-3. Abplanalp HA. [Hemodynamic effects after i.v. application of thyrotropin releasing factor (author's transl)]. Arzneimittelforschung 1976 Feb;26(2):271-7.

2. Clinical studies/publications

The MAH himself did not conduct any paediatric studies pertaining to article 45 of the paediatric regulation. Therefore no study reports but publications have been submitted. These are shortly summarized and discussed below, focussing on TRH tests if several tests have been performed. For simplification articles have been group in different categories reflecting the Chapters of the critical expert overview. Publications are discussed at the end of each section. Pharmacodynamics Intravenous preparation


Borkenstein M, Stoffler G, Stogmann W, Fueger G, Falk W. [Normal values for circulating thyroid hormones, T3 uptake and thyrotropin before and after TRH. Radioimmunoassay determinations on 182 euthyroid children (author's transl)]. Monatsschr Kinderheilkd 1980 Jun;128(6):422-7. 182 euthyroid children aged 2 months to 14 years were treated with 5 µg/kg BW intravenously administered TRH (brand not given). Blood samples were drawn before TRH administration and 30 minutes as well as 60 minutes thereafter. Blood samples were analysed for T4, T3 rT3, T3 uptake and TSH.using RIAs. Geometric mean serum concentrations of T4, T3, rT3 and TSH showed no age related differences. T4 showed a not significant slope with age. The ratio of rT3/T3 remained constant. TRH induced TSH release was constant from 2 months to 14 years of age (TSH (µU/ml) 0’: 2.25 ±1.96, 30’ 14.33 ± 9. 29, 8.33±5.16). Foley TP, Jr., Owings J, Hayford JT, Blizzard RM. Serum thyrotropin responses to synthetic thyrotropin-releasing hormone in normal children and hypopituitary patients. A new test to distinguish primary releasing hormone deficiency from primary pituitary hormone deficiency. J Clin Invest 1972 Feb;51(2):431-7. This study enrolled 20 healthy children (4-13 years of age), 13 children with idiopathic hypopituitarism and normal thyroid function, 13 children with hypopituitarism and deficient thyroid function. TRH was administered intravenously at 7 µg/ kg BW (Abbott Laboratories). Blood was drawn at -20, 0, 15 , 30, 45 and 60 minutes in all subjects. Hypopituitary patients had additional analysis after 90 and 120 minutes. The primary objective was to see if the reaction to TRH in children was similar to the one in adults which was confirmed. The second objective was to test if the TRH test could be used to test the pituitary reserve. This was also confirmed. Side effects (mainly nausea shortly after drug administration) were reported in 76% of the patients. Zabransky S, Cunow E, Lengle D. [Optimal TRH-testdose in children: 1 microgram TRH/kg (i. v.) (author's transl)]. Padiatr Padol 1981;16(3):335-41. 70 euthyroidic children from 25 months to 16 years of age were treated with 1 µg/kg BW TRH i.v.(Relefact (Hoechst), evaluations at baseline,and +30 minutes)and 200 µg TRH, respectively. There was a significant TSH increase in all children (1µg/kg BW: 400% , 200 µg: 430±160%). Values were significantly higher in children < 2 years of age (previous publication on children from 2 weeks to 2 years of age). The authors conclude that 1µg/kg BW TRH is the optimal dose and further increases do not provide any additional clinical information. Delitala G, Meloni T, Masala A, Corti R. Thyrotropin, prolactin and growth hormone response to synthetic thyrotropin-releasing hormone in newborn infants. Biol Neonate 1978;33(5-6):236-9. 8 healthy, male newborns were treated with 50 µg TRH i.v. (Relefact (Hoechst), evaluations at -20,-10, 0, 10, 20, 30, 45, 60, 90 minutes). The control group of 8 healthy newborns matched for age, sex and body weight was administered saline solution. The test group experienced significant increases in TSH and prolactin, while growth hormone remained stable. The TSH peak was observed after 60 minutes. No adverse events were observed. Jacobsen BB, Andersen H, ge-Petersen H, Hummer L. Pituitary-thyroid responsiveness to thyrotropin-releasing hormone in preterm and small-for-gestational age newborns. Acta Paediatr Scand 1977 Sep;66(5):541-8. 12 preterm neonates (27-36 weeks gestational age) and 15 small for gestational age (SGA) babies between 5 to 167 hours after birth were administered 40 µg TRH i.v.(15.2-34.6 µg/kg BW, Hoechst AG). TSH concentrations were measured at baseline and after 30 and 180 minutes respectively. A significant increase in TSH comparable to those seen in full-term neonates and in adults was observed in all patients (median increase: 7-times in preterm neonates and 4-5 times in SGA neonates). The increase in TSH was more pronounced than in


later infancy. No correlation between the TRH dose per kg BW and the TSH response was noticed. No side effects were seen. Zabransky S. TRH test dose in children. Lancet 1980 Oct 18;2(8199):864. This is a letter by Siegfried Zabransky, who performed several studies on TRH doses in children. The author argues in favour of the 1µg/kg BW dose. Jacobsen BB, Andersen H, Dige-Petersen H, Hummer L. Thyrotropin response to thyrotropin-releasing hormone in fullterm, euthyroid and hypothyroid newborns. Acta Paediatr Scand 1976 Jul;65(4):433-8. 16 euthyroid full-term neonates were treated with 40 µg TRH i.v. (Hoechst AG) 16-172 hours after birth. In addition two patients with known hypothyroidism were treated with the same dose of TRH at the age of 3 days and 28 days, respectively. TRH was measured at baseline and at + 30 minutes and +180 minutes. In the euthyroid infants the increase in TSH was correlated to baseline levels and was comparable to that seen in adults. In the hypothyroid patients no further increase from the already very high baseline TSH levels was observed. The authors conclude that a TRH test seems without diagnostic value in congenital hypothyroidism. Rose SR, Nisula BC. Circadian variation of thyrotropin in childhood. J Clin Endocrinol Metab 1989 Jun;68(6):1086-90. This study mainly evaluates the circadian variation in serum TSH in children. In addition 76 healthy children aged 5-18 years were treated with TRH (7 µg/kg BW, brand not given, evaluations at baseline, +15, +30, +45, +60, +90, +120 and +180 minutes). TSH peaked 30 minutes after application in 92% of the children. Age, gender and pubertal status did not correlate with the TSH response. Ruppert F, Adonyi M, Ertl T, Sulyok E, Zámbó K, Csaba IF, et al. Thyrotropin and prolactin response to thyrotropin-releasing hormone in healthy and asphyxiated fullterm neonates. Acta Paediatr Hung 1983;24(2):111-8. 11 healthy and 11 asphyxiated newborns were treated with 40 µg TRH i.v. (Hoechst AG). TRH and prolactin were measured at baseline and at 30 and 180 minutes. Baseline levels of TSH were slightly higher and prolaktin baseline levels were significantly higher in the asphyxiated group. In the healthy newborns the TSH response was equal to that of adults but lower than the one in the asphyxiated group. Prolaktin response also was more pronounced in the asphyxiated group. The authors concluded that the pituitary reserve for prolaktin and TSH are maintained in asphyxiated newborns.

Assessor’s comment: The applicant submitted a number of studies investigating the feasibility and the results of the TRH test in healthy subjects and patients of different age groups. Antepan is already licensed for all paediatric age groups. This is supported by the submitted data although most of these studies investigated higher doses that the one listed in the SPC for Antepan. The 1 µg/ kG BW dose is supported by the publication by Zabransky et al. for children from 2 weeks of ag.. A short description of the results of TRH tests in different age groups is given in section 5.1 of the SPC.

Pharmacodynamic drug interaction I.v. preparation Cavagnini F, Maraschini C, Dubini A, Ramella G, Danesi L, Fossati R. Inhibition by phospholipid liposomes of the prolactin and cortisol response to insulin hypoglycemia in man. Psychopharmacology (Berl) 1984;82(3):157-60. This study mainly investigates the dopamine-mimetic activity of phospholipid liposomes. Among other tests, 8 female subjects (14-65 years of age) were submitted to two TRH tests (200 µg Relefact i.v.). One test with concomitant application of 500 mg of phospholipid liposomes and


one with concomitant application of placebo. The authors conclude that phospholipid liposomes did not alter the prolaktin and TSH response to TRH. TSH response had a >100 fold inter-individual variation while the individual response was rather constant. Van den Berghe G, de Zegher F, Vlasselaers D, Schetz M, Verwaest C, Ferdinande P, et al. Thyrotropin-releasing hormone in critical illness: from a dopamine-dependent test to a strategy for increasing low serum triiodothyronine, prolactin, and growth hormone concentrations. Crit Care Med 1996 Apr;24(4):590-5. This was a prospective, open label, randomized, controlled clinical study. 15 critically ill patients (2 adolescents) receiving dopamine treatment (5 µg/ kg BW/min) for > 21 hours were enrolled. Patients performed two TRH tests with 200 µg TRH i.v. (no brand given) separated by 6 hours. TSH, prolactin and growth hormone were measured at baseline and at +20, +40, +60, and +120 minutes. T4, T3, rT3 and TBG were measured at baseline and at 120 min. Patients were randomized for continuous dopamine infusion or for dopamine withdrawal 3 hours after the first TRH test. Two consecutive doses of TRH increased T4 concentration by a mean 16% and T3 concentration by a mean 47%. Growth hormone concentrations were increased in both groups. In the group who discontinued dopamine the TSH increase was three fold higher than in the dopamine group. T3 response as well as prolactin response was also increased. The authors conclude that TSH response in critically ill patients is dopamine dependent. Repeated administration of TRH is capable to increase TSH, prolactin, growth hormone, T4 and T3 thereby potentially reversing the euthyroid sick syndrome. Westwood ME, Butler GE, McLellan AC, Barth JH. The combined pituitary function test in children: an evaluation of the clinical usefulness of TRH and LHRH stimulation tests through a retrospective analysis of one hundred and twenty six cases. Clin Endocrinol (Oxf) 2000 Jun;52(6):727-33. 126 children aged 2-17 years with short stature were included in this retrospective trial. Patients had performed full pituitary tests between 1992 and 1998. TRH tests were done with 7 µg/ kg BW (up to 200 µg ,no brand given, evaluations at baseline, +20, +30, +60, +180 minutes). The TSH response was positively correlated to basal TSH levels but not basal total T4 concentration. There were no significant differences in response to TRH stimulation between patients with GH deficiency, or hypopituitarism and those with idiopathic short stature. In patients with an impaired response to stimulation, basal TSH concentrations were < 2.0 mIU/l and significantly lower than in patients with a normal response (p<0.0001). An impaired response to TRH stimulation had a positive predictive value of 0.43 and a negative predictive value of 0.90 for the diagnosis of hypopituitarism. A basal TSH concentration of <2.0 mIU/l had a positive predictive value of 0.22 and a negative predictive value of 0.92. A low basal T4 in combination with an inappropriately low or normal basal TSH was always associated with a diagnosis of hypopituitarism. The authors conclude that TRH tests should not routinely be used in the investigation of children with short stature. The applicant submitted this study in this section because the TRH and the LHRH test were done concomitantly. Girard J, Staub JJ, Baumann JB, Nars PW. Assessment of Hypothalamo-Anterior Pituitary Secreting Capacity in Children on the Basis of A Single Test. Pediatric Research 1975;9(8). This is a short summary on the combined use of insulin, TRH and LH-RH in the evaluation of the anterior pituitary function. This test was performed in 60 children with suspected hypothalamo-pituitary disorders. TRH dose was 200 µg ( no further information given. No cross reactions were seen. The authors state that the TSH response to TRH alone does not differ from that observed during a combined test ( no data provided). Ning C, Jiang Q, Wei H, Wang S, Wang MT. Hypothalamic-pituitary function assessment in children by a combined stimulation test. J Tongji Med Univ 1992;12(4):219-22.


32 Chinese children of short stature (median age 8.6 ± 3.7 years) and 10 girls with idiopathic central precocious puberty (median age 8.6 ± 1.7 years) and 8 girls with premature thelarche (median age 3.3 ± 1.5 years) were concomitantly treated with insulin, LHRH , levodopa and TRH (200 µg/m2, no brand given, evaluations at baseline, +15, +30, +60 and + 90 minutes) to assess pituitary function. The authors conclude that this combined stimulation test can assess multiple hormone response with satisfactory results in a single 90-min test. Savage DC, Swift PG, Johnston PG, Goldie DJ, Murphy D. Combined test of anterior pituitary function in children. Arch Dis Child 1978 Apr;53(4):301-4. 21 boys with short stature or delayed puberty were simultaneously treated with insulin, LHRH and TRH (200 µg i.v., no brand given, evaluations at baseline, +15, +30, +60, +90, +120, +160, +180, +200, +220, +240) and L-dopa. The authors conclude that a comprehensive evaluation can be made of GH, TSH, ACTH and gonadotropin reserve. Okada Y, Onishi T, Tanaka K, Morimoto S, Tsuji M, Watanabe K, et al. Prolactin and TSH responses to TRH, chlorpromazine and L-dopa in children with human growth hormone deficiency. Acta Endocrinol (Copenh) 1978 Jun;88(2):217-26. 23 children with GH deficiency 86-20 years of age were treated with TRH i.v. (500 µg, no brand given, evaluations at baseline, +30, +60, +90, +120 and +150 minutes), chlorpromazine and L-dopa. The applicant submitted this publication in this section because of the concomitant use of insulin, arginine hydrochloride, chlorpromazine and levodopa. From the publication it is not really clear, if al substances were given simultaneously

Assessor’s comment: The applicant submitted 7 publications concerning the concomitant use of TRH with other substances. Phospholipid liposomes did not affect TRH testing. The effect of dopamine is already reflected in Chapter 4.5 of the SPC. Combined anterior pituitary function testing is indirectly addressed in Chapter 4.5, which states that “the increase in TSH is potentiates, albeit only to a minor extent in most cases by GnRH, GH-RH, CRH,…”. A note on combined testing could also make sense in Chapter 4.2 of the SPC. However, the publications submitted for this worksharing procedure do not really prove that concomitant use does not alter the results of the respective test, as single testing has not been compared to combined testing in the same subjects. The applicant is asked to comment, if additional data might be available. Regarding the publication by Okada it is not clear if the substances have been administered simultaneously or sequentially. Anyway L-Dopa and chlorpromazine are already mentioned in Chapter 4.5 of the SPC.

TRH testing for pituitary diagnostics Zabransky S. Der TRH (Thyreotropin-Releasing-Hormon)-Stimulationstest. Pädiat Prax 1974;14:379-81. This publication summarizes the role of the TRH test in paediatrics in 1974. Costom BH, Grumbach MM, Kaplan SL. Effect of thyrotropin-releasing factor on serum thyroid-stimulating hormone. An approach to distinguishing hypothalamic from pituitary forms of idiopathic hypopituitary dwarfism. J Clin Invest 1971 Oct;50(10):2219-25. 11 children (with constitutional short stature and 2 with primordial dwarfism, mean age 7.7 years), 8 patients with isolated growth hormone deficiency (mean age 13.7 years) and 9 patients with multiple anterior pituitary hormone deficiencies (mean age 15.8 years) were tested with 500 µg TRH.i.v. (supplied by Salk institute, California, evaluations -15, 0, +5, +10, +20,+30,+45,+60 and +120 minutes) . All 11 patients without growth hormone deficiency and those with isolated growth hormone deficiency had a positive response (baseline TSH 4.1 and 3.9 µU7ml, increase to 12-45 µU/ml at +20-30 minutes). In the group of patients with multiple anterior pituitary deficiencies one patient failed to react at all. Four patients had a delayed response. The authors conclude that TRH test is useful in distinguishing between primary hypothalamic and pituitary forms of TSH deficiency.


Milhaud G, Rivaille P, Moukhtar MS, Binet E, Job JC. Response of normal, hypothyroid and hypothalamo-pituitary insufficient children to synthetic thyrotrophin releasing hormone. J Endocrinol 1971 Nov;51(3):483-8. This study evaluates the administration of TRH to paediatric patients. 8 healthy children (2-14 years of age), 3 patients with congenital hypothyroidism, and two patients with deficiencies of several pituitary factors including TSH were treated with 200 µg TRH (synthesized by the authors(?), evaluations at baseline, +10,+20,+30,+40,+60,+90,+120 minutes). In healthy children peak TSH levels occurred 20 minutes after injection and remained high for 60 minutes (baseline values between 3-5 µU/ml, peak at 10-30 minutes after injection at 10-35 µU/ml). In the hypothyroid children basal values and values after stimulation were distinctly higher. In one of the hypopituitary children the response was reduced. The authors concluded that TRH testing can distinguish between pituitary and hypothalamic defects. Kaplan SL, Grumbach MM, Friesen HG, Costom BH. Thyrotropin releasing factor (TRF) effect on secretion of human pituitary prolactin and thyrotropin in children and in idiopathic hypopituitary dwarfism: further evidence for hypophysiotropic hormone deficiencies. J Clin Endocrinol Metab 1972 Dec;35(6):825-30. 13 children with constitutional short stature, 13 children with isolated growth hormone deficiency and 13 patients with idiopathic hypopituitary dwarfism including TSH deficiency were treated with 500 µg TRH i.v. (provided by Salk Institute, California, evaluations at –15, 0, +5, +10, +20, +30, +45, +60 and +120 minutes). Plasma concentrations of prolactin and TSH rose within 5 minutes. The response to prolactin was not statistically significant different between groups. With regard to TSH one patient with multiple pituitary hormone deficiencies had no detectable TSH rise but a normal prolactin response. The rise in the group of children with idiopathic hypopituitarism was lower than in the other groups. The authors conclude that the TRH stimulation test provides a means to distinguish primary from secondary hypopituitary conditions. Girard J, Staub JJ, Nars PW, Bühler U, Studer P, Baumann JB. Experience with thyrotropin releasing hormone (TRH): test in suspected thyroid disorders in childhood. Recent Progress in Pediatric Endocrinology 1977;12:197-211. 130 patients (2 days to 18 years of age) with different diagnosis (“Stunted” growth, anorexia nervosa, obesity, goiter, hyper- and hypothyroidsm and hypothalamo-pituitarism) were treated with 200 µg (infants < 6 months of age 100 µg) TRH i.v. (Hoffmann-La-Roche, evaluations at baseline +20,+30,+60,+90 minutes). The maximum TSH response occurred 20-30 minutes after injection (mean maximum 11.3 µU/ml (6.1-22.3 µU/ml, 10th-90th percentile) in children and mean maximum of 16.7 ± 7.4 µU/ml in infants). Statistically significant increases in T3 were seen after 120 minutes. T4 increased only slightly. Oral stimulation (20mg/m2 BSA) had a depot effect and led to a prolonged rise of TSH with a maximum of 14.4 µU/ml after three hours. The authors summarize the findings in different disease of the thyroid gland and its regulators and conclude that the oral or intravenous TRH test has proved to be the most sensitive parameter of thyroid function. Gruñeiro de Papendieck L, Iorcansky S, Rivarola MA, Heinrich JJ, Bergada C. Patterns of TSH response to TRH in children with hypopituitarism. J Pediatr 1982 Mar;100(3):387-92. 42 children with hypopituitarism and growth hormone deficiency were treated with 200 µg TRH i.v. (Laboratorios Elea, evaluations at baseline, +20, +30, +45, +60, +90 minutes). A group of 55 healthy children functioned as control group. Basal TSH was elevated in 7 children in the test group. These children also showed an altered response to TRH. Patients with normal basal TSH showed three different pattern of TSH response: normal response, deficient response and delayed and exaggerated response pointing to different pathologies. In the patients with normal basal TSH three different patterns in response to TRH were seen. The authors conclude that


TRH testing is useful in the diagnosis of hypothalamic-pituitary thyroid abnormalities and helps to unmask thyroid dysfunction. Milner RD, Herber SM. Response to TRH in suspected hypopituitarism. Arch Dis Child 1983 Mar;58(3):195-7. This is a retrospective analysis of 405 TRH tests (200 µg TRH i.v., no brand given, evaluations at baselin, +20, +60 minutes, tests were done as sinlge or combined anterior pituitary tests) on children who were successful applicants of growth hormone therapy in the UK between 1977 and 1981 inclusive. TSH response was divided into normal response and those indicating hypothalamic or pituitary disorders on the basis of criteria which eliminated variation in TSH assay between laboratories. Among children who were known to be hypothyroid 93% had abnormal TRH tests. 35% of the euthyroid children also had abnormal TSH responses. Abnormal TRH tests in the latter group were most common in those patients who had growth hormone deficiencies with defined aetiologies (structural CNS damage). The authors advise to keep these children under regular review with respect to thyroid function. Malvaux P, Beckers C. Serum thyrotrophin response to thyrotrophin-releasing hormone in normal children and in patients with short stature and various endocrine or genetic diseases. Clin Endocrinol (Oxf) 1973 Jul;2(3):219-25. 42 children 2-16 years of age (8 healthy controls, 8 patients with short stature and without growth hormone deficiency, 12 hypopituitary patients, 7 patients with thyroid disorders, 4 patients with Turner syndrome and three with “various” diseases) were treated with TRH i.v. (200 µg, Hofmann Laroche, evaluations at baselin, +20, +60 minutes). All healthy children, the children with short stature and without growth hormone deficiency as well as the patients with Turner syndrome had a normal TSH response (mean basal TSH 7.1±1.1 µ U/ml, peak 36± 5.7 µU/ml at 20 minutes). One patient with organic hypopituitarism had a delayed response while one patient with pseudohypoparathyroidism had an enhanced response. Illig R, Krawczynska H, Torresani T, Prader A. Elevated plasma TSH and hypothyroidism in children with hypothalamic hypopituitarism. J Clin Endocrinol Metab 1975 Oct;41(4):722-8. 6 patients with growth hormone deficiency and hypothyroidism with elevated basal TSH levels were treated with 200 µg/m2 i.v. (Roche, evaluations at baselin, +20, +60 minutes). TSH response was exaggerated in these patients. The authors suggest that in certain patients with hypothalamic disorders, TSH is secreted in a biologically less active form. Cacciari E, Bernardi F, Salardi S, Tassoni P, Cicognani A, Pirazzoli P, et al. The thyrotropin releasing hormone test in idiopathic pituitary dwarfism. Helv Paediatr Acta 1974 Nov;29(5):481-7. 30 healthy children aged 6 to 12 years and 19 children with idiopathic hypopituitary dwarfism (11 euthyroid) aged 4 to 21 years were treated with 100 µg TRH i.v. (Hoechst-Boehringer, evaluations at baseline, +20, +60 minutes). All healthy children had a normal TSH response. Most euthyroid patients also had a normal response. The authors discuss the results of the remaining patients in relation to the suspected pathology. They conclude that in secondary hypothyroidism the basal TSH level can be normal or high and the TRH test does not clearly differentiate the thyroid deficit of pituitary nature from that of a hypothalamic nature. Crofton PM, Tepper LA, Kelnar CJ. An evaluation of the thyrotrophin-releasing hormone stimulation test in paediatric clinical practice. Horm Res 2008;69(1):53-9. This is retrospective study to evaluate the clinical usefulness of the TRH test in children with suspected hypothalamic or pituitary dysfunction. Results from 85 healthy children (group1) and 42 children who were investigated for possible pituitary or hypothalamic insufficiency (group2) were investigated . TRH testing was carried out with 7mg(?)/kg BW TRH i.v. (no brand given, evaluations at baseline, +20, +60 minutes usually as combined anterior pituitary test), . In healthy children TSH responses were higher in females than in males (p<0.01). In group two, TSH responses were normal for gender in 26 patients, subnormal in 5, and


exaggerated/delayed in 11. 4 patients with normal TSH responses and 4 with exaggerated/delayed responses had persistently low free fT4 or later developed low fT4 and were treated with thyroxine. All those with subnormal TSH response had normal fT4 and were not treated. The result of the TRH test did not match the pre-assigned location of the lesion (e.g. by MR imaging) in all patients. The authors conclude that as the TRH test did not reliably discriminate between hypothalamic and pituitary disorders, it was clinically not useful and should be abandoned in paediatric practice. Foley TP, Jr., Jacobs LS, Hoffman W, Daughaday WH, Blizzard RM. Human prolactin and thyrotropin concentrations in the serums of normal and hypopituitary children before and after the administration of synthetic thyrotropin-releasing hormone. J Clin Invest 1972 Aug;51(8):2143-50. 20 healthy children, 11 patients with growth hormone deficiency and 10 patients with growth hormone and TSH deficiency were administered 7 µg/kg BW TRH i.v. (brand not given, evaluations at -20, 0, +15, +30, +45, +60, +90, +120 minutes). All healthy patients responded normally as regards prolactin and TSH: The patients with growth hormone deficiency had a normal TSH response while the prolactin response was diminished. In the patients with the combined deficiency baseline prolactin levels and prolactin as well as TSH response were increased. These finding normalized after thyroid replacement therapy. Two patients with pan-hypopituitism didn’t respond to TRH. Parks JS, Snyder PJ, Utiger RD, Moshang T, Jr., Bongiovanni AM. Thyrotropin and thyroidal responses to consecutive doses of thyrotropin-releasing hormone. J Clin Endocrinol Metab 1973 Sep;37(3):466-8. 15 healthy children and 7 children with growth hormone deficiency were administered two 5 µg/kg BW doses TRH i.v. (Abbott laboratories, evaluations at -5, 0,+10, 20,+30,+60,+90,120,+180,+190,+200,+210,+240,+270,+300,+360 minutes) 180 minutes apart. T3 levels peaked after 120 minutes. The TSH response to the second dose was comparable to the one after the first dose. The authors conclude that the well-documented inhibition of serum TSH response to TRH by rises in serum T3 and T4 levels require longer than 60 minutes to develop.

Assessor’s comment: The applicant submitted a number of publications on the use of the TRH tests in paediatric patients. Some date from the early days of TRH testing. Numerous different protocols and doses have been evaluated. The out-come, of course, does also mainly depend on the underlying pathology which can not really been known from these publications. The opinions on the usefulness of the TRH test also differ between authors.

TRH testing for thyroid diagnostics I.v. Preparation Zabransky S. [What significance has the plasma TSH determination (thyrotropin) for the diagnosis and course control of thyroid function?]. Monatsschr Kinderheilkd 1974 Jul;122(7):617-8. The author summarizes and discusses the laboratory findings in different diseases of the thyroid and the pituitary gland. Mizukami Y, Michigishi T, Kawato M, Sato T, Nonomura A, Hashimoto T, et al. Chronic thyroiditis: thyroid function and histologic correlations in 601 cases. Hum Pathol 1992 Sep;23(9):980-8. 601 patients with chronic thyroiditis including 1091 subjects 0-20 years of age are assessed to correlate histological findings and thyroid function. In 19 patients under the age of 10 years no difference in the distribution of histiologic varieties was observed between juvenile and adult patients.


Suter SN, Kaplan SL, Aubert ML, Grumbach MM. Plasma prolactin and thyrotropin and the response to thyrotropin-releasing factor in children with primary and hypothalamic hypothyroidism. J Clin Endocrinol Metab 1978 Nov;47(5):1015-20. The authors describe the response to 200 µg TRH i.v. (no further information given) in 41 children with primary hypothyroidism, 28 children with hypothalamic hypothyroidism, 18 children with hypopituitarism due to a mass lesion and 15 children with hyperthyroidism. Patients with primary hypothyroidism showed an increased sensitivity to TRH. No increase in plasma TSH occurred in children with hyperthyroidism while in those with tertiary and primary hypothyroidism there was a delay in return of plasma TSH to baseline values. Sheth JJ, Thakore PB, Trivedi BB, Shah NN, Vaidya RA. Sub-biochemical hypothyroidism: an exaggerated thyroid stimulating hormone response to thyrotrophin releasing hormone. J Assoc Physicians India 1999 Mar;47(3):275-9. The author report on 11 age and sex matched controls and 71 patients with minimal signs of hypothyroidism and normal thyroid function tests (age range: 6-67 years). 38 patients showed an exaggerated response to 200 µg TRH i.v. (brand not given, evaluations at baseline, +30, +60 minutes) suggestive of hypothyroidism. The authors conclude that TRH testing still has a role to mark the early stage of hypothyroidism. Tan SH, Lee BW, Uma R, Aw SE, Tay SH. TRH stimulation in non-toxic goitres in children and adolescence. J Singapore Paediatr Soc 1990;32(1-2):27-31. 30 asymptomatic, euthyroid school children (age range 11 to 18 years) with non-toxic goitres were administered 200 µg TRH i.v.(no brand given, evaluations at baseline, +20, +60, +120 minutes). 18 patients showed normal responses while 9 patients had an exaggerated response and 3 patients showed blunted responses. Elevated basal TSH levels and a history of frequent cough mixture ingestion (which contained ammonium chloride) correlated significantly with an exaggerated TSH responses (p=0.008 and 0.007, respectively). The authors conclude that asymptomatic children with non-toxic goitres might have subclinical hypothyroidism. Gruñeiro-Papendieck L, Chiesa A, Martínez A, Heinrich JJ, Bergadá C. Nocturnal TSH surge and TRH test response in the evaluation of thyroid axis in hypothalamic pituitary disorders in childhood. Horm Res 1998;50(5):252-7. 24 healthy, euthyroid controls (5.7-15.4 years) and 42 patients with hypothalamic pituitary disorders were study by means of nocturnal TSH secretion and TRH test (7 µg/kg BW i.v., no brand given, evaluations at baseline, +30, +60, +90 minutes, normal results: basal TSH: 2.16±0.18 mU/l , peak 16.2 ±0.9 mU/l at 30 minutes, decline of 25-82% 90 minutes after injection). Patients were divided by serum T4 values (group1≥ 10.3 pmol/l (n=27), group 2< 10.3 pmol/l (n=15)). Both groups differed significantly from the control in TSH surge (group1: p<0.05, group 2: p<0.01). TRH test was abnormal in 11/27 patients of group 1 and 10/15 patients in group 2. In group two all patients presented thyroid axis abnormalities while 7 patients had normal tests in group1, 2 had abnormalities in TSH secretion and TRH test and in 18 had one pathological test. No relationship was found in either group between the nocturnal surge and the peak TSH level after TRH in either group. There were no significant differences in the sensitivity of both tests. The authors conclude that in patients with hypothalamic pituitary disorders with low FT4 no further investigations are required to demonstrate thyroid axis alterations. In patients with normal FT4 nocturnal TSG secretion and TRH test may be required to evidence thyroid abnormalities. Mehta A, Hindmarsh PC, Stanhope RG, Brain CE, Preece MA, Dattani MT. Is the thyrotropin-releasing hormone test necessary in the diagnosis of central hypothyroidism in children. J Clin Endocrinol Metab 2003 Dec;88(12):5696-703. Rapaport R, Sills I, Patel U, Oppenheimer E, Skuza K, Horlick M, et al. Thyrotropinreleasing hormone stimulation tests in infants. J Clin Endocrinol Metab 1993 Oct;77(4):889-94. This is a retrospective study of case records of patients attending the London centre for Pediatric Endocrinology based at Great Ormond Street Children’s Hospital and University


College London Hospitals. Results of unstimulated serum T4 and TSH levels were reviewed in 54 children (age range: 0-11 years) with central hypothyroidism. Midline brain defects and combined pituitary hormone deficiencies were present in 30 and 52 patients, respectively. Patients with acquired lesions were excluded. TRH tests (7 µg/kg BW i.v. (maximum 200µg), brand not given, time-points of evaluations not given) had been performed in 30 patients. A normal TRH test (increase in TSH 4.5-17.8 µU/ml, based on data from 30 controls) was documented in 23.3% of patients despite subnormal T4 concentrations. Brisk, absent/blunted and delayed responses were documented in 16.7%, 30% and 30% of patients, respectively. Patients with brisk or delayed responses had significantly higher basal TSH levels compared to the ones with absent/blunt or normal responses. It was not possible to differentiate patients as having pituitary or hypothalamic disease based solely on the results of the TRH test. The authors conclude that a normal TRH test does not exclude abnormalities in the hypothalamic-pituitary-thyroid axis. Although full pituitary function assessment is mandatory to identify combined pituitary hormone deficiencies, a TRH test is not essential and the diagnosis should be made by serial T4 measurements. Rapaport R, Sills I, Patel U, Oppenheimer E, Skuza K, Horlick M, et al. Thyrotropinreleasing hormone stimulation tests in infants. J Clin Endocrinol Metab 1993 Oct;77(4):889-94 TRH tests (7 µg/kg BW i.v., brand not given, single sample 30 minutes after injection) were performed in 68 children (0.5-7.5 months of age, 22 with gestational age of 31-36 weeks) with abnormal T4 screening tests and only mildly abnormal serum thyroid function tests (TSH level > 5.0 mU/L <11mU/L). 33 infants received a full test with measurements at 0, +15, +30, +60, +90, +120 and +180 minutes. As the TSH peak occurred after 30 minutes in 32 out of 33 patients, subsequently measurements were reduce to 0 and 30 minutes. 28 patients had normal results (peak < 35 mU/l). Forty patients (10 premature) were hyperresponsive ( TSH response > 35 mU/L). This group also had higher baseline TSH levels (8.8± 2.3 versus 4.4± 2.2 mU/L) with overlapping ranges (1.9-10.6 versus 0.9-10 mU/L). Mean peak TSH levels were significantly higher in the hyperresponsive group (60.3 ± 26.1 versus 24±7.7 mU/L). During long term follow-up all available subjects with normal TRH tests were conformed to be clinically and biochemically normal while 14 children with an abnormal TRH test had evidence of thyroid dysfunction. The authors conclude that the TRH test (with measurements at 0 and 30 minutes) is a useful tool for the evaluation of infants suspected of having primary hypothyroidism. Rose SR, Manasco PK, Pearce S, Nisula BC. Hypothyroidism and deficiency of the nocturnal thyrotropin surge in children with hypothalamic-pituitary disorders. J Clin Endocrinol Metab 1990 Jun;70(6):1750-5. 52 children (1.5-18 years of age) with hypothalamic-pituitary disorders were studied for abnormalities in the nocturnal TSH surge. 11 children with central hypothyroidism also received a TRH test (7 µg/kb BW i.v., brand not given). The TRH test was abnormal in 2 patients while the nocturnal surge test was abnormal in 10 out of 11. The authors conclude that the nocturnal TSH surge test is much more sensitive than the TRH test for the diagnosis of central hypothyroidism. Sack J, Shafrir Y, Urbach D, Amado O. Thyroid-stimulating hormone, prolactin, and growth hormone response to thyrotropin-releasing hormone in treated children with congenital hypothyroidism. Pediatr Res 1985 Oct;19(10):1037-9. 12 congenitally hypothyroid, L-thyroxine treated, children aged 1.6 to 9.3 years and 7 children with primary acquired hypothyroidism present for several month before initiation of therapy aged 9 to 15.5 years were administered TRH (7 µg/ kg BW i.v., Hoechst, evaluations at baseline and every 15 to 30 minutes for 75 minutes). TSH, growth hormone and prolaktin response were measured. Six children with congenital hypothyroidism had elevated basal TSH levels. Serum T3 and T4 were normal in all patients. All children with elevated basal TSH had an exaggerated TSH response. 4 also had an augmented prolactin response. Children with normal basal TSH


had normal TSH and prolactin responses. Four out of seven children with prolonged untreated primary hypothyroidism showed an abnormal exaggerated growth hormone response. Beyer J, Happ J, Kollmann F, Menzel H, Grabs V, Althoff P, et al. [The TRH-test in children with hyperthyroidism, primary and secondary hypothyroidism, and clinically euthyroid goitre (author's transl)]. Dtsch Med Wochenschr 1974 Sep 27;99(39):1901- 6. The author reports the results of TRH tests (5µg/kg BW i.v., brand not given, evaluations at baseline, +20,+30,+45,+60 minutes) in 41 children (age range 8-14 years) with various diseases of the thyroid gland. The authors conclude that the TRH test with measurements at baseline and after 30 minutes is feasible in children. Weight based TRH doses might be advantageous to delineated discreet pathologies. Cuestas RA. Thyroid function in healthy premature infants. J Pediatr 1978 Jun;92(6):963-7. The author describes thyroid function in healthy premature (30-37 weeks GA) and term infants. Five premature infants (30-32 weeks GA, age: 12-58 days) were injected with TRH (10 µg/kg BW, brand not given, evaluations at baseline, +30 minutes). Mean TSH increase of 29.4 ± 20.7 µU/ml occurred at 30 minutes after injection resembling the one described for term infants. van Tijn DA, de Vijlder JJ, Vulsma T. Role of the thyrotropin-releasing hormone stimulation test in diagnosis of congenital central hypothyroidism in infants. J Clin Endocrinol Metab 2008 Feb;93(2):410-9. The authors report on a Dutch nationwide, prospective study (1994-1996). Patients were included if neonatal congenital hypothyroidism screening results were indicative of central congenital hypothyroidism and could be tested within 3 months of birth. 10 male and 5 female infants with central, congenital hypothyroidism and 6 infants with false positive screening results, nonthyroidal illness or transient hypothyroidism were included. TRH (no brand given, evaluations at baseline, +15, +30, +45, +60, +120 + 180 minutes, normal TSH response peak > 15 µg/ml + return to baseline within 3 hours) was administered at 10 µg/ kg body mass. All six children without central hypothyroidism had normal TSH responses. All 15 children with central hypothyroidism had abnormal results (decreased TSH peak or delayed TSH peak and delayed decrease of TSH plasma concentration). Peak serum levels of the TSH response, AUC of TSH responses and ratios of TSH concentrations of several time points were compared. Significant differences between normal and pathological results were identified. All patients with multiple pituitary hormone deficiencies had delayed TSH peaks and delayed decrease of TSH plasma concentration and could therefore be identified. The authors conclude that the TRH test has a pivotal role in the diagnosis of TSH deficiency in young infants. The authors recommend that the TRH test should last for three hours for optimal discrimination. Hadeed AJ, Asay LD, Klein AH, Fisher DA. Significance of transient postnatal hypothyroxinemia in premature infants with and without respiratory distress syndrome. Pediatrics 1981 Oct;68(4):494-8. 23 premature infants (with and without RDS) with T4 cord blood levels <6.5 µg/100 ml were administered TRH (20 µg/ kg KG, brand not given, TSH measurements at baseline, +30 and +180 minutes). All infants had normal TSH responses (mean increase from baseline. 6-fold). Responses were not different between infants with and without RDS. No correlation between ΔTSH and baseline free T4 concentrations was seen. Patel YC, Burger HG. Serum thyrotropin (TSH) in pituitary and-or hypothalamic hypothyroidism: normal or elevated basal levels and paradoxical responses to thyrotropin-releasing hormone. J Clin Endocrinol Metab 1973 Aug;37(2):190-6. 21 patients (1 paediatric patient, 9 years of age) with pituitary or hypothalamic lesions and hypothyroidism were administered 200 µg TRH (no further details are given). 12 patients had normal results while, 6 patients showed exaggerated responses. 2 patients showed an impaired


TSH response. The authors conclude that TRH tests can not adequately differentiate between hypothalamic and pituitary hypothyroidism. The applicant also discussed the publications by Jacobsen et al, 1976 and Milhaud et al. 1971, (both displayed above) in this chapter.

Assessor’s comment: the separation between this chapter and the previous one seems a little artificial. The publication by van Tijin et al is of special interest as the authors recommend that the TRH test should last at least 180 minutes in infants suspected to have congenital central hypothyroidism. The applicant is asked to comment. Otherwise the comments made in the previous chapter apply.

Paediatric dose I.v. preparation Zabransky S, Cunow E. [The optimal TRH test dosage in children. Discussional comment]. Monatsschr Kinderheilkd 1978 May;126(5):345-7. 69 children (age range: 2 weeks- 18 months) were administered TRH (Relefact, Hoechst, doses: 0.5 µg,1 µg, 1 µg /kg BW, 2 µg /kg BW, 200 µg) once (group A). 8 infants received three consecutive TRH tests during two weeks (group B). 7 infants received doses of1 µg /kg BW, 2 µg/kg BW and 200 µg/ kg BW, respectively. 1 infant received three TRH tests at 1µg total dose (group B). 10 children from 4-12 years of age were administered 1µg/kg BW (group C). TSH levels were measured at baseline and +30 minutes. In group A 0.5 µg and 1 µg TRH generally resulted in an at least three-fold increase in TSH. However 4/11 children in the 0.5 µg group had a negative TRH test (increase < 2.5 µU/ml) . ΔTSH 30’ was significantly higher in the 1 µg/kg BW group compared to the lower dose groups. Further increases in dose did not lead to significant increases in TSH response. In group B medium Δ TSH 30’ values increased with dose. However, a dose of 1 µg/kg BW was sufficient to trigger a medium Δ TSH 30’ of 14.2±8.6 µU/ml. There were no significant differences in Δ TSH 30 ‘ between the 1 µg /kg BW, the 2 µg /kg BW and the 200 µg dose groups. The authors conclude that 1 µg/kg BW is the optimal TRH dose. The publications by Zabransky S, Cunow E, Lengle D. [Optimal TRH-testdose in children: 1 microgram TRH/kg (i. v.) (author's transl)]. Padiatr Padol 1981;16(3):335-41 and Zabransky S. TRH test dose in children. Lancet 1980 Oct 18;2(8199):864 (both discussed above) are also cited in this chapter.

Assessor’s comment: Numerous protocols were applied in the publications submitted for this worksharing procedure. Antepan i.v. solution is licensed at a dose of 1µg/kg BW in children. This is supported by the data displayed in this Chapter for children from 2 weeks of age. However the evidence supporting this dose in younger children seems to be rather weak. The applicant is asked to comment.

Nasal spray Borkenstein M. Intranasal application of TRH in children. Acta Endocrinologica 1982 Apr 1;99(3 Supplement):69-70. 10 euthyroid children (age range: 5.6-13.0 years) were administered with 500 µg synthetic TRH in aqueous solution as a nasal spray (Behring). TSH levels were measured at baseline and after +30, +60, +90 and +120 minutes. No side effects were observed. Intranasal TRH induced a prompt rise in TSH and prolactin levels with a peak at +30 minutes. Δ TSH was significantly higher in those children receiving >10 µg/kg BW TRH compared to those receiving < 10 µg/kg BW TRH. Borkenstein MH. The effects of intranasally sprayed synthetic TRH on TSH and on


PRL secretion in children. Eur J Pediatr 1983 Mar;140(1):17-8. It seems that this publication reports on the same study as the publication by Borkenstein M. Intranasal application of TRH in children. Acta Endocrinologica 1982Apr 1;99(3 Supplement):69-70 displayed above. Henderson JM, Brodsky DA, Fisher DM, Brett CM, Hertzka RE. Pre-induction of anesthesia in pediatric patients with nasally administered sufentanil. Anesthesiology 1988 May;68(5):671-5. This study does not concern TRH. It was submitted because a nasal preparation is successfully used in children 6 months to 7 years of age. Karl HW, Keifer AT, Rosenberger JL, Larach MG, Ruffle JM. Comparison of the safety and efficacy of intranasal midazolam or sufentanil for preinduction of anesthesia in pediatric patients. Anesthesiology 1992 Feb;76(2):209-15. This study does not concern TRH. . It was submitted because a nasal preparation is successfully used in children 6 months to 10 years of age.

Assessor’s comment: The applicant submitted one study on the nasal administration of Antepan. The licensed dose for Antepan nasal spray is 1 mg. The publication by Borkenstein does not support this dose. 0,5 mg TRH are used, here. However, as this worksharing does only include data, which has not already been submitted to the competent authorities, additional data supporting the 1 mg dose might be available. The applicant is asked to comment.

TRH test used in paediatric studies I.v. preparation Sato T, Suzuki Y, Taketani T, Ishiguro K, Nakajima H. Age-related change in pituitary threshold for TSH release during thyroxine replacement therapy for cretinism. J Clin Endocrinol Metab 1977 Mar;44(3):553-9. The authors tried to determine the appropriate L-T4 dose in nine patients with athyrotic or ectopic “cretinism” aged 6 months to 17 years. TRH (10 µg/kg BW, no brand given, evaluations at baseline, +30, +60 minutes) was administered under therapy with L-T4. The L-T4 dosage which was associated with normal TSH responsiveness to TRH was determined and is discussed in this article. Huang TS, Huang SC, Hsu MM. A prospective study of hypothalamus pituitary function after cranial irradiation with or without radiosensitizing chemotherapy. J Endocrinol Invest 1994 Sep;17(8):615-23. The authors study the effect of radio- and/or chemotherapy on pituitary function in 37 patients with nasopharyngeal carcinoma (aged 16- 65 years). TRH tests (400 µg, brand not given, evaluations at baseline, +20,+40,+60,+90,+120,+180 minutes, combined anterior pituitary test) were carried out before, 6 months, 1 and 2 years after therapy. The TSH response to TRH increased progressively and significantly after radiotherapy. Battelino T, Krzisnik C, Gottschalk ME, Zeller WP. Testing for thyroid function recovery in children and adolescents with Hashimoto thyroiditis. Ann Clin Lab Sci 1994 Nov;24(6):489-94. Thyroid function in 29 children and adolescents (age range: 8.5-19.7 years) with primary hypothyroidism due to Hashimoto thyroiditis was studied for one year to evaluate criteria for the discontinuation of thyroxine therapy. TRH tests (100 µg, brand not given, measurements at baseline and +30 minutes) were carried at the beginning and 6 and 12 months later. The authors conclude that discontinuation of therapy can not be based on a single test. Considerable possibility of relapse remains. Schopohl J, Mojto J, Losa M, Mehltretter G, Müller OA, von WK. Changes in anterior


pituitary response in patients with idiopathic hypothalamic hypogonadism caused by pulsatile GnRH therapy and testosterone replacement. Exp Clin Endocrinol Diabetes 1995;103(3):184-90. The anterior pituitary response in 9 males (two patients 16 and 17 years of age) with idiopathic hypothalamic hypogonadism was tested before, during and after (on testosterone replacement) pulsatile GnRH therapy. TRH was administered in the context of a combined pituitary stimulation test (200µg, no brand given, evaluations -30,0, +5, +15, +30,+45,+60,+90,+120 minutes). No significant differences were observed before and during the treatment modalities for TRH while the prolactin response was significantly higher during GnRH therapy. Rose SR, Leong GM, Yanovski JA, Blum D, Heavner G, Barnes KM, et al. Thyroid function in non-growth hormone-deficient short children during a placebo-controlled double blind trial of recombinant growth hormone therapy. J Clin Endocrinol Metab 1995 Jan;80(1):320-4. The authors evaluated the effect of growth-hormone therapy on thyroid function. Among other evaluations, 20 non-growth-hormone-deficient children with short stature were enrolled in a placebo-controlled trial (growth hormone: n=9 (age: 12.5±1.7), placebo:n=11(age: 12.4±1.2)). They received TRH tests (no details given) 6 months before and 6 months after initiation of growth hormone therapy. No significant differences in TSH response were observed between groups. Wyatt DT, Gesundheit N, Sherman B. Changes in thyroid hormone levels during growth hormone therapy in initially euthyroid patients: lack of need for thyroxine supplementation. J Clin Endocrinol Metab 1998 Oct;83(10):3493-7. The authors evaluated the effect of growth hormone therapy on thyroid function. 15 euthyroid, prepubertal patients with classic growth hormone deficiency were monitored. Among other evaluations, TRH tests (Abbot Labs, 7 µg/kg BW i.v., TSH levels at baseline, +10, +20,+30,+60,+120 minutes) were carried out at baseline and after 1, 3 and 9 months of therapy. No changes in TRH-stimulated TSH levels were observed. Sharma VK, Sialy R, Kumar B, Gupta S. Evaluation of thyroid function in north Indians with alopecia areata: response to intravenous injection of 100 micrograms thyrotropin releasing hormone (TRH). J Dermatol 1999 Jun;26(6):339-42. 22 patients with alopecia areata (no further details given) randomly selected from patients attending a dermatology outpatient clinic in Northern India performed (among other evaluations) TRH tests (100 µg, Hoechst, TSH levels at -20,0,+20,+60,+120 minutes). 4 of them had results which were suggestive of hypothyroidism. Radetti G, Bernasconi S, Bozzola M, Volta C, Tonini G, Gentili L, et al. Pyridostigmine and metoclopramide do not restore the TSH response to TRH inhibited by L-thyroxine treatment in children with goiter. J Endocrinol Invest 2000 Dec;23(11):744-7. The authors studied the role of somatostatin and dopamine in TSH suppression induced by L-thyroxine. 16 children (age range 8-14 years) with endemic goitre treated with suppressive doses of L-thyroxine were subjected to two TRH (200 µg, brand not given, measurements at baseline, +20,+40,+60 minutes) tested at an interval of one week. The first test confirmed TSH suppression, while prolactin increased significantly and growth hormone levels remained stable. One hour before the second test 9 patients received 60 mg pyridostigmin and 7 patients received 10 mg metoclopramide. In patients treated with pyridostigmin TSH did not increase. Prolactin and growth hormone were significantly raised. After application of metoclopramide TSH and growth hormone levels did not raise. A significantly greater prolactin increase was observed. The authors conclude that. L-thyroxine suppresses the TSH response but does not affect growth hormone and prolactin secretion. Somatostatin and dopamine do not seem to play an important role in the L-thyroxine-induced TSH suppression. Pasqualini T, Zantleifer D, Balzaretti M, Granillo E, Fainstein-Day P, Ramirez J, et al.


Evidence of hypothalamic-pituitary thyroid abnormalities in children with end-stage renal disease. J Pediatr 1991 Jun;118(6):873-8. In order to evaluate the mechanisms of altered thyroid function, among other evaluations, TRH tests (200 µg i.v., Glea, measurements at baseline, +20, +30,+60,+90 minutes) were administered to nine patients (7.6-17.1 years of age) with end-stage renal disease. All but one patient had normal basal TSH levels. Three patients showed a deficient TSH response (increase <4.5 mU/L). TSH response was prolonged in all patients. The authors conclude that some patients with end-stage renal disease have central hypothyroidism. Pasqualini T, Ferraris J, Fainstein-Day P, Balzaretti M, Ramirez J, Ruiz S, et al. Hypothalamic-pituitary thyroid abnormalities in children after renal transplantation. Pediatr Nephrol 1996 Oct;10(5):621-4. TRH tests (200 µg i.v., Glea, measurements at baseline, +20,+30,+60,+90 minutes) were performed in 18 children (age range: 6.6-19.4 years) who underwent renal transplantation under immunsupression with glucocorticosteroids. TSH increase was significantly lower compared to controls (p< 0.001). The authors conclude that after renal transplantation some patients have hypothalamic-pituitary thyroid abnormalities in which glucocorticosteroids might play a significant role. Wilson JH, Lamberts SW. The effect of obesity and drastic caloric restriction on serum prolactin and thyroid stimulating hormone. Int J Obes 1981;5(3):275-8. The authors studied the effect of calorie restriction on prolactin and TSH response to TRH (400 µg, Relefact, evaluations at baseline, +20, +30, +60 and 120 minutes) in 11 obese women (1 patient aged 17 years). While the TSH response was not altered, prolactin response was diminished. Guzzaloni G, Grugni G, Moro D, Calò G, Tonelli E, Ardizzi A, et al. Thyroidstimulating hormone and prolactin responses to thyrotropin-releasing hormone in juvenile obesity before and after hypocaloric diet. J Endocrinol Invest 1995 Sep;18(8):621-9. Among other evaluations TRH tests (200 µg i.v., Ares Serono, evaluations at baseline, +15, +30,+60,+90,+120 minutes ) were conducted in 36 obese children (8.5-17.4 years of age, 14 boys, 22 girls) before and after a 1000 kCal/day diet. 14 age and sex matched normal weight subjects were included as controls. In patients of both sexes the prolactin peak was earlier but not greater than in controls at baseline. The TSH response was similar to the one seen in controls. After weight loss the prolactin peak occurred at 30 minutes as in controls in females but was unchanged in boys. Differences with regard of pubertal development were found. The authors conclude that thyroid function is substantially normal in adolescent obese subjects and not influenced by a prolonged period of caloric restriction, even though a reduced hypothalamic dopaminergic tone on pituitary thyreotrophs and lactotrophs could cause subtle alterations on TSH and prolactin release, partially influenced by gender and sexual development. l Campbell M, Hollander CS, Ferris S, Greene LW. Response to thyrotropin-releasing hormone stimulation in young psychotic children: a pilot study. Psychoneuroendocrinology 1978 Apr;3(2):195-201. TRH tests (400 µg i.v., brand unknown, evaluations at baseline, +15,+30,+45,+60,+90,+120 minutes, blunted response: ΔTSH ≤ 7µIU/ml) were performed in 10 psychotic patients (2,6-7,7 years of age). Results were not uniform. In general they were compatible with but not diagnostic of hypothalamic disease. Khan AU. Sensitivity and specificity of TRH stimulation test in depressed and nondepressed adolescents. Psychiatry Res 1988 Jul;25(1):11-7. TRH tests (500 µg i.v., brand unknown, evaluations at baseline, +15, +30, +60 minutes) were carried out in 100 adolescents with various psychiatric diagnoses. Patients with major depression and substance abuse disorders showed lower TSH responses compared to other diagnostic groups.


Caston JC, Baber CB. The relationship between plasma amino acid ratios, the dexamethasone suppression test, the thyrotropin-releasing hormone test, and clinical response in affective disorders in children and adolescents: case reports. Advances In Therapy 1991;8(6):297-304. The authors report the findings of TRH tests, dexamethasone suppression tests and plasma amino acid rations in three patients with affective disorders. Tests were performed to establish the diagnosis and select the appropriate medical treatment. Caston JC, Baber CB, Petty LK. TRH test blunting changes and clinical response in adolescents with affective disorders treated with valproate: case reports. Advances In Therapy 1992;9(4):222-32. This is another case report series of three adolescent patients with affective disorders. All patients showed blunting of the TRH test, which improved and normalized after treatment with valproic acid. Conran MJ, Kearney PJ, Callaghan MN, Murphy D, Goggin T. Hypothalamic pituitary function testing on children receiving carbamazepine or sodium valproate. Epilepsia 1985 Nov;26(6):585-8. TRH tests (200 µg, Roche, details of the evaluation not given) were carried out in 20 epileptic children (age range: 8-15 years) receiving long-term carbamazepine or sodium valproate therapy. TSH response was similar in both groups. The authors conclude that HPA function in these children is not comprised by long-term carbamazepine or valproate therapy. Yüksel A, Yalçin E, Cenani A. Influence of long-term carbamazepine treatment on thyroid function. Acta Paediatr Jpn 1993 Jun;35(3):229-32. TRH test (7 µg/kg BW, no brand given, evaluations at baseline, +20, +60 minutes) were carried out in 16 children with a recent diagnosis of epilepsy receiving carbamazepine (mean age: 6.5/12 years), 13 children receiving long-term treatment with carbamazepine (mean age: 5.11/12years) and 13 healthy controls (mean age: 7.1/12 years). Serum TSH levels increased rapidly after TRH stimulation. The response was normal or slightly increased after 12 months of treatment. The authors conclude that carbamazepine does not disturb TRH-stimulated TSH secretion. Cansu A, Serdaroglu A, Çamurdan O, Hirfanoglu T, Bideci A, Gücüyener K. The evaluation of thyroid functions, thyroid antibodies, and thyroid volumes in children with epilepsy during short-term administration of oxcarbazepine and valproate. Epilepsia 2006 Nov;47(11):1855-9. This publication will not be discussed in more detail as TRH test were only used to establish normal thyroid function at baseline. Hirfanoglu T, Serdaroglu A, Camurdan O, Cansu A, Bideci A, Cinaz P, et al. Thyroid function and volume in epileptic children using carbamazepine, oxcarbazepine and valproate. Pediatr Int 2007 Dec;49(6):822-6. TRH test (7 µ/kg BW i.v., brand not given, evaluations at baseline, +20, +40, +60 minutes) were used to evaluate the thyroid status after treatment with either carbamazepine, oxcarbazepine or valproic acid for at least 1 year. 53 children (age range: 3-17 years were included). The study showed that a considerable percentage of children were hypothyroidic according to the TRH stimulation test (TSH at +20 minutes > 35µIU/ml). Verrotti A, Laus M, Scardapane A, Franzoni E, Chiarelli F. Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate. Eur J Endocrinol 2009 Jan;160(1):81-6. This was a prospective study in 32 newly diagnosed epileptic children (mean age 7.2±3.1 years) and 32 controls. Among other evaluations TRH tests (7 µg/kg BW i.v., brand not given, evaluation at baseline, +20,+40,+60 minutes, response > 35 µIU/ml = subclinical


hypothyroidism) were carried out at baseline and three, six and twelve months after the start of antiepileptic therapy with either carbamazepine or valproate. All tests were normal at all time-points and the authors concluded that alterations seen in thyroid hormone profiles are not associated with hypothyroidism.

Assessor’s comment: this chapter summarizes paediatric studies in which TRH tests have been used in conditions which do not primarily affect the pituitary or thyroid gland.. The applicant submitted these studies merely to complete this overview. These studies support the view that TRH tests have been widely used in paediatric patients.

Safety I.V. preparation McFarland KF, Strickland AL, Metzger WT, Smith JS. Thyrotrophin-releasingT hormone test: an adverse reaction. Arch Intern Med 1982 Jan;142(1):132-3. The authors report on two patients (male and female, both 16 years of age) who experienced loss of consciousness and absence of pulse/ apical heart tones after injection of TRH (no brand given). The male patient with Graves disease treated with propylthiouracil was injected with100 µg TRH and lost consciousness 30 to 60 seconds after injection. He received two blows to the chest. Afterwards bradycard heart sounds were audible. The female patient was diagnosed with prolactinoma. She was injected with 375 µg of TRH (no brand given) and also received insulin i.v.. Immediately after the injection, she complained of light-headedness, feeling hot and nauseated. At this time heart beat was 120 per minute. The i.v. line was opened but did not appear to be functional any longer. About one minute after TRH injection 2 minutes after insulin) she did not have detectable pulses and subsequently became drowsy and after a few minutes completely unresponsive. Ten minutes after injection of TRH the patient regained consciousness when a second i.v. line was inserted. During these episode both patients maintained spontaneous respirations. No ECGs were obtained. Both patients recovered without squeals. Abplanalp HA. [Hemodynamic effects after i.v. application of thyrotropin releasing factor (author's transl)]. Arzneimittelforschung 1976 Feb;26(2):271-7. The authors report on 20 patients and healthy volunteers (1 adolescent) who were subjected to hemodynamic tests before and after rapid i.v. injection of 200 µgTRH during a right side heart catherization. A statistically significant rise in arterial blood pressure and heart rate 1 minute after injection was observed. After 5 minutes the effect had vanished. Other hemodynamic parameters did not change. A placebo-effect could not be shown among patients who received only the added solvent. The authors suggest a direct effect of TRH on the smooth muscle cells of arterial walls responsible for vascular resistance in systemic vessels. The applicant also provided a table summarising safety data of the submitted publications:


Source: Table 10, critical expert overview

Assessor’s comment: McFarland et al report on two patients who experienced loss of consciousness and bradycardia/asystolia after injection of TRH. The reason for this is unknown. The first patient reacted directly after the injection. Vasovagal response might be one explanation. In the second patient the pathogenesis also is unclear. However it is hard to imagine that the patient lost consciousness “a few minutes” after asystolia and both patients maintained spontaneous respiration although no heart beats were detectable (for 9 minutes in the second patient).No ECGs were taken. In summary, both cases are noteworthy but not sufficiently monitored to draw final conclusions. Severe hypotension as well as unconsciousness is listed in the SPC in Chapter 4.8/ section on anaphylactic reactions to TRH. Increases in blood pressure and pulse rate are also listed in the SPC. The AEs listed in the table above are well-known and listed in the SPC.

V. RAPPORTEUR’S OVERALL CONCLUSION AND RECOMMENDATION AND LIST OF QUESTIONS


Overall conclusion See section VII. Non-clinical

The applicant submitted 8 publications describing the in vivo TSH response to TRH in newborn or juvenile rats and sheep. Considering the human paediatric data available, the animal data do not appear to be clinically relevant, although they may have supported the paediatric use of the TRH-test at the time. From the clinical publications it is clear that TRH tests have widely been used in the paediatric population. Therefore, the animal studies are of minor relevance for this application. Clinical: The applicant submitted 72 publications on the clinical use of synthetic TRH. Some date from the early days of TRH testing. Most publications concern the i.v. preparation. From these publications it is clear that TRH tests have widely been used in the paediatric population. Numerous different protocols have been applied. Results mainly depend on the underlying pathology which can not be completely known from the submitted publications. Without this information it is difficult to evaluate the results and draw conclusions. Antepan i.v. solution is licensed at a dose of 1µg/kg KG for all paediatric subsets. Evidence for this dose can be found for children from 2 weeks of age. The applicant is asked to justify this dose in younger children. Van Tijn et al reported on the use of TRH testing in infants with congenital central hypothyreodism. The authors recommend that the TRH test should last for at least three hours in these patients. This should be discussed as the SPC recommends evaluations at baseline and +30 minutes for all age groups. In a number of studies, TRH has been used as part of a combined test on anterior pituitary function. Robust evidence (cross-over study) indicating comparable results after combined and after single testing has not been submitted for this worksharing. Combined testing is not explicitly mentioned in Chapter 4.2 of the SPC. Such a note might be helpful, if additional evidence was available. The applicant is asked to explain. Different opinions regarding the usefulness of the TRH test are expressed. Although the number of paediatric patients in need of such a test might have diminished over time, this functional test might still be helpful as evidenced in some of the newer publications (e.g. van Tijn et al.). Regarding safety, the applicant submitted a publication by McFarland et al, on two 16 year old patients who lost consciousness and experienced bradycardia/asystolia after having been injected with TRH. These cases are not well-documented and no final conclusions can be drawn. Unconsciousness and severe hypotension are already listed in the SPC. All other AEs reported in the studies submitted for this worksharing are also well-known for TRH. Only one publication concerned Antepan nasal spray. In this publication a lower dose than the one recommended in the SPC was used. The applicant is asked to discuss this issue. List of questions 1.) The applicant is asked to provide data on the use of TRH for therapeutic purposes.

i.v. preparation

2.) The applicant is asked to justify the 1µg/kg BW dose in children < 2 weeks of age.

3.) Van Tijn et al reported on the use of TRH testing in infants with congenital central hypothyreodism. The authors recommend that the TRH test should last for at least three


hours in these patients. The SPC recommends one evaluation at baseline and one at + 30 minutes. Please discuss.

4.) In a number of studies TRH has been used in a combined test on anterior pituitary function.

A note in Chapter 4.2 of the SPC on the possibility of combined testing might be helpful, if additional evidence indicating comparable results after single and combined testing was available.The applicant is asked to comment. Nasal spray

5.) Only one study (Borkenstein et al, Numbers 56,57 of List of references) concerned Antepan nasal spray. In this publication a lower dose than the one recommended in the SPC was used. The applicant is asked to discuss.

Recommendation Based on the data submitted, the MAH should provide additional clarifications as requested as part of this worksharing procedure. (see section List of questions)

VI. ASSESSMENT OF RESPONSE TO QUESTIONS

Question 1 General 1.1 Assessor’s comment The MAH’s effort to provide the requested information is acknowledged. However, the intention of article 45 is to conduct a complete review of the available paediatric information. Therefore publications on the therapeutic use of protirelin in the paediatric population should also be provided. Assessor’s question: The applicant is asked to provide data on the use of TRH for therapeutic purposes. 1.2 MAH’s response The assessor refers to point 1 of Article 45 of regulation 1901/2006, which states: “By 26 January 2008, any paediatric studies already completed, by the date of entry into force, in respect of products authorised in the Community shall be submitted by the marketing authorisation holder for assessment to the competent authority.” According to the question and answers document by the CMDh (CMDh/EMA/007/2007/Rev8 January 2011), Question 5, “Article 45 refers to any studies for an authorised product”. Question 14 of the same document states: “Studies or trials mean here those not yet submitted to Competent Authorities, involving the paediatric use of medicinal products authorised in the Community.” In the Community, Antepan® is authorised for diagnostic use only. Since all MAHs in the Community must submit studies according to article 45, it seems appropriate that each MAH should submit studies relevant to their own authorised medicinal products only. Studies on other indications of TRH, in this case therapeutic use, will be submitted by those MAHs who have medicinal products authorised for this indication.


Also, in the two countries in the Community in which Antepan® is authorised (Germany and Austria), there are no TRH-products authorised for therapeutic use. Therefore the MAH does not consider it necessary to provide data on the use of TRH for therapeutic purposes.

Assessor’s comment: Although the applicant’s rationale is not fully agreed, this approach seems acceptable in this context.

Question 2 IV preparation 2.1 Assessor’s comment Numerous protocols were applied in the publications submitted for this worksharing procedure. Antepan i.v. solution is licensed at a dose of 1µg/kg BW in children. This is supported by the data displayed in this Chapter for children from 2 weeks of age. However, the evidence supporting this dose in younger children seems to be rather weak. The applicant is asked to comment. Assessor’s question: The applicant is asked to justify the 1µg/kg BW dose in children < 2 weeks of age. 2.2 MAH’s response The data provided in the clinical overview show that the TRH test has also been successfully used in neonates, at doses ranging from 7 to 20 µg/kg. An additional extensive literature search in PubMed and the DIMDI database has not provided any information on the use of TRH at 1 µg/kg BW dose in children < 2 weeks of age.

Assessor’s comment: the applicant’s response is acknowledged. As there seems to be no evidence for the efficacy and safety of the 1 µg/kg BW dose in neonates <2 weeks of age the SPC will have to be amended as follows: “Chapter 4.2: Dosage for children: Antepan 200: In children ≥ 2weeks of age: the dosage is 1 microgram protirelin/kg body weight. Only very limited data is available for neonates < 2 weeks. Doses of 7 to 20 µg/kg BW have been published.”

Question 3 IV preparation 3.1 Assessor’s comment The publication by van Tijn et al is of special interest as the authors recommend that the TRH test should last at least 180 minutes in infants suspected to have congenital central hypothyroidism. The applicant is asked to comment. Assessor’s question: Van Tijn et al reported on the use of TRH testing in infants with congenital central hypothyroidism. The authors recommend that the TRH test should last for at least three hours in these patients. The SPC recommends one evaluation at baseline and one at + 30 minutes. Please discuss.


3.2 MAH’s response The publication by van Tijn et al. is concentrated on 21 neonates aged 14 to 93 days with low plasma free T4 (FT4) and low plasma TSH, from a total of 385,042 infants screened for FT4 and TSH from April 1994 to April 1996 [1]. Of these 21 neonates, 6 were already shown to have been false positive for congenital hypothyroidism of central origin (CH-C), since repeat testing of FT4 revealed normal values. Of the remaining 15 infants, 7 had a TSH response of ≤ 15 µU/mL after 30 min, and would therefore have been confirmed as hypothyroid if only a 30 min sample had been taken. Of the remaining 8 infants with a type 3 response (high delayed and prolonged response), 1 had an exceedingly high TSH-value of nearly 75 µU/mL after 30 min, classifying as an abnormal test result, leaving 7 infants which would have had a ‘normal’ TSH response (i.e. false negative) if only a 30 min sample had been taken. In these 7 infants, prolonged testing would have confirmed the hypothyroidism. It appears that the study group is very experienced in the investigation of hypothyroidism in infants, with several further publications on screening and follow-up procedures published [2;3;4]. In their first publication, the authors noted that a diagnosis of CH-C was made if both FT4 and TSH were low and at least one other entity suggested disintegrity of the thyroid’s regulatory system, such as an abnormal TRH-response, multiple pituitary hormone deficiencies, anatomical abnormalities on brain magnetic resonance imaging, etc [2]. Thus, by their own standards, the TRH test was only one of many required to confirm the diagnosis of CH-C. In their publication of 2006, the study group presented screening data and the final diagnosis of 430,764 infants screened between 2002 and 2004 [3]. These data showed that of a total of 772 infants with abnormal test results, 410 infants had low FT4 and low TSH, of which only 16 had permanent congenital hypothyroidism, based on a determination of FT4 and TSH in venous plasma in addition to the screening test. How many of these had congenital hypothyroidism of central (rather than of thyroidal) origin is not specified, but these data show that the number of infants for which a prolonged TRH-test would be useful is very small. For the large majority of infants for which the TRH-test would be considered based on screening results of low FT4 and only mildly elevated TSH levels, a single 30-min sample was found to be sufficient for separating normal from hyperresponsive infants [5]. In their 2008 publication [1], the authors also referred to a publication by Mehta et al. [6], who did not consider the TRH test essential in infants with low serum FT4 and TSH, pointing out that they investigated older infants referred because of neurodevelopmental disorders, whereas the infants investigated by van Tijn et al. were referred based only on neonatal screening results. Thus, although van Tijn et al. have shown that it is important to follow up on infants with low FT4 and TSH screening results, they also showed that a TRH-test with a single sample after 30 min would have confirmed the diagnosis of CH-C in 8 of 15 suspects and that the diagnosis would have been made based on other investigations in the remaining 7. Therefore, as a rule, a single sample taken after 30 min is sufficient for the diagnosis of thyroid and pituitary dysfunction. However, it would be appropriate to add a 180 min sample in infants tested for CH-C. Based on these considerations, the MAH proposes to include a note in Chapter 4.2 of the SmPC under Method of administration: “In infants suspected to have congenital central hypothyroidism an additional 180 minutes sample is required.”

Assessor’s comment: The applicant’s proposal is acceptable.


Question 4 IV preparation 4.1 Assessor’s comment The applicant submitted 7 publications concerning the concomitant use of TRH with other substances. Phospholipid liposomes did not affect TRH testing. The effect of dopamine is already reflected in Chapter 4.5 of the SPC. Combined anterior pituitary function testing is indirectly addressed in Chapter 4.5, which states that “the increase in TSH is potentiated, albeit only to a minor extent in most cases by GnRH, GH-RH, CRH,…”. A note on combined testing could also make sense in Chapter 4.2 of the SPC. However, the publications submitted for this worksharing procedure do not really prove that concomitant use does not alter the results of the respective test, as single testing has not been compared to combined testing in the same subjects. The applicant is asked to comment, if additional data might be available. Assessor’s question: In a number of studies TRH has been used in a combined test on anterior pituitary function. A note in Chapter 4.2 of the SPC on the possibility of combined testing might be helpful, if additional evidence indicating comparable results after single and combined testing was available. The applicant is asked to comment.


4.2 MAH’s response A more specific search in PubMed and the DIMDI database for studies investigating the use of combined testing (TRH + GnRH + insulin) has provided additional data on comparisons with single testing [7;8;9]. Girard et al. reported in an abstract that the normal response to IV insulin (0.1 U/kg) was not altered by simultaneous IV injection of TRH (200 µg) and LHRH (100 µg) and that the TSH- response to TRH alone did not differ from that observed during a combined test [10]. No other details such as age or individual test results were given. Harsoulis et al. reported that in 24 people (4 normal, 20 with hypothalamic or pituitary disease, age not given), there was no significant difference in the degree of any of the responses to IV insulin (0.05-0.3 U/kg), TRH (200 or 500 µg) and LHRH (100 µg) after combined or single testing [7]. They did, however, observe a difference in response with GH in patients with disorders of the hypothalamic-pituitary axis (not in the normal subjects), but noted that in their experience, two-fold differences in peak GH levels are possible after comparable degrees of hypoglycaemia with repeat insulin hypoglycaemia tests on different occasion in the same subject. Therefore, they did not think this difference was significant. Mortimer et al. reported that in 12 normal male volunteers aged 26-41 years, intravenous LHRH (100 µg) did not cause a release of prolactin, GH, acetylcholine (ACTH) or TSH, and that intravenous TRH (200 µg) did not release LH, GH or ACTH, when given as a combined test (LHRH + 0.15 U insulin/kg or TRH + LHRH) or separately [11]. They also quoted their previous work, that there was no interaction between the release of TSH after intravenous TRH and the GH and ACTH response to insulin. They did, however, note that TRH caused a small but significant increase in serum FSH, a finding they confirmed in 6 separate healthy male volunteers aged 23-32 years. Overall, the authors concluded that clinical testing with insulin, TRH and LHRH may be performed simultaneously. Similar observations were made by Judd et Lazarus, who reported that in 6 normal volunteers (3 males and 3 females) aged 24-35, there was no significant difference between the maximum increments of growth hormone (GH), cortisol, FSH, LH, TSH or T3 after administration of neutral porcine insulin (0.1 U/kg IV), TRH (20 mg orally or 400 µg IV) and GnRH (100 µg IV) either simultaneously or separately [8]. Rochiccioli et al. reported comparative results in 76 children (44 boys and 32 girls, aged 1 to 13 years) without endocrine disease (n=10), with growth retardation but without endocrine abnormalities (n=57) or with hypothyroidism (n=9), using IV insulin (0.1 U/kg), TRH (200 µg) and LHRH (150 µg/m2) [9]. The results for GH, TSH, T3, cortisol, LH and FSH were compared to previous data obtained after single testing, although it is not clear from the publication which children were used for this comparison. However, the authors noted that there was no significant difference between the values for TSH, T3, LH, FSH or cortisol after single or combined testing, but that the mean growth hormone response was lower after combined testing (8.8 ng/mL) than after a single insulin test (13.8 ng/mL). The authors refer to a study by Maeda et al., who demonstrated a significant inhibition of GH release (31%) induced by IV insulin (0.1 U/kg) in 7 healthy male volunteers aged 22 to 24 years [12]. However, in that study, a very large dose of 1 mg TRH was used as a continuous infusion over 150 min, throughout the insulin test. Also, please note the large intra-individual variation noted by Harsoulis et al. [7] and the lack of effect for GH noted in normal volunteers [8;11].


Ferrer et al. reported comparative results in 51 prepubertal children (34 boys and 17 girls, no age given) with constitutional delay of growth and/or retarded bone maturation, using IV insulin (0.1 U/kg), TRH (200 µg) and LHRH (100 µg), either combined (n=31) or separately (n=20) [13]. They showed that there was no interference between plasma GH, TSH, prolactin and cortisol after combined testing, but did note a lack of additional cortisol response with combined testing, if the basal cortisol was already high (near 25 µg/100 mL). The authors suggested that in such patients, the high basal cortisol level could indirectly be considered as a positive response. Based on these data supporting the concomitant use of TRH with GnRH and insulin, the MAH proposes to include a note in Chapter 4.2 of the SmPC as suggested by the assessors: “TRH can be administered at the same time as insulin and GnRH for combined testing.”

Assessor’s comment: As this is a paediatric worksharing procedure, only paediatric data can be taken into account. The applicant submitted two additional paediatric studies on single and concomitant use of TRH. Rochiccioli et al.(article in French, English abstract)investigated single and combined testing with insulin, TRH and LHRH in children. The source of the control data is not really clear. TRH was used at a dose of 200 µg. GH response was lower after combined testing, while no significant differences were found as regards TSH, T3, LH, FSH and cortisol response. Ferrer et al.(article in Spanish, English abstract) compared the results of single (n= 31) and combined (n=20) testing of pituitary function in prepubertal children. A dose of 200 µg TRH was used. No differences between combined and single testing were found except for a lower cortisol response in patients with high basal cortisol levels. Both publications administered much higher doses of TRH than the one which is licensed for Antepan. Therefore the transferability and relevance regarding Antepan is not clear. In the study published by Ferrer a parallel group design instead of the more appropriate cross-over design was used. In summary, the evidence provided by the applicant is not sufficient to modify the SPC.

Question 5 Nasal spray 5.1 Assessor’s comment The applicant submitted one study on the nasal administration of Antepan. The licensed dose for Antepan nasal spray is 1 mg. The publication by Borkenstein does not support this dose. 0,5 mg TRH are used, here. However, as this worksharing does only include data, which has not been submitted to the competent authorities, additional data supporting the 1 mg dose might be available. The applicant is asked to comment. Assessor’s question: Only one study (Borkenstein et al, Numbers 56,57 of List of references) concerned Antepan nasal spray. In this publication a lower dose than the one recommended in the SPC was used. The applicant is asked to discuss. 5.2 MAH’s response A more extensive literature search in PubMed and the DIMDI database has shown that further data on the nasal administration of TRH are only available for healthy adults [14;15;16;17;18]. These data confirm that 1 or 2 mg TRH given nasally provides a clear TSH response after 30 min, with prolonged elevated levels. The reported ‘bioavailability’ (TSH-


response after 1 or 2 mg nasal TRH compared to 200 µg IV TRH) was variable, ranging from approximately 10 to 20% [14;15;18]. Three authors noted fewer and milder side effects with nasal compared to IV TRH [15;16;17]. Although these data were not obtained in children, they do support the argumentation for a 1 mg nasal dose in children, as provided in the submitted paediatric clinical overview: “With a nasal bioavailability of 10%, at the recommended dose for Antepan nasal spray of one single dose containing 1 mg protirelin, the systemic dose is approximately 100 µg. This dose would provide a diagnostic TSH-response in all paediatric patients, being sufficient even for older, heavy patients (i.e. ≥ 1 µg/kg) and being below the highest test dose of 500 µg reported for paediatric patients in the literature.”

Assessor’s comment: Based on the applicant’s response it seems that the evidence supporting the licensed dose in children is rather weak. The licensed dose is distinctly higher than the one used by Borkenstein et al.. The applicant was asked to provide additional information on the number and nature of AEs which have been reported with this preparation after paediatric use to identify potential safety issues. The applicant provided the following information: “As of 30 April 2013, we received a cumulative of 11 protirelin cases in children with adverse reactions (1978 - current). After paediatric use of the nasal preparation in one case (16Yr/F #2013SA029567) numbness left side of face occurred together with numbness in hand and tingling paraesthesia left side of the face and hands; in another case (17Yr/F #94001586) following adverse reactions were mentioned: blood pressure decreased, difficulty breathing, flushing and swollen face. The remaining 9 cases occurred after i. v. application.” Based on this information, only two cases of AEs have been reported in 35 years. Although no data on exposure has been included, no safety concern can be deduced from this very low number of reported AEs. Therefore the dose might be acceptable. The study by Borkenstein enrolled patients from 5.6 years of age. As no other data seems to be available, the use of this medicinal product should be restricted to patients from 6 years of age.

VII. FINAL RAPPORTEUR’S OVERALL CONCLUSION AND

RECOMMENDATION

Overall conclusion Recommendation Type IB variation to be requested from the MAH within 60 days after publication of this PAR. The following changes to the SPC/PIL are deemed necessary: Chapter 4.2 SPC and corresponding section of PIL: Antepan 200: Dosage for children: Antepan 200: Deletion of:” In children, the dosage is 1 microgram protirelin/kg body weight.” Inclusion of: “In children ≥ 2weeks of age: the dosage is 1 microgram protirelin/kg body weight.


Only very limited data is available for neonates < 2 weeks of age. Doses of 7 to 20 µg/kg BW have been published.” Method of administration: Inclusion of : “In infants suspected to have congenital central hypothyroidism an additional 180 minutes sample is required.” after ” After approximately 30 minutes, a further 5 ml of blood is taken for a second serum TSH assay.” Antepan nasal: Dosage for children: Deletion of: “Antepan nasal can be used in children of all ages.” Inclusion of: “Antepan nasal can be used in children from 6 years of age”. Antepan 400 On 6/11/2013 the RMS received a notification from the applicant indicating that there was an additional 400 µg/ml strength available in Austria. Section 4.2 (SPC)/Section 3 How to use Antepan (PL): The current SPC/PL indicate that this strength is not suitable for the paediatric population. However paediatric dosing recommendations are given. These should be removed from the SPC/PL of this strength. Section 4.3 (SPC)/ Do not use… (PL) “Antepan 400µg Ampoules should not be given to children due to the risk of overstimulation” should be added.

VIII. LIST OF MEDICINCAL PRODUCTS AND MARKETING AUTHORISATION HOLDERS INVOLVED

MAH Name of the medicinal product

Strength Pharmaceutical form

Sanofi-Aventis Deutschland GmbH (Germany)

Antepan 200 200µg/ml Solution for injection


Sanofi-Aventis Deutschland GmbH (Germany)

Antepan nasal 1mg Nasal spray, solution

sanofi-aventis GmbH (Austria)

Antepan 200 µg Ampullen

200µg/ml Solution for injection


Antepan 400 µg Ampullen

400µg/ml Solution for injection


Antepan Nasal Spray

1mg Nasal spray, solution

1-07-a de 003 - protirelin - art 45 public ar

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