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

Transcription

1 Public Assessment Report for paediatric studies submitted in accordance with Article 45 of Regulation (EC) No1901/2006, as amended Andriol Testocaps, Sustanon and Testosterone Implants [] NL/W/0026/pdWS/001 Rapporteur: The Netherlands Finalisation procedure (day 120): 23 January 2012 Date of finalisation of PAR 20 February 2013 NL/W/0026/pdWS/001 Page 1/8

2 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 studies... 5 IV.2 Non-clinical aspects... 5 IV.3 Clinical aspects... 5 V. Rapporteur s Overall Conclusion AND RECOMMENDATION... 7 VI. List of Medicinal products and marketing authorisation holders involved... 7 VII. References... 8 NL/W/0026/pdWS/001 Page 2/8

3 ADMINISTRATIVE INFORMATION Invented name of the medicinal product(s): INN (or common name) of the active substance(s): MAH (s): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Andriol Testocaps Sustanon 100 mg/ml Sustanon 250 mg/ml Testosterone Implants Organon (Merck Sharp & Dohme) Testosterone (G03BA03) Solution for injection Capsule Implant NL/W/0026/pdWS/001 Page 3/8

4 I. EXECUTIVE SUMMARY Based on the submitted paediatric data on is concluded that new safety information should be included in the SmPC s of Andriol, Sustanon and implants. For Andriol the following statement should be included in section 4.2: Safety and efficacy have not been adequately determined in children and adolescents. In addition, the text already included in the SmPC section 4.2 of Sustanon and Testosterone implants should be amended accordingly to include and adolescents. Summary of outcome No change Change for Andriol, Sustanon and Testosterone Implants New study data New safety information: section 4.2 Paediatric information clarified New indication II. RECOMMENDATION For Andriol the following statement should be included in section 4.2: Safety and efficacy have not been adequately determined in children and adolescents. In addition, the text already included in the SmPC of Sustanon and Testosterone implants should be changed accordingly. III. INTRODUCTION The MAH submitted eight (8) paediatric articles for, in accordance with Article 45 of the Regulation (EC) No 1901/2006, as amended on medicinal products for paediatric use. Short critical expert overviews have been provided for each of the 3 formulations separate. The MAH stated that the submitted paediatric articles do not influence the benefit risk for Testosterone Implants, Sustanon and Andriol and that there is no consequential regulatory action. In addition, the following documentation has been included as per the procedural guidance: - None NL/W/0026/pdWS/001 Page 4/8

5 IV. SCIENTIFIC DISCUSSION IV.1 Information on the pharmaceutical formulation used in the clinical studies This paediatric article 45 worksharing procedure includes three pharmaceutical forms of : 1. Testosterone Implants for subcutaneous administration Testosterone implants contain 25 mg, 50 mg, 100 mg or 200 mg of pure without any excipients, and are intended for subcutaneous use. 2. Sustanon for intramuscular administration Sustanon is a preparation containing a mixture of esters. It is available in two formulations, both of which are injected intramuscularly. Sustanon 100 contains 20 mg propionate, 40 mg phenylpropionate, and 40 mg isocaproate. Sustanon 250 contains 30 mg propionate, 60 mg phenylpropionate, 60 mg isocaproate, and 100 mg decanoate. 3. Andriol for oral use. Andriol contains undecanoate (TU) a fatty acid ester of. Each Andriol capsule contains 40 mg TU dissolved in oleic acid. No specific paediatric or extemporaneous formulation is available. IV.2 Non-clinical aspects Introduction Studies in juvenile animals have not been conducted with Andriol. No information on Sustanon or Testosterone Implants has been submitted. IV.3 Clinical aspects Introduction The submitted additional information consists of eight publications 1-8 on six completed paediatric studies all preformed using Andriol 1-6. These articles were published between 1980 and No information on Sustanon or Testosterone implants has been submitted. Summary of the clinical studies Clinical trials in children and adolescents with Andriol have been published in literature 1,2,3,4,5,6. In total 50 boys (anorchid or with constitutional delayed growth and puberty) were studied in six trials. Treatment of prepubertal boys with Andriol ( mg/day) for up to 24 months resulted in increased plasma levels of and DHT 1,2,3,4. Single and multiple doses of Andriol (40-80 mg/day) in boys suffering from delayed puberty did not clearly affect gonadotropin levels 1,2,3. Moreover, the gonadotropin response to GnRH stimulation was also not affected by Andriol 3. A double blind placebo-controlled study was performed to assess whether 20 mg/day Andriol for six months can accelerate growth without an undue advance in bone age in prepubertal boys with constitutional delay of growth. Boys taking Andriol (n=11) showed NL/W/0026/pdWS/001 Page 5/8

6 a significantly greater height velocity and sitting height velocity during treatment than the placebo treated boys (n=12). There was no significantly greater rise in bone age when compared with controls 3. A double-blind placebo-controlled trial was performed in 18 boys with constitutionally delayed puberty treated with 40 mg/day Andriol or placebo for three months. Andriol significantly increased height velocity and fat-free mass velocities after six months but not muscle strength, endurance or total daily energy expenditure 5. An open randomized comparative trial with 40mg/day Andriol (n=17) with 2.5 mg/day oxandrolone (n=16) showed that these treatments were equally effective. Both sex steroid and anabolic steroid treatment induced significant growth acceleration in 14 out of 17 patients on Andriol and 15 out of 16 patients on oxandrolone. No significant difference was found in the anthropometric response. The pattern of epiphysial maturation during treatment was also similar. In both groups there was a similar increase in testicular volume during treatment, followed by a further increase during the six months after treatment. There was also a progressive development in secondary sexual characteristics with a similar rate of maturation in both groups. No adverse effects from administration of either Andriol or oxandrolone were reported 6. One uncontrolled trial in 12 boys showed that mg/day Andriol induced a progressive sexual maturation in 11 out of 12 boys, and induced a gradual advance in bone-maturation in all boys 2. Discussion on clinical aspects and conclusion None of the formulations discussed have a specific childhood indication. In the SmPC of Testosterone Implant and Sustanon is stated - under section that safety and efficacy have not been adequately determined in children (below 18 years of age). Andriol lacks such a statement. The post-marketing surveillance database contains serious adverse events (SAEs) from clinical trials and (S)AEs from spontaneous case reports and literature case reports associated with the use of Andriol. Post-marketing surveillance from introduction (International Birth date March 31, 1978) up to January 1, 2008, includes capsules sold, corresponding to more than 2.1 million patients treated for 1 year with 80 mg/day. The pharmacovigilance database of Andriol has been searched for published case reports from subjects under the age of 18 years treated with Andriol. This search concerns 2 boys; one boy (aged 17 years) had Fabry s disease and developed priapism after 17 days of treatment with 40 mg/day Andriol. He discontinued treatment; his brother (age 18 years) with the same disease discontinued treatment after 4 months, without any AE. The other boy (age 8 years) suffered from Hemophilia B Leyden and was treated with Andriol 40 mg/day resulting in a rise of the clotting factor IX to levels sufficient to prevent most hemorrhages. However, signs of masculinazation and increased growth rate developed. Because the effects on the boy s development were unacceptable the treatment with Andriol was stopped. The above data do not point to any safety issues that would be specific to this age category or requiring warnings other than the ones currently present in the labelling of Testosterone Implant and Sustanon. The few case reports in children and adolescents, not previously submitted to regulatory authorities, do not point to notable safety issues other than known from adults treated with Andriol. However, the safety and efficacy of Andriol has not been established in clinical studies with children and adolescents and cannot be extrapolated from data obtained in adults. NL/W/0026/pdWS/001 Page 6/8

7 Long-term efficacy and safety data in children and adolescents with Andriol are lacking. For these reasons the MAH proposes to include the following statement in section 4.2 of the SmPC of Andriol: Paediatric patients: Safety and efficacy have not been adequately determined in children. Given the comparable active substance and the lack of submitted information, the same conclusion is drawn for Sustanon and Testosterone Implants. The text already included in the SmPCs for Sustanon and Testosterone implants should be changed accordingly with the inclusion of adolescents. V. RAPPORTEUR S OVERALL CONCLUSION AND RECOMMENDATION Overall conclusion No new or unexpected adverse events are reported. Long-term efficacy and safety data in children and adolescents with is still lacking. This justifies the already included comment in section 4.2: Safety and efficacy have not been adequately determined in children in the SmPC of Sustanon and Testosterone Implants. The MAH however should add and adolescents to the sentence, as long-term efficacy and safety data on in children and adolescents up to 18 years of age are lacking. Recommendation For Andriol it is agreed with the MAH to include the proposed statement in section 4.2, with addition of adolescents : Safety and efficacy have not been adequately determined in children and adolescents. In addition, the text already included in the SPC of Sustanon and Testosterone implants should be changed accordingly. The patient leaflets for Andriol, Sustanon and Testosteron should be updated conform the proposed changes in the SmPC: Children and Adolescents Safety and efficacy have not been adequately determined in children and adolescents Request for supplementary information Not applicable VI. LIST OF MEDICINAL PRODUCTS AND MARKETING AUTHORISATION HOLDERS INVOLVED In the Netherlands Andriol Testocaps, capsules 40 mg (RVG 07531) Sustanon 100 mg/ml, oplossing voor injectie (RVG 00026) Sustanon 250 mg/mi, oplossing voor injectie (RVG 00027) Testosterone Implants Sustanon is marketed in Estonia, Ireland, Slovak Republic, United Kingdom, the Netherlands NL/W/0026/pdWS/001 Page 7/8

8 VII. REFERENCES 1 Geere G, Jones J, Atherden SM, Grant DB. Plasma androgens after a single oral dose of undecanoate. Arch Dis Child 1980;55: Weil J, Bidlingmaier F, Butenandt O, Sippell WG, Baumgartner W, Knorr D.Treatment of anorchia with oral undecanoate; pharmacodynamics and clinical effectiveness. Acta Endocrinol 1980;95: Brown DC, Butler GE, Kelnar CJH, Wu FCW. A double blind, placebo controlled study of the effects of low dose undecanoate on the growth of small for age, prepubertal boys. Arch Dis Child 1995;73: Katz M, De Sanctis V, Vullo C, Wonke B, McGarrigle HHG, Bagni B. Pharmacokinetics of sex steroids in patients with β-thalassaemia major. J Clin Pathol 1993;46: Gregory JW, Greene SA, Thompson J, Scrimgeour CM, Rennie MJ. Effects of oral undecanoate on growth, body composition, strength and energy expenditure of adolescent boys. Clin Endocrinol 1992;37: Albanese A, Kewley GD, Long A, Pearl KN, Robins DG, Stanhope R. Oral treatment for constitutional delay of growth and puberty in boys: a randomised trial of an anabolic steroid or undecanoate. Arch Dis Child 1994;71: Endres W, Shin YS, Rieth M, Block T, Schmiedt E, Knorr Dl. Priapism in Fabry's disease during treatment. Klin Wochenschr 1987;65: Briet, E Wijnands MC, Veltkamp JJ. The prophylactic treatment of hemophilia B Leyden with anabolic steroids. Ann. Intern. Med. 1985; 103: NL/W/0026/pdWS/001 Page 8/8