ANNEX I LIST OF THE NAMES, PHARMACEUTICAL FORMS, … · 2010. 6. 3. · Italy Molteni Farmaceutici L. Molteni E C. Dei F .Lli Alitti Societa' di Esercizio S.P.A. Strada Statale 67

1

ANNEX I

LIST OF THE NAMES, PHARMACEUTICAL FORMS, STRENGTHS OF THE MEDICINALPRODUCTS, ROUTES OF ADMINISTRATION, MARKETING AUTHORISATION

HOLDERS, PACKAGING AND PACKAGE SIZES IN THE MEMBER STATES

National Marketing Authorisations

MemberState

MarketingAuthorisationHolder

Inventedname

Strength Pharmaceutical Form Route of administration Packaging Content(concentration)

Package size

2

Italy A. MenariniIndustrieFarmaceuticheRiunite S.R.LVia Sette Santi, 3IT-50131 Firenze

Osteotonina 50 IU/ml100 IU/ml

Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1ml 5

OsteotoninaSpray

200IU/dose

Nasal spray, solution nasal use Vial (12 doses) 1

Osteotonina 400IU/2ml


Vial Multidose 2 ml

Italy Alfa WassermannS.P.A.Contrada S. Emidio65020 AlannoITALY

Tonocalcin 50 IU100 IU


Ampoule 1 ml 5

Italy Aventis PharmaS.P.A.Piazzale Turr, 5IT-20100 Milano

Rulicalcin 50 IU100 IU


Ampoule 1 ml 5

Italy Laboratorio ChimicoGarant S.R.L.Via MelchiorreGioia, 47IT-20100 Milano

Salmocalcin 50 IU100 IU

Solution for injection Intramuscular useIntravenous use

Ampoule 1ml

Italy Dompe'Farmaceutica SPAVia S. Martino, 12IT-20122 Milano

Prontocalcin 50 IU/0,5ml


Ampoule 0,5 ml 6

Prontocalcin 100 IU/ml Solution for injection Intramuscular useIntravenous use

Ampoule 1 ml 5

3

Italy Esseti FarmaceuticiS.P.A.Via dei Mille, 40IT-80046 Napoli

Biocalcin 50 IU/ml100 IU/ml


Ampoule 1 ml 5

Italy F.I.R.M.A. SPAVia di Scandicci, 37IT-50143 Firenze

CalcibenFiale

50 IU Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

CalcibenFiale


Ampoule 1 ml 5

CalcibenSpray

200IU/dose

Nasal spray, solution Nasal use Vial (12 doses) 1

Italy Francia FarmaceuticiIndustriaFarmaco BiologicaS.R.LVia dei Pestagalli, 720138 MilanoITALY

Miadenil 50 IU/ml100 IU/ml


Ampoule 1 ml 5

Italy Instituto BiochimicoNazionaleSavio SRLVia E. Bazzano, 14IT-16019 RoncoScrivia

Porostenina 50 IU/ml100 IU/ml

Solution for injection Intramuscular useSubcutaneous use

Ampoule 1 ml 5

Italy L P B InstitutoFarmaceutico SPAStrada Statale 233(Varesina) Km 20,5IT-21040 Origgio

Miacalcic 50Fiale


Ampoule 1 ml 5

Miacalcic100 Fiale


Ampoule 1 ml 5

MiacalcicSpray

200IU/dose


4

Italy MolteniFarmaceuticiL. Molteni E C. DeiF .Lli AlittiSocieta' di EsercizioS.P.A.Strada Statale 67Tosco RomagnolaIT-50018 FrazioneGranatieri-Scandicci

Calcitene 50 IU Solution for injection Injectable use Ampoule 1 ml 5

Calcitene 100 IU Solution for injection Injectable use Ampoule 1 ml

Italy La.Fa.Re. S.R.L.Via SacerdoteBenedettoCozzolino, 77IT-80056 ErcolanoResina (NA)

Salmofar 50 IU Solution for injection Intramuscular useSubcutaneous use

Ampoule 1 ml

Salmofar 100 IU Solution for injection Intramuscular useSubcutaneous use

Ampoule 1 ml 5

Italy Laboratorio ItalianoBiochimicoFarmaceuticoLisapharma S.P.A.Via Licinio 11-15IT-22036 Erba

Calco 50 IU Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Calco 100 IU Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Italy MagisFarmaceuticiniS.P.A.Via Cacciamali, 3436 38AIT-25128 Brescia

Catonin 100 IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

1 ml 5

Italy Novartis FarmaS.P.A.Strada Statale 23

CalcitoninaSandoz Fiale

50 IU Solution for injection Intramuscular useIntravenous use

Ampoule +Syringe

1 ml Ampoule1 ml + 5 syringes

5

Km 20,5IT-21040 Origgio(VA)

Subcutaneous use

CalcitoninaSandoz Fiale


Ampoule +Syringe

1 ml Ampoule 1 ml + 5 Syringes

CalcitoninaSandozSpray

200IU/dose

Nasal spray, solution Nasal use Vial (12doses) 1 vial

Italy Nuovo ConsorzioSanitario NazionaleS.R.L.Via Svetonio, 6IT-00136 Roma

Osteovis 50 IU/ ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Osteovis 100 IU/ ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Italy Pierre Fabre ItaliaS.P.AVia G.G.Winckelmann, 1IT-20146 Milano

Ellecalcin 50 IU/ ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Italy Procter & GambleHolding S.P.A.Viale Cesare Pavese,385IT-00144 Roma(Rep: Mrs SilviaEtock:T:39 06 50090058, F:39 06 50090092

Carbicalcin 0.25 mg Powder for solutionsolution for injection

Subcutaneous use Ampoule 1 ml 5

Calcitonina50 Armour

50 IU/0.5ml

Solution for injcection Intramuscular useIntravenous useSubcutaneous use

Prefilled syringe 0.5 ml 6 s

6

Calcitonina100 Armour

100 IU/ml Solution for injcection Intramuscular useIntravenous useSubcutaneous use

Prefilled syringe 1 ml 5

Italy Pulizer ItalianaS.R.L.Via Tiburtina, 1004IT-00156 Roma

Calciosint 50 IU/ ml100 IU/ ml


Ampoule 1 ml 5

Italy Rottapharm S.R.L.Via Valosa di Sopra,9IT-20052 Monza

Sical 50 50 IU/ml solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Sical 100 100 IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Sical 200 200 IU/neb Nasal spray, solution Nasal use

Italy Salus ResearchesS.P.A.Via Aurelia, 58IT-00165 Roma

IpocalcinFiale

50 IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

IpocalcinFiale


Ampoule 1 ml 5

Italy San CarloFarmaceutici SPATorre MaggioreIT-00040 SantaPalombaPomezia

Calcioton 50 IU/ml Solution for injection Intramuscular useIntravenous use

Ampoule 1 ml 5

Calcioton 100 IU/ml Solution for injection Intramuscular useIntravenous use

Ampoule 1 ml 5

Italy Sigma-Tau IndustrieFarmaceuticheRiunite SPAViale Shakespeare,

Eptacalcin 50 IU/0,5ml


Ampoule 0,5 ml 6 x 0,5 ml + 6 syringes

7

47IT-00144 Roma

Eptacalcin 100 IU/ml Solution for injection Intramuscular useIntravenous use

Ampoule 1 ml 5 x 1 ml + 5 syringes

Italy GlaxoSmithklineS.p.AVia ZambelettiIT-20021 Baranzatedi Bollate (Milano)

Turbocalcin Solution for injection Intramuscular useIntravenous use

Ampoule 1 ml

Italy So.Se.Pharm S.R.L.Societa'DiServizio perL'industriaFarmaceutica Ed AffVia dei CastelliRomani, 22IT-00040 Pomezia(Roma)

Steocin 50 IU Powder for solution forinjection

Intramuscular useSubcutaneous use

Ampoule+ampoule solvent

1 ml + 2 ml 6 x 1 ml + 6 amp solvent

Steocin 100 IU Powder for solution forinjection


Ampoule +Ampoule solvent

1 ml + 2 ml 5 x 1 ml + 5 amp solvent

Tosi FarmaceuticiS.A.S.Corso della Vittoria,12/BIT-28100 Novara

Osteocalcin 50 IU/ml Solution for injection Intramuscular useIntravenous use

Ampoule 1 ml 5

Osteocalcin 100 IU/ml Solution for injection Intramuscular useIntravenous use

Ampoule 1 ml 5

FAGENS.S. 233 (Varesina)Km. 20.5Origgio Varese

CalcitoninaFagen

200 IU Nasal spray, solution Nasal use Vial (14 doses) 1 vial

Germany ct-ArzneimittelGmbHLengeder Str. 42a

Calcitoninvon ctnasenspray

100IU/dose

Nasal spray solution Nasal use Spray container 1,39 ml (14doses)

1

8

D-13407 Berlin

Calcitoninvon ctnasenspray

100IU/dose

Nasal spray solution Nasal use Spray container 2,78 ml (28doses)

1

Calcitonin 50von ct Amp.

50 IU/ml Solution for injection Subcutaneous use Ampoule 5,10,20, 50

Calcitonin100 von ctAmp.

100 IU/ml Solution for injection Subcutaneous use Ampoule 5,10,20, 50

Germany Ratiopharm GmbHGraf-Arco-Str. 3D-89079 Ulm

Calcitonin-Ratiopharmnasenspray

100IU/dose

Nasal spray, solution Nasal use Spray container 1,39 ml (14doses)

1

Calcitonin-Ratiopharmnasenspray

100IU/dose

Nasal spray, solution Nasal use Spray container 2,78 ml (28doses)

1

CaltoninRatiopharmanasenspray

100IU/dose

Nasal spray, solution Nasal use Vial

Caltoninnasenspray

100IU/dose

Nasal spray, solution Nasal use Vial

Calcitonin-Ratiopharm50

50 IU/ml Solution for injection Injectable use Ampoule 1 ml 5, 10, 20, 50

Calcitonin-Ratiopharm100


Lachscalcitonin –ratiopharm50

50 IU/ml Solution for injection Injectable use Ampoule 1 ml

Lachscalcitonin –

100 IU/ml Solution for injection Injectable use Ampoule 1 ml

9

ratiopharm100

Germany Jenapharm GmbH &Co. KGOtto-Schott-Str. 15D-07745 Jena

Ostostabil 50I.E


Prefilledsyringe/Ampoule

1 ml ampoule Pre-filled syringe: 5, 25Ampoules 5, 10, 20 x1ml

Ostostabil100 I.E


Prefilledsyringe/Ampoule

1 ml ampoule Pre-filled syringe: 5, 25Ampoules 5, 10, 20 x1ml

Germany Rotexmedica GmbHArzneimittelwerkBunsenstr. 4D-22946 Trittau

Calcitonin 50I.E. -Rotexmedica


Ampoule 1 ml 5, 10, 20, 50

Calcitonin100 I.E -Rotexmedica


Ampoule 1 ml 5, 10, 20, 50

Germany Hexal AGIndustriestr. 25D-83607Holzkirchen

Osteoposan50

50 IU/ml Solution for injection Injectable use Ampoule 1 ml 5, 10, 20, 50 (5x10)

Osteoposan100

100 IU/ml Solution for injection Injectable use Ampoule 1 ml 5, 10, 20, 50 (5x10)

Calcibio 50 50 IU Solution for injection Intravenous infusionIntramuscular injectionSubcutaneous injection

Ampoule 1 ml 5, 10, 20, 50 (5x10)

Calcibio 100 100 IU Solution for injection

Germany TAD Pharma GmbHHeinz-Lohman-Str.5D-27472 Cuxhaven

Osteos 50 50 IU Solution for injection Subcutaneous useIntramuscular use

Ampoule 1 ml 5, 10, 25

Osteos 100 100 IU Solution for injection Subcutaneous useIntramuscular use


10

Germany Wieb PharmVertriebs GmbHJohann-Sebastian-Bach Str. 45D-59457 Werl

CalcitoninWieb 50 I.E


Ampoule 1 ml (50 I.E/ml) 5, 20, 50 (5x10)

CalcitoninWieb 100 I.E


Ampoule 1 ml (100I.E/ml)

5, 20, 50 (5x10)

Germany Exterius HelathcareBmbHRobert-Kock-Str 2D-51674 Wiehl

CalcitoninExterius 50I.E.

50 IU/ml Solution for injection Injectable use Pre-filled syringe 1 ml 5, 25

CalcitoninExterius 100I.E.

100 IU/ml Solution for injection Injectable use Pre-filled syringe 1 ml 5, 25

CalcitoninOpfermann50 I.E.


CalcitoninOpfermann100 I.E.


Germany Azupharma GmbH& CoDieselstr.5D-70839 Gerlingen

Azucalcitonin 50 I.E.

50 IU/ml Solution for injection Injectable use Ampoule 5, 20, 50

Azucalcitonin 100 I.E.

100 IU/ml Solution for injection Injectable use Ampoule 5, 20, 50

Azucalcit 50I.E.



Azucalcit100 I.E.


Ampoule 5, 20, 50

11

CalcitoninAZUNasenspray

100IU/dose

Nasal spray, solution Nasal use Spray container 2 ml 1, 3 vials

Germany Stadapharm GmbHStadastr. 2-18D-61118 Bad Vilbel

Calcitoninstada 50 IE


Ampoule 1 ml 5, 10, 20, 50

CalcitoninStada 100 IE


Ampoule 1 ml 5, 10, 20, 50

MIBE GmbHArzneimittelLuise-Ullrich-Str. 6D-82031

Calcitex 50 50 IU Solution for injection Injectable use Vial + solventampoule

Calcitex 100 100 IU Solution for injection Injectable use Vial + solventampoule

3, 5, 10, 20, 50, 60

Germany Novartis PharmaGmbHRoonstr. 25D-90429 Nuernberg

Cibacalcin0,25 mg

0,25 mg Powder and solvent forsolution for injection

Intramuscular useIntravenous useSubcutaneous use

Vial + solventampoule

(50 IU/ml afterreconstitution)

5, , 50, 60 vials + ampoules

Cibacalcin0,5 mg



Vial + solventampoule

(100 IU/ml afterreconstitution)

5, 50 vials + ampoules

Human-Calcitonin-Novartis


Injectable use Vial + solventampoule

5, 50

Miacalcic200 I.E.Nasenspray

200 IU/neb Nasal spray, solution Nasal use Vial (14 doses) 1

Ostulex 200I.E.Nasenspray


Karil 50 I.E.Injektionsloesung


Ampoule 0,5 ml 5, 50, 100

12

Karil 50 I.E.Injektionsloesung


Prefilled syringe 0,5 ml 5, 10, 20

Karil 100I.E.Injektionsloesung


Ampoule 5, 10, 50, 100

Karil 100I.E.Injektionsloesung

100 IU Solution for injection Injectable use Prefilled syringe 1 ml 5, 10, 100

Karil 100 I.ENasenspray

100 IU Nasal spray, solution Nasal use Spray container 2 ml 1

Karil 200I.E.Nasenspray

200 IU Nasal spray, solution Nasal use Vial (14 doses) 1

Germany Aventis Rhone-Poulenc-RorerGmbHnattermannallee 1Koeln D-50829

Calsynar 100 100 IU Solution for injection Intramuscular useIntravenous useSubcutaneous use

Prefilled syringe 5 x 1 ml,2 x 5 à 1 ml,5 x 5 à 1 ml

Greece Proel S.A. KoronisE.G.Dilou 9GR-12134 Peristeri

Nylex 100 IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Nylex 100 IU/ml Nasal spray, solution Nasal use Vial 2 ml (14 doses)

Nylex 100 IU/ml Nasal spray, solution Nasal use Vial 4 ml (28 doses)

Greece Pharmacia &Upjohn Hellas A.E.Mar. Antypa 62-66GR-14121 N.

Ostosalm 50 IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

13

Irakleio, Attiki

Ostosalm 100 IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous useIntr.For.Inf

Ampoule 1 ml 5

Ostosalm 50 IU/dose Nasal spray, solution Nasal use Vial 2 ml (14 doses)

Ostosalm 100IU/dose

Nasal spray, solution Nasal use Vial 1 ml (7 doses)

Ostosalm 100IU/dose


Greece Iasis ChemipharmaA.E.Ag. Kon/nou 40GR-15124 Marousi

Calco 100IU/ml Solution for injection Intramuscular useSubcutaneous use

Ampoule 1 ml 5

Calco 100IU/ml Nasal spray, solution Nasal use Vial 0,9 ml (7 doses)



Greece Aventis PharmaA.E.B.E.2, AftokratorosNikolaou str.GR-17671 Athens

Calsynar 100 IU/ml Solution for injection Intramuscular useSubcutaneous use

Ampoule 1 ml 5

Calsynar 100 IU/ml Solution for injection Intramuscular useSubcutaneous use

Prefilled syringes 1 ml 5

Calsynar 100IU/dose

Nasal spray, solution Nasal use Vial 0,5 ml (7 doses)

Calsynar 100IU/dose

Nasal spray, solution Nasal use Vial Monodose (7, 14, 28 Doses)

Calsynar 200IU/dose

Nasal spray, solution Nasal use Vial 1, 4 ml (14 doses

Greece PharmanelPharmaceutical S.A.

Tosicalcin 100 IU/ml Solution for injection Intramuscular useIntravenous use

Ampoule 1 ml 5

14

Marathonos 106GR-15344 Gerakas

Subcutaneous useIntr. For Inf.

Tosicalcin 100IU/dose

Nasal spray, solution Nasal use Vial 2 ml (15 doses) 2 ml


Nasal spray, solution Nasal use Vial 4 ml (28 doses) 4ml


Nasal spray, solution Nasal use Vial 2 ml (14 doses) 2 ml

Greece Alvia. S.A18 km Athens-Marathonos Ave.Gr-153 44 Pallini

Calciplussolution forinjection

100IU/ampoule

Solution for injection Ampoule 5

Calciplusnasal spray100 IU/dose

100 IU/puff Nasal spray Nasal use Pulverisations 14, 28

Calciplusnasal spray,200 IU/dose

200 IU/puff Nasal spray Nasal use Pulverisations 14

Greece Genepharm S.A.18th KlmMarathonos Ave.GR-15344 Pallini

Genecalcin 100IU/dose


Genecalcin 100IU/dose

Nasal spray, solution Nasal use Vial 4 ml 1x 4ml (28 doses), 2x4 ml(56 doses)

Greece Alfa WassermannDistributor:Demo Abee21st Klm Athina-Lamias Ave.GR-14565 Athens

Tonocalcin 100IU/dose


100IU/dose


100IU/dose


Tonocalcin 100 IU/ml Solution for injection Injectable use Ampoule 1 ml 5

15

Greece Farmedia S.A.2b, Algaiou PelagousStr.GR-15341 Ag.ParaskeviAthens

Ostifix 100IU/ml Solution for injection Parenteral use Ampoule 1 ml 5

Ostifix 50IU/dose Nasal spray, solution Nasal use Vial 2 ml (14 doses)Ostifix 100IU/dose Nasal spray, solution Nasal use

Greece Anfarm Hellas S.A.Acharnon 442GR-11143 Athina

Miadenil 100IU/ml Solution for injection Ampoule 1 ml 5

Greece Biomedica - ChemicaS.A.25 G. Lyra Str.14564 KiphisiaGreece

Osticalcin 50IU/dose Nasal spray, solution Nasal use Vial 2 ml

Osticalcin 100IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Norcalcin 100IU/dose Nasal spray, solution Nasal use Vial 2 ml (15 doses)

Norcalcin 100IU/dose Nasal spray, solution Nasal use Vial 4 ml (28 doses)

Norcalcin 50IU/ml Solution for injection Norcalcin 100IU/ml Solution for injection Ampoule 1 ml 5

Greece V. Niadas & SonsS.A. Agias Marinas Str. GR-19002 Peania -Attica

Neostesin 100IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Neostesin 50IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Neostesin 50IU/dose Nasal spray, solution Nasal use Vial 2 ml (14 doses) Neostesin 100IU/dose Nasal spray, solution Nasal use

16

Greece Kleva E.P.E.Parnithos Ave. 189GR-13671 Acharnai

Alciton 50IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Alciton 100IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Alciton 100IU/dose Nasal spray, solution Nasal use Vial 0,9 ml (7 doses)

Alciton 100IU/dose Nasal spray, solution Nasal use Vial 1x14 doses x 10IU/dose

Alciton 100IU/dose Nasal spray, solution Nasal use Vial 1x28 doses 1 100IU/dose

Greece Rafarm A.E.B.E.Korinthou 12GR-15451 N.Psychiko

Rafacalcin 50IU/dose Nasal spray, solution Nasal use Vial 2 ml (14 doses)

Rafacalcin 100IU/dose Nasal spray, solution Nasal use Vial 2 ml (14 doses)Rafacalcin 100IU/dose Nasal spray, solution Nasal use Vial 4 ml (28 doses)

Rafacalcin 50IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Rafacalcin 100IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Greece Elpen S.A.PharmaceuticalIndustry21st Klm MarathonosAve.GR-19009 Pikermi

Tendolon 50IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Tendolon 100IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

17

Tendolon 100IU/dose Nasal spray, solution Intramuscular useIntravenous useSubcutaneous use

Vial 2 ml (14 doses)

Tendolon 100IU/dose Nasal spray, solution Intramuscular useIntravenous useSubcutaneous use

Vial 4 ml (28 doses)

Greece FARAN S.A.Production &Marketing ofMedicinesAchaias & Trizinias145 64 KifissiaGreece

Latonina 100IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Prefilled syringes 1 ml 5

Latonina 100IU/dose Nasal spray, solution Vial 2 ml

Latonina 100IU/dose Nasal spray, solution Vial 3,5 ml (28 doses)

Greece BoehringerIngelheim HellasS.A.Ellinikou 2GR-16777 Elliniko

Crocalcin 100IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Crocalcin 100IU/dose Nasal spray, solution Nasal use Vial 2 ml (15 doses)Crocalcin 100IU/dose Nasal spray, solution Nasal use Vial 4 ml (28 doses)

Greece Vocate Ltd.Gounari 150GR-16674 AnoGlyfada

Iricalcin 100IU/dose Nasal spray, solution Nasal use Vial 1,3 ml (14 doses)

Iricalcin 100IU/dose Nasal spray, solution Nasal use Vial 3,3 ml (28 doses)

Iricalcin 100IU/ml Solution for injection Ampoule 1 ml 5

Greece ADIPHARM Ltd.54 Marni StreetGR-10437 AthensGreece

Salmoten 100IU/ml Solution for injection Vial 2 ml (14 doses)

18

Salmoten 100IU/ml Solution for injection Vial 4 ml (28 doses)

Salmoten 100IU/dose Nasal spray, solution Nasal use Ampoule 1 ml 5

Salmofar 100IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Greece Novartis (Hellas)S.A.C.I12 km of NationalRoad no1GR-14451MetamorphosiAttikis, Athens

Cibacalcin 0,5mg Powder for solution forinjection

Miacalcic 100IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Miacalcic 100IU/dose Nasal spray, solution Nasal use Vial 2 ml 1

Miacalcic 200IU/dose Nasal spray, solution Nasal use Vial (14 doses)

Ireland NovartisPharmaceuticals UKLtdt/a SandozPharmaceuticalsFrimley BusinessParkFrimley CamberleySurreyUK

miacalcic 50 IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Miacalcic 100 IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

miacalcic 400 IU/2ml


Multidose vial 2 ml 1

19

miacalcic 100 IU Nasal spray, solution Nasal use Vial (14 doses) 1

miacalcic 200 IU Nasal spray, solution Nasal use Vial (14 doses) 1

ostulex 200 IU Nasal spray, solution Nasal use Vial (14 doses) 1

miakaril 200 IU Nasal spray, solution Nasal use Vial (14 doses) 1

Ireland Rhone-Poulenc Rorer50 Kings HillAvenueWest MallingKent ME19 4AH

calsynar 100 IU Solution for injection Nasal use Vial (14 doses) 1

calsynar 200 IU Solution for injection Nasal use Vial (14 doses) 1

Netherlands Novartis PharmaB.V.Raapopseweg 1NL-6824 DP ArnhemPO-Box 241NL-6800 LZArnheim

Calcitonine-Sandoz

100 IU/ml Solution for injection Intravenous use Ampoule 5

Portugal Novartis Farma,ProdutosFarmacêuticos SARua do CentroEmpresarial, Edifício8Quinta da Beloura2710-444 SintraPortugal

Cibacalcina 0,25 mg/ml Powder and solvent forsolution for injection


Ampoules 1 ml 5

Cibacalcina 0,5 mg/2ml Powder and solvent forsolution for injection


Ampoules 2 ml 5

Miacalcic 50 IU/ml100 IU/ml

Solution for injection Intramuscular useSubcutaneous useIntravenous use

Ampoule 1 ml 5

20

Miacalcic 100 IU/ml Solution for injection Intramuscular useSubcutaneous useIntravenous use

Ampoule 1 ml 5

Miacalcic 200Spray Nasal

200IU/dose

Nasal spray, solution Nasal use Spray container 1 unit 1 x 14 doses, 1 x 28 doses

Portugal Aventis Pharma Lda.PRT EstradaNacional 249, km 15P.º Box 392726-922 MemMartinsPortugal

Calsyn 100 IU/2ml Solution for injection Intravenous use Vial 2 ml 6

Calsyn 400 IU/2ml Solution for injection Intravenous use Vial 2 ml 1

Calsyn 50 IU/0,5ml

Solution for injection Intravenous use Pre-filled syringe 0,5 ml 2, 5

CalsynMonospray

100IU/dose

Nasal spray, solution Nasal use Bottle 1 1 x 14 doses, 1 x 28 doses

Calsyn 100IU/dose

Nasal spray, solution Nasal use Bottle 1 1 x 7 doses

Portugal Laboratórios Delta,LdaRua Direita no°148Massamá2745-751 QueluzPortugal

Bionocalcin 50 IU/ml Solution for injection Intramuscular useSubcutaneous useIntravenous use

Ampoule 1 ml 5

Bionocalcin100

100 IU/ml Solution for injection Intramuscular useSubcutaneous useIntravenous use

Ampoule 1 ml 5

Bionocalcin 50 IU/dose Nebuliser, solution Nasal use Spray container 1 unit 1 x14 doses

Bionocalcin100

100IU/dose

Nasal spray, solution Nasal use Spray container 1 unit, 2 units 1 x 14 doses, 1 x 28 doses

21

Portugal BYK Portugal –Produtos Quimicos eFarmacêuticos, LdaQuinta da Fonte-Edíficio Gil Eanes2780 –730 PaçoD’ArcosPortugal

Calcimon 50 IU/ml Solution for injection Intramuscular useSubcutaneous useIntravenous use

Ampoule 1 ml 5

Calcimon 100 IU/ml Solution for injection Intramuscular useSubcutaneous useIntravenous use

Ampoule 1 ml 5

Calcimon 50 IU/dose Nebuliser, solution Nasal use Spray container 2 ml 1 x14 doses

Portugal PharmaciaCorporationLaboratórios, Lda.Avenida do Forte, 3-Edifício Suécia IIP.O. Box 2062795-505 CarnaxidePortugal

Salcat 100IU/dose

Nasal spray, solution Nasal use Bottle 1 unit 1 x 21 units, 1x 28 units

Salcat 200IU/dose

Nasal spray, solution Nasal use Bottle 1 unit 1 x 7doses, 1x 14 doses

Portugal Euro LaborLaboratórios deSíntese Quimica eEspecialidadesFarmaceuticas, S.A,Rua Alfredo Silva,n.º16, P.O. Box602702720-028 AmadoraPortugal

Ostinate 100 100 IU Nasal spray, solution Nasal use Bottle 1 unit 1 x 7doses, 1x 14 doses, 1 x28 doses

Ostinate 200 200IU/dose

Nasal spray, solution Nasal use Bottle 1 unit 1x 14 doses, 1 x 28 doses

22

Portugal PH&T, SpAVia Ariosto, 3420145 MilanoItaly

Neostesin 50 IU/dose Nasal Spray, solution Nasal use Bottle 1 ml 1

Neostesin 50 IU/dose Nasal Spray, solution Nasal use Bottle 2 ml 1

Portugal Sociedade deProdutosFarmacêuticosWander Lda.Rua do CentroEmpresarial, Edifício8Quinta da Beloura2710-444 SintraPortugal

CalcitoninaWander 200

200IU/dose

Nebuliser, solution Nasal use Spray container 1 unit 1 x 14 doses

Portugal Laboratório Normal,ProdutosFarmacêuticos,SA.Rua do CentroEmpresarial, Edifício8Quinta da Beloura2710-444 SintraPortugal

Osseocalcina200

200IU/dose


Portugal Probios ProdutosQuímicos eFarmacêuticos LdaRua João Chagas 53– A, 2°- Escritório2011495-072 AlgésPortugal

Calogen 100 IU/ml Solution for injection Intramuscular useSubcutaneous useIntravenous use

Ampoules 1 ml 6

Calogen 100IU/dose


23

Portugal Zambon-ProdutosFarmacêuticos, Lda.Rua ComandandanteEnrique Maya n°1.1500-370 LisboaPortugal

Tonocaltin100

100IU/dose

Nebuliser solution Nasal use Bottle 1 unit 1 x 7 doses, 1 x 14 doses

Portugal Sanofi-Syntelabo-ProdutosFarmacêuticos SAPraça Duque deSaldanha nº1-4º1050-094 Lisboa

Calco 50 IU/ml100 IU/ml

Solution for injection Subcutaneous useIntramuscular use

Ampoule 1 ml 5

Calco 50 IU/dose100IU/dose

Nasal spray, solution Nasal use Bottle 0,9 ml 1

Portugal Rotta Farmacêutica,Unipessoal Lda.R. Direita daMassamá, 1502745-751 Sintra

Bionocálcio100

100IU/dose

Nasal spray, solution Nasal use Spray container 1 unit (2 ml) 1

Spain Almirall -Prodesfarma S.A.General Mitre, 15108022 BarcelonaSPAIN

CalcitoninaAlmirallinjectable

100 IU/ml Injection Subcutaneous useIntramuscular use

Ampoule 1 ml 10

CalcitoninaAlmirall 200UImonodosespray nasal

200IU/dose

Nasal spray, solution Nasal use Vial Monodose spray28 vials

CalcitoninaAlmirall 200UI multidosespray nasal

200 IU/vial Nasal spray, solution Nasal use Vial (14 doses) Monodose spray1

CalcitoninaAlmirall 200UI multidosespray nasal

200 IU/vial Nasal spray, solution Nasal use Vial (28 doses) Monodose spray2

24

Calogenspray nasal100 aerosol

100IU/NEB

Nasal spray, solution Nasal use Vial (28 doses) 1 multidose vial

Calogeninjectable

100 IU/ml injection Subcutaneous useIntramuscular use

Ampoule 1 ml 10

Spain ICN-Ibericac/Casanova, 27-3108757 Corbera deLlobregatBarcelonaSPAIN

CalcitoninaHubber 100UI injectable

100 IU/ml Solution for injection Subcutaneous useIntramuscular use

Ampoule 1 ml 10

CalcitoninaHubber 200UI solucionparapulverazacionnasalmultidosis

200 IU/neb Nasal spray, solution Nasal use Vial 14 doses

CalcitoninaHubber Nasal200 UImonodosis


CalcitoninaHubber Nasal200 UImonodosis


Spain Aventis Pharma S.A.Martinez Villergas5228027 MadridSPAIN

Calsynar 100 100 IU/vial Vial Subcutaneous useIntramuscular use

Vial 1 vial + 1 ampoule solvent,10 vials + 10 ampoulesolvent

Calsynar 50 50 IU/vial Vial Subcutaneous useIntramuscular use

Vial 2 ml 10 vials 2 ml+ 10 ampoulesolvent

Calsynarintranasal 200UI monodosis

200 IU Nasal spray, solution Nasal use Vial (28 doses)

Calsynar 200 IU/neb Nasal spray, solution Nasal use Vial 1 vial multidoses 1 vial 14 neb

25

Intranasal Calsynar

Intranasal200IU/dose

Nasal spray, solution Nasal use (28 doses)

Spain NovartisPharmaceutica S.A.Gran Vía de les CortsCatalanes, 76408013 BarcelonaSPAIN

Miacalcic 100100 IU/ml Injection Patenteral use Ampoules 1 ml 1, 10

Miacalcic 200Spray nasal

200 IU/neb Nasal spray, solution Nasal use Vial 1 vial 2 ml (14doses/vial)

1

Miacalcic 200Spray nasal

200 IU/neb Nasal spray, solution Nasal use Vial 2 vials (2ml/vial) (14doses/vial)

2

Spain Altana Pharma S.AFrancisca Delgado 11Parque EmpressarialArroyo de la Veja28 108 AlconbendasMadridSPAIN

Kalsimin 100UI

100 IU/ml Solution for injection Injectable use Ampoule 1 ml 10

Kalsimin 50UI


KalsiminNasal


Spain Faes S.A.Máximo Aguirre, 14LejanaVizcayaSPAIN

Oseototal 100IU

100 IU/ml Injection Subcutaneous useIntramuscular use

Ampoule 1 ml 1, 10

Oseototal 200Spray nasalAerosol

200 IU/neb Nasal spray, solution Nasal use Vial 2 ml (14 doses) 1, 2

26

Spain Laboratorio PadroS.AGran Vía de les CortsCatalanes, 76408013 BarcelonaSPAIN

Ospor Spraynasal

200 IU/neb Nasal spray, solution Nasal use Vial 2 ml (14doses/vial)

2

Ospor Spraynasal

200 IU/neb Nasal spray, solution Nasal use Vial 4 ml (14doses/vial)

2

Spain LaboratoriosCENTRUM S.ASagitario 1403006 AlicanteSpain

Osteobion200 Soluciónparapulverizaciónnasal

200 IU/neb Nasal spray, solution Nasal use Vial (14 doses) 1 vial

Spain RottapharmCarretera deBarcelona, 246132 Almacera(Valencia)SPAIN

Sical 50 UIinjectables


Sical 100 UIinjectables

100 IU/ml Solution for injection Injectable use Ampoule

Sical nasal 50 IU/neb Nasal spray, solution Nasal use Vial 2 ml 2

Spain Zambonc/Haresme s/n Pol.UrvasaSta Perpetua deMogodaBarcelonaSPAIN

Tonocaltin100 IUSpray nasal

100 IU/ml Solution for injection Injectable use Ampoule 1, 10

Tonocaltin200 UISolución parapulverizaciónnasal

200IU/dose

Nasal spray, solution Nasal use Vial 2,1 ml (14 pul) 14 pulv

27

Tonocaltin 50UI ampoule


Spain Alcalá Farma , S.LCtra. M-300, km.29,920Alcalá de Henares(Madrid)Spain

CarbicalcinSpray Nasal


Carbicalcininyectable

40 IU/ml Solution for injection Intramuscular use Ampoule 1 ml 10

Spain Ferrer Internacional,S.A.Grand Via Carlos III,9408028 BarcelonaSPAIN

Diatininjectable

40 IU/ml Solution for injection Injectable use Ampoule 1ml 10

Diatin spraynasal


Spain Cepa SchwarzPharma S.LPuerta de laCastellana 141Ed. Cuzco IV Planta1528046 MadridSpain

ElcatoninaCEPAinyectable


28

ElcatoninaCEPA Spraynasal

40 IU/neb Nasal spray Nasal use Vial 1 (24 doses)

Spain I.F.CIndustrialFarmaceuticaCantabria, S.A.C/ Arequipa, 128043 MadridSPAIN

ElcatoninaCEPAinjectable


ElcatoninaCEPA Spraynasal


ElcatoninaUR 40 UIaerosol


Sweden Novartis LäkemedelNovartis Sverige ABBox 1150S-18311 TäbySweden


1 ml 5

UnitedKingdom

Novartispharmaceuticals UKltdTrading as: SandozpharmaceuticalsFrimley businesspark

Frimley camberleyUK – Surrey GU16


Ampoules

29

7SR


Ampoules

Miacalcic 200 IU/ml Nasal spray, solution Nasal use Vial (14 doses) 1

Miacalcic 400 IU/2ml Solution for injection Injectable use Vial 2 ml 1

UnitedKingdom

May & Baker Ltd50 Kings HillAvenueWest MallingKent ME19 4AH

Calsynar 100 IU/ml Injection Subcutaneous useIntramuscular use

Ampoule 1, 4, 5

Calsynar 200 IU/ml Injection Subcutaneous useIntramuscular use

Ampoule 1, 4, 5

Austria Novartis PharmaGmbHBrunner Straße 59A-1235 Wien

calcitonin"Novartis"100IE -Ampullen

100 IU/ml Injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

calcitonin"Novartis"50IE -Ampullen

50 IU/ml Injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

calcitonin"Novartis"100 I.E. -Nasalspray

100IU/dose

Nasal spray, solution Nasal use Spray container (16 doses) 1, 3

30

calcitonin"Novartis" 50I.E. -Nasalspray

50 IU/dose Nasal spray, solution Nasal use Spray container (14 doses) 1, 3

Calcitonins“Novartis”200 IEnasalspray

200IU/dose

Nasal spray, solution Nasal use Spray container (14 doses) 1

calcitonin"Novartis"100IE -Spritzampullen


Ampoule 1 ml 5 ,20 , 25 ,5 x5

cibacalcin 0,5mg -Doppelkammerspritzampullen

0,5mg/ml Solution for injection Injectable use Syringe 1, 5, 5 x 5

cibacalcin 0,5mg -Trockensubstanz mitLösungsmittel

0,5mg Powder Injectable use Vial 5 vials + 5 solvent5 x 5 vials + 5 solvent

Miacalcic50IE -Ampullen -


Miacalcic 100I.E.-Nasalspray

100IU/dose

Nasal spray, solution Nasal use Vial (14 dose) 1, 3


50 IU/dose Nasal spray, solution Nasal use Vial (14 doses) 1 , 3


200 IU/ml Nasal spray, solution Nasal use Vial (14 doses) 1

Austria F. Joh. KwizdaGesmbH.Dr Karl Lueger-Ring

Calco 100 mgAmpullen

100 mg/ml Injection Subcutaneous useIntramuscular use

Ampoule 1 ml 5

31

6A- 1010 Wien

Calco 50 mgAmpullen

50 mg/ml Injection Subcutaneous useIntramuscular use

Ampoule 1 ml 5

Austria UCB PharmaGesmbHBrünnerstraße 73/5A-1210 Wien

Ucecal 50I.E.Injectionslösung


Ampoule 1 ml 1, 5, 5x5

Ucecal 100I.E.Injectionslösung


Ampoule 1 ml 1, 5, 5x5

Ucecal 100I.E.Nasalspray

100 IU/ml Solution for injection Nasal use Vial 0,1 ml 2,1 ml, 3,5 ml

Ucecal 200I.E.Nasalspray

200 IU/ml Solution for injection Nasal use Vial 0,1 ml 2,1 ml, 3,5 ml

Austria PHARMACIA &Upjohn Pharma-Handels GesmbHOberlaaerstraße 247-251 A-1100 Wien

casalm 100I.E./ml -Spritzampullen


Prefilled syringe 1 ml 5, 5x5

casalm 50I.E./ml -Spritzampullen

50 IU/ml Solution for injection Injectable use Prefilled syringe 1ml 5, 5x5

Austria Nycomed AustriaSt. Peter-Straße 25A-4020 LinzAustria

ELCIMENAmpullen

40 IU/ml Solution for injection 1ml 5, 25

Belgium Aventis Pharma SA-Boulevard de laPlaine 91150 BrusselsBelgium

CalsynarIntranasal

100IU/dose

Nasal spray, solution Nasal use Vial monodose 0,1 ml 14 vials28 vials

32

CalsynarIntranasal

100IU/dose

Nasal spray, solution Nasal use Vial 1 (14 doses )

Calsynar 50 UI/0,5ml


Ampoule-syringe 0,5 ml 5, 15, 30

Calsynar 100 UI/1ml


Ampoule-syringe 1 ml 5, 15, 30

Calsynar 400 UI/2ml


Vial 2 ml 1 vial multidose

Belgium Sanico N.V.Industrieterrein 42300 TurnhoutBelgium

Calcivera 100 IU/0,1ml

Nasal spray, solution Nasal use Monodose 0,1 ml7 doses

Belgium Novartis PharmaN.V.Medialaan 40 bus11800 VilvoordeBelgium

MiacalcicNasal

100IU/dose

Nasal spray, solution Nasal use Vial (14 doses) 1, 4

MiacalcicNasal

200IU/dose


Ostulex 200IU/dose


Miacalcic 50 IU/0,5ml

Solution for injection Injectable use Prefilled syringe 0,5 ml 5,15, 30 x 0,5 ml

Miacalcic 50 IU/ml Solution for injection Injectable use Ampoule 1 ml 5

Miacalcic 100 IU/ml Solution for injection Injectable use Prefilled syringe 1 ml 5, 15, 30, x 1 ml

Belgium Christiaens PharmaS.C.Chaussée de Gand615

Steocalcin 50 IU/ml Solution for injection Injectable use Ampoule 1 ml 5

33

1080 BrusselsBelgium

Steocalcin 50 IU/ml Solution for injection Injectable use Prefilled syringes 1 ml 5l

Steocalcin 100 IU/ml Solution for injection Injectable use Ampoule 1 ml 5

Steocalcin 100 IU/ml Solution for injection Injectable use Prefilled syringes 1 ml 5, 15, 30 x 1 ml

SteocalcinNasal

100IU/dose

Nasal spray, solution Nasal use Vial 1 (14 doses)

Belgium GlaxoSmithKlineS.A.Boulevard duSouverain 1911160 BrusselsBelgium

Carbicalcin 40 UI/0,1ml

Nasal spray, solution Nasal use Vial 1,2 ml (12 doses) 1

Carbicalcin 40 UI/1 ml Solution for injection Intramuscular use Ampoule 1 ml 5

Turbocalcin 40 UI/0,1ml

Nasal spray, solution Nasal use Vial 1,2 ml (12 doses) 1

Turbocalcin 40 UI/1 ml Solution for injection Intramuscular use Ampoule 1 ml 5Denmark Novartis Healthcare

ASLyngbyvej 172DK- 2100Køpenhavn


MiacalcicNasal

100 IU /dos Nasal spray, solution nasal use Vial (14 doses) 1

MiacalcicNasal

200 IU/ dos Nasal spray, solution nasal use Vial (14 doses) 1

Denmark Aventis Pharma A/SSlotsmarken 13DK-2970 Hørsholm

Calsynar 200 IU/ml Solution for injection Parenteral use

34

Finland Novartis Finland OyMetsanneidonkuja 10FI-02130 Espoo

miacalcic 100 IU/ml Solution for injection Injectable use Ampoule 1 ml 5

miacalcicNasal

100 IU/dos Nasal spray, solution nasal use Bottle (14 doses) 1

France Specia15 rue de la VanneFR-92545 MontrougeCedex

LaboratoireAVENTIS46, quoi de la Rapée75601 Paris Cedex12

Calsyn 50 IU Powder for solution forinjection

1 vial 50IU + 1 ampoule 2ml solvent1 vial 50IU

Calsyn 100 IU Powder for solution forinjection

1 vial 100IU + 1 ampoulesolvent1 vial 100IU

Calsyn 50 IU/0.5ml


Ampoule 0,5 ml 1

Calsyn 100 IU/1ml


Ampoule 1 ml 1

France Novartis Pharma S.A2-4 rue Lionel TerrayBP 308FR-92506 ReuilMalmaison Cedex

Miacalcic 50UI/1ml

50 IU/1 ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Miacalcic 80UI/0,8 ml

80 IU/0,8ml


Ampoule 0,8 ml 6

Cibacalcine 0.25 mg Powder and solvent forsolution for injection


Powder ampoulesolvent ampoule

(0,25 mg) + 1 mg (1 ampoule of powder + 1ampoule of solvent) x 5

35

Cibacalcine 0.50 mg Powder and solvent forsolution for injection


Powder ampoule,solvent ampoule

(0,5 mg) + 1 mg (1 ampoule of powder + 1ampoule of solvent) x 5

France GNR Pharma49, avenue GeorgesPompidouFR-92593 LevalloisPerret cedex

CalcitonineGNR 50UI/1ml


CalcitonineGNR 80UI/0.8 ml

80 IU/0.8ml

Solution for injection Injectable use Ampoule 0,8 ml 6

FranceCephalon France20 rue CharlesMartigny94700 Maisons-Alfort

CalcitonineL.lafon


CalcitonineL.Lafon


France Zambon France13 rue Rene Jacques92138 Issy lesMoulineaux Cedex,France

Cadens Gé 50 IU/ml Solution for injection Intramuscular useIntravenous useSubcutaneous use

Ampoule 1 ml 5

Cadens Gé 80IU/0.8ml


Ampoule 0,8 ml 6

France Laboratoires PharmyII – Strategy senter26, rue des GaudinesFR-78100 SaintGerman en Laye

CalcitoninePharmy II


Ampoule 1 ml 5

CalcitoninePharmy II

100 IU/ml Solution for injection Ampoule 1 ml 5

36

France PharmaceutiqueNoroit7, rue Jean-BaptisteClémentFR-94250 Gentilly

Staporos 50UI/1ml

50 IU/ml Solution for injection Ampoule 1 ml 5

Staporos 100UI/1ml

100 IU/ml Solution for injection Ampoule 1 ml 5, 6

Staporos 50UI/1ml

50 IU/ml Pre-filled syringe 1 ml 5

Staporos 100UI/1ml

100 IU/ml Pre-filled syringe 1 ml 6

Luxembourg

Aventis Pharma SA-NV9 Boulevard de laPlaineB-1050 Bruxelles

CalsynarIntranasal

100 IU/0,1ml

Nasal spray, solution Nasal use Bottle 0,1 ml 14

Calsynar 50 IU/0,5ml


Ampoule 0,5 ml 5, 15, 30

Calsynar 100 IU/0,5ml


Ampoule 0,5 ml 5, 15, 30

Calsynar 200 IU/2ml


Bottle 2 ml 1

Luxembourg

Novartis PharmaGmBHRoonstrasse 25D-90429 Nuernberg

Cibacalcin 0.25 mg Powder for injection Injectable use Vial +solventampoule

0,25 mg 5, 20, 50, 60 vial + ampoule

Cibacalcin 0,5 mg Powder for injection Injectable use Vial +solventampoule

0,50 mg 5, 20, 50, 60 vial + ampoule

Karil 50 IU/0.5ml

Solution for injection Prefilled syringe 0,5 ml 50, 100

Karil 100 IU/ml Solution for injection Injectable use Prefilled syringe 1 ml 50, 100

37

Karil 50 IU/0,5ml

Solution for injection Injectable use Ampoule 0,5 ml 5, 50, 100

Karil 100 IU/ml Solution for injection Injectable use Ampoule 1 ml 5, 50, 100

Karil 200IU/dose

Nasal spray, solution Nasal use Bottle 2 ml 1

Miacalcic 200IU/dose

Nasal spray, solution Nasal use Bottle 2 ml 1

Ostulex 200IU/dose


Luxembourg

GlaxoSmithKline s.a.Rue du Tilleul, 131332 GenvalBelgium

Carbicalcin 40 UI/1 ml Nasal spray solution Nasal use Bottle 1 ml 1

Carbicalcin 40 UI/2 ml Nasal spray solution Nasal use Bottle 2 ml 1

Carbicalcin 40 UI/1 ml Solution for injection Intramuscular Ampoule 1 ml 5

38

Norway NovartisPostbox 237, Økern,N- 0510 OsloNorway

MiacalcicNasal

200IU/dose

Nasal spray, solution Nasal use Vial (14 doses) 1 vial

Miacalcic inj.100 IE/ml


39

Iceland Thorarsen LyfLynghals 13110 Reykjavik,Iceland




40

ANNEX II

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARIES OF PRODUCT CHARACTERISTICS PRESENTED BY THE EMEA

41

SCIENTIFIC CONCLUSIONS OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF CALCITONINSCONTAINING MEDICINAL PRODUCTS (see Annex I) Calcitonin has been used since 1973 when injectable forms became available for the treatment ofosteoporosis-related indications. In 1987 preparations for intranasal use became available. Theindications for which calcitonin has been approved varied within the MS and included, prevention andtreatment of osteoporosis from different aetiologies, bone pain due to osteolysis or osteoporoticfractures, Paget’s disease, hypercalcaemia of malignancy and Sudeck syndrome.Calcitonin from different origins is approved in all EU Member States and has been used in clinicalpractice for more than 20 years.

� OVERVIEW OF EFFICACYA discussion on the efficacy of calcitonins containing medicinal products took place in CPMP basedon the Rapporteur’s and Co-Rapporteurs’ Assessment Reports and the data presented by the MAHs.Considerations made on this issue are summarised below.

OSTEOPOROSIS RELATED INDICATIONS- Osteoporosis in post-menopausal women; treatment of osteoporosis in patients who have

established low bone mineral density and/or radiographic evidence of vertebraldegeneration of fractures; treatment of established postmenopausal osteoporosis

- Prevention of postmenopausal osteoporosis; prevention of fast loss of bone mass inhealthy postmenopausal women with risk factors for osteoporosis

There are numerous publications analysing the effects of calcitonin on bone mineral density or contentin osteoporosis. In most of the studies, calcitonin was used intramuscularly or subcutaneously in dosesvarying from 50UI every second day to 100 UI every day. The studies are relatively small, themethods for measuring bone mass are limited, randomisation is insufficiently described and moststudies are not blinded at all. In one study, where biopsies are done on 30 patients, there is no evidenceof mineralisation defect and bone turnover is not abnormally suppressed.Data on fractures, detailed in a case-control study, are very limited. No randomised controlled trialswith fracture as primary endpoint has been performed.Therefore, the CPMP considered that injectable calcitonin lacks efficacy in the treatment ofestablished postmenopausal osteoporosis.No trials are published in which the efficacy of injectable salmon calcitonin for the prevention ofosteoporosis has been studied. However, several controlled studies show that calcitonin administereddaily or intermittently, reduces bone resorption and increases bone mass or bone mineral density,especially at the lumbar spine in patients with postmenopausal osteoporosis. Furthermore calcitonininhibits bone resorption by inducing an almost immediate quiescence of osteoclast motility, which isfollowed by a gradual retraction of the osteoclasts and in inhibiting other components of theosteoclasts playing a role in bone resorption. Therefore through its inhibitory effects upon osteoclast,calcitonin is successfully used for the therapy of disorders of bone loss with of rapid bone turnover.Therefore, the CPMP considered that injectable calcitonin shows efficacy in the prevention of acutebone loss due to sudden immobilisation such as in patients with recent osteoporotic fractures.Efficacy of intranasal calcitonin in “established” osteoporotic patients has been assessed in severalprospective trials. Published studies show a slight increase of bone mass at the lumbar spine in patientsreceiving salmon calcitonin intranasally, as compared to placebo (calcium and vitamin D).The evidence that calcitonin decreases vertebral fracture frequency was investigated in several oftenrelatively small studies. The pivotal study for demonstrating efficacy of the intranasal formulation astreatment of postmenopausal osteoporosis is the PROOF study (Prevention Recurrence ofOsteoporotic Fractures Study). The PROOF study was a randomised, double blind, placebo-controlledtrial of five years duration in 1255 patients. The protocol of the PROOF study was amended and themain focus of interim and final analyses became the pair wise comparison of intranasal calcitonin 200IU versus placebo on new and worsening fractures for the intention to treat group.

42

For non-vertebral fractures, especially hip-fractures, a significant reduction in fractures was measuredfor the 100 IU dose. However, the small number of hip and femoral fractures precluded a meaningfulstatistical analysis.Therefore the CPMP considered that intranasal calcitonin in a daily dose of 200 I.U. shows efficacyin the treatment of established postmenopausal osteoporosis in order to reduce the risk of vertebralfractures. A reduction in hip fractures has not been demonstrated.In studies in the prevention of post-menopausal osteoporosis with intranasal calcitonin the incrementof bone mass was minimal (mean 1.9%), lower than with HRT, but no head-to-head comparisons havebeen reported. The increase occurred during the first 12 months; thereafter no further increase wasmeasured. No fracture data are available.Therefore the CPMP considered that intranasal calcitonin lacks efficacy in the prevention ofestablished postmenopausal osteoporosis.

PREVENTION OF BONE LOSS DURING PROLONGED IMMOBILISATION,ESPECIALLY DURING PARAPLEGIA

For the indication “Prevention of bone loss during prolonged immobilisation, especially duringparaplegia”, no literature was submitted by any of the MAHs further to the List of questions(CPMP/1307/00. A search in Medline by the assessor did not provide any relevant literature on thisitem.Further to the List of Outstanding issues addressed to MAHs (CPMP/4421/00), two studies werediscussed (Minaire P, Depassio J, Meunier P, Edouard C, et al. Calcitonin treatment of acuteosteoporosis resulting from paraplegia. Osteoporosis Proceeding of the International Symposium onosteoporosis 1984; 111-118 and Minaire P, Meunier P, Edouard C, Messy P et al. Acute osteoporosisin paraplegic patients: pathophysiology and effects of treatment with calcitonin ordichlorodimenthylene diphasphonate in osteoporosis. Menczel J & co. John Wiley & sons, p 412-428).In these studies the effect of salmon calcitonin was studied after immobilisation in paraplegic human.The results of both studies are not consistent because the second study does not confirm the positiveeffect found in the first, where it is suggested that salmon calcitonin might prevent bone loss duringimmobilisation due to paraplegia.

The CPMP considered that injectable and intranasal calcitonin lacks efficacy in the indication“Prevention of bone loss during prolonged immobilisation, especially during paraplegia.

OSTEOPOROSIS AND PAIN- Pain caused by vertebral fractures due to postmenopausal osteoporosis;- Treatment of fractures syndrome in recent acute and painful osteoporosis crush- Osteoporosis induced bone pain (chronic pain)

Numerous clinical studies have been conducted with calcitonin in the treatment of vertebral crushsyndrome in osteoporosis, which seems to suggest an analgesic effect of calcitonin, but only fewplacebo-controlled studies have been conducted. No comparative studies have been performed withanalgesics.Studies have been undertaken to determine whether the analgesic effect of calcitonin might be used inpain due to osteoporosis, particularly in the vertebral crush fracture syndrome. Whereas open studieshave indicated relief of pain, the adequate evaluation of the end-point should be based on placebocontrolled randomised studies.None of the trials has given any radiographic definition of vertebral fracture at baseline among theincluded patients. The studies have included a small sample size and no sample size calculation wasperformed. The delay between occurrence of fracture and treatment has not been reported in 3 studies.The population demographic data were usually lacking. Various doses of calcitonin have been usedamong clinical trials. The evaluation criteria varied among studies. Data reports were usually lackingor have insufficient quality. The statistical method of most studies were neither explained nor detailed.Repeated measurements were performed but not evaluated in an adequate statistical way. Patientwithdrawals for side effects were neither analysed nor reported.

43

Therefore, the CPMP considered that injectable and intranasal calcitonin lacks efficacy in thetreatment of Pain caused by vertebral fractures due to postmenopausal osteoporosis, treatment offractures syndrome in recent acute and painful osteoporosis crush and inosteoporosis induced bonepain (chronic pain).

BONE PAIN DUE TO MALIGNANCYSeveral published studies regarding the use of calcitonins in this indication, including several doubleblind placebo controlled and numerous uncontrolled studies were assessed by the CPMP.Further to the assessment of these studies, the CPMP felt that it is unclear which dose is optimal as theeffects are variable and a clear dose response has not been defined. The optimal duration of use isunclear. Therefore, the CPMP considered that injectable and intranasal calcitonin lacks efficacy in thetreatment of bone pain due to malignancy.

PAGET´S DISEASECalcitonin has been used for treatment of Paget’s disease of bone since the late 1960s and there aremany published reports on its efficacy. Remission of symptoms, radiological manifestations and/orbiochemical markers is obtained in about 50-70% of patients with an 80% reduction in markers ofbone turnover.Therefore, the CPMP considered that injectable calcitonin shows efficacy in the treatment of Paget’sdisease.The CPMP found that the efficacy for the injectable formulation has been sufficiently demonstratedbased on the data derived from literature. The opinion differs on the efficacy of intranasal calcitonin inthis indication. In a small study by Gagel et al (1988) 7 patients were treated with intranasal calcitoninand 8 with subcutaneous injected calcitonin. In the group treated by nasal route the decrease in theserum levels of alkaline phosphatase was 33% at the end of 3 months of treatment, whereas in thegroup treated by subcutaneous route the decrease was 40%. The differences between both groups werenot statistically significant.Therefore, the CPMP considered that intranasal calcitonin lacks efficacy in the treatment of Paget’sdisease.

HYPERCALCAEMIA OF MALIGNANCY.Treatment of malignant hypercalcaemia is based on the treatment of the underlying disease (ifpossible), rehydration and drug treatment aimed at decreasing excessive osteoclastic bone resorption.Marketing Authorisation Holders had submitted published data on the efficacy of injectable calcitoninin the treatment of malignant hypercalcaemia. It was shown that calcitonin reduces serum calcium byinhibition of bone resorption and by increasing renal tubular resorption of calcium.Therefore the CPMP considered that injectable calcitonin shows efficacy in the treatment ofhypercalcaemia of malignancy.Further to the List of Outstanding Issues adopted in December 2001, no new data were provided tosupport the efficacy of intranasal calcitonin.Therefore, as this indication is not supported by scientific data, the CPMP considered that intranasalcalcitonin lacks efficacy in the treatment of hypercalcaemia of malignancy.

SUDECK SYNDROME (ALGODYSTROPHY)There are hardly any prospective, randomised trials in this indication. Limitations of treatment studydesigns include use of variable criteria, lack of placebo-treated groups, failure to control for symptomduration, and small patient numbers.Therefore, the CPMP considered that injectable and intranasal calcitonin lacks efficacy in thetreatment of Sudeck syndrome (algodystrophy).

44

� OVERVIEW OF SAFETY

Calcitonin is usually very well tolerated. The WHO database listed adverse event reports from 28countries over a period of approximately 25 years. The most commonly reported terms were nausea(250), vomiting (148) and flushing (145).During the 24 year period from 12 December 1975 to 25 October 1999 a total of 160 reports listing323 adverse drug reactions related to salmon calcitonin containing products were received by the DrugAlert Unit of the Committee on Safety of Medicines at the Medicine Control Agency. There werethree events of fatal outcomes. The fatal events were one non-specific tachycardia and two cases ofhypercalcaemia.Severe allergic reactions are rare, chronic use has been associated with antibody formation, but theclinical relevance of this antibody response is unknown.Based on the above, the use of calcitonins is considered safe.

� OVERALL CONCLUSION ON BENEFIT/RISK

The CPMP concluded that injectable calcitonins have not proven therapeutic efficacy in theprevention of postmenopausal osteoporosis, the Sudeck syndrome (algodystrophy), the treatment ofosteoporosis induced pain, the treatment of established postmenopausal osteoporosis and the bone paindue to malignancy and that intranasal calcitonins have not proven therapeutic efficacy in theprevention of post-menopausal osteoporosis, the Paget´s disease, the hypercalcaemia of malignancy,the Sudeck syndrome (algodystrophy), the treatment of osteoporosis induced pain and the bone paindue to malignancy.

Furthermore the CPMP considered that according to the available data injectable calcitonins areeffective in the prevention of acute bone loss due to sudden immobilisation such as in patients withrecent osteoporotic fractures, the Paget´s disease and the hypercalcaemia of malignancy, and thatintranasal calcitonins can be effective in the treatment of established postmenopausal osteoporosis inorder to reduce the risk of vertebral fractures. However, a reduction in hip fractures has not beendemonstrated.

Therefore the CPMP considered that the benefit/risk balance of calcitonins containing medicinalproducts in the agreed restricted indications is favourable and the Marketing Authorisations should bemaintained. A Summaries of Product Characteristics is amended according to changes detailed inAnnex III of the CPMP Opinion.

GROUNDS FOR AMENDMENT OF THE SUMMARIES OF PRODUCTCHARACTERISTICS

Whereas - The Committee considered the referral made under Article 31 of Council Directive 2001/83/EEC asamended, for calcitonins containing medicinal products; -The Committee agreed that injectable calcitonins containing medicinal products lack therapeuticefficacy in the prevention of postmenopausal osteoporosis, the Sudeck syndrome (algodystrophy), thetreatment of osteoporosis induced pain, the treatment of established postmenopausal osteoporosis andthe bone pain due to malignancy and that intranasal calcitonins containing medicinal products lacktherapeutic efficacy in the prevention of post-menopausal osteoporosis, the Paget´s disease, thehypercalcaemia of malignancy, the Sudeck syndrome (algodystrophy), the treatment of osteoporosisinduced pain and the bone pain due to malignancy.

-The Committee agreed that injectable calcitonins containing medicinal products have a place in theprevention of acute bone loss due to sudden immobilisation such as in patients with recentosteoporotic fractures, the treatment of Paget´s disease and the treatment of hypercalcaemia of

45

malignancy and that intranasal calcitonins containing medicinal products have a place in thetreatment of established postmenopausal osteoporosis in order to reduce the risk of vertebral fractures.A reduction in hip fractures has not been demonstrated.

- The Committee, as a consequence, considered the benefit/risk balance of injectable calcitoninscontaining medicinal products to be favourable in the prevention of acute bone loss due to suddenimmobilisation such as in patients with recent osteoporotic fractures, the Paget´s disease and thehypercalcaemia of malignancy.

- The Committee, as a consequence, considered the benefit/risk balance of intranasal calcitoninscontaining medicinal products to be favourable in the treatment of the treatment of establishedpostmenopausal osteoporosis in order to reduce the risk of vertebral fractures. A reduction in hipfractures has not been demonstrated.

As a result, the CPMP has recommended the maintenance of the Marketing Authorisations forcalcitonins containing medicinal products (see Annex I) as amended in accordance with theSummaries of Product Characteristics set out in Annex III and under the conditions set out in AnnexIV.

46

ANNEX III

SUMMARY OF PRODUCT CHARACTERISTICS

47

INJECTABLE SALMON CALCITONIN

48

1. NAME OF THE MEDICINAL PRODUCT

{(Trade) name of product <strength> <pharmaceutical form>}

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Company- specific.

For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Solution for injection

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Calcitonin is indicated for:

� Prevention of acute bone loss due to sudden immobilisation such as in patients with recentosteoporotic fractures

� Paget’s disease

� Hypercalcemia of malignancy

4.2 Posology and method of administration

For subcutaneous, intramuscular or intravenous (product specific) use in individuals aged 18 years ormore.

Salmon calcitonin may be administered at bedtime to reduce the incidence of nausea or vomitingwhich may occur, especially at the initiation of therapy.

Prevention of acute bone loss:The recommended dosage is 100 I.U. daily or 50 I.U. twice daily for 2 to 4 weeks, administeredsubcutaneously or intramuscularly. The dose may be reduced to 50 I.U. daily at the start ofremobilisation. The treatment should be maintained until patients are fully mobilized.

Paget’s disease:The recommended dosage is 100 IU per day administered subcutaneously or intramuscularly,however, a minimum dosage regimen of 50 IU three times a week has achieved clinical andbiochemical improvement. Dosage is to be adjusted to the individual patient’s needs. The duration oftreatment depends on the indication for treatment and the patient´s response. The effect of calcitoninmay be monitored by measurement of suitable markers of bone remodeling, such as serum alkalinephosphatase or urinary hydroxyproline or deoxypyridinoline. The dose may be reduced after thecondition of the patient has improved.

Hypercalcemia of malignancy:

49

The recommended starting dose is 100 IU every 6 to 8 hours by subcutaneous or intramuscularinjection. In addition, salmon calcitonin could be administered by intravenous injection after previousrehydration.If the response is not satisfactory after one or two days, the dose may be increased to a maximum of400 IU every 6 to 8 hours. In severe or emergency cases, intravenous infusion with up to 10 IU/kgbody weight in 500ml 0.9% w/v sodium chloride solution may be administered over a period of atleast 6 hours.

Use in elderly, hepatic and renal impairment patientsExperience with the use of calcitonin in the elderly has shown no evidence of reduced tolerability oraltered dosage requirements. The same applies to patients with altered hepatic function. The metabolicclearance is much lower in patients with end-stage renal failure than in healthy subjects. However, theclinical relevance of this finding is not known (see section 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Calcitonin is also contraindicated in patients with hypocalcaemia.

4.4 Special warnings and special precautions for use

Because calcitonin is a peptide, the possibility of systemic allergic reactions exists and allergic-typereactions including isolated cases of anaphylactic shock have been reported in patients receivingcalcitonin. Such reactions should be differentiated from generalised or local flushing, which arecommon non-allergic effects of calcitonin (see 4.8). Skin testing should be conducted in patients withsuspected sensitivity to calcitonin prior to their treatment with calcitonin.

4.5 Interaction with other medicinal products and other forms of interaction

Serum calcium levels may be transiently decreased to below normal levels following administration ofcalcitonin, notably upon initiation of therapy in patients with abnormally high rates of bone turnover.This effect is diminished as osteoclastic activity is reduced. However, care should be exercised inpatients receiving concurrent treatment with cardiac glycosides or calcium channel blocking agents.Dosages of these drugs may require adjustment in view of the fact that their effects may be modifiedby changes in cellular electrolyte concentrations.

The use of calcitonin in combination with bisphosphonates may result in an additive calcium-loweringeffect.

4.6 Pregnancy and lactation

Calcitonin has not been studied in pregnant women. Calcitonin should be used during pregnancy onlyif treatment is considered absolutely essential by the physician. It is not known if the substance is excreted in human milk. In animals, salmon calcitonin has beenshown to decrease lactation and to be excreted in milk (see 5.3). Therefore, breast-feeding is notrecommended during treatment.

4.7 Effects on ability to drive and use machines

No data exist on the effects of injectable calcitonin on the ability to drive and use machines. Injectablecalcitonin may cause transient dizzines (see 4.8. Undesirable effects) which may impair the reaction ofthe patient. Patients must therefore be warned that transient dizzines may occur, in which case theyshould not drive or use machines.

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4.8 Undesirable effects

Frequency categories:Very common ( >1/10); common (>1/100, <1/10); uncommon (>1/1,000, < 1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports.

Gastrointestinal disorder:Very common: Nausea with or without vomiting is noted in approximately 10% of patients treatedwith calcitonin. The effect is more evident on initiation of therapy and tends to decrease or disappearwith continued administration or a reduction in dose. An antiemetic may be administered, if required.Nausea/vomiting are less frequent when the injection is done in the evening and after meals.Uncommon: diarrhoea

Vascular disorders:Very common:Skin flushes (facial or upper body). These are not allergic reactions but are due to a pharmacologicaleffect, and are usually observed 10 to 20 minutes after administration.

General disorders and administration site conditionsUncommon: local inflammatory reactions at the site of subcutaneous or intramuscular injection

Skin and subcutaneous tissue disordersUncommon: skin rash

Nervous system disorders:Uncommon: metallic taste in the mouth; dizziness

Renal and urinary disorders:Uncommon: diuresis

Metabolic and nutrition disorders:Rare :In case of patients with high bone remodelling (Paget’s disease and young patients) a transientdecrease of calcemia may occur between the 4th and the 6th hour after administration, usuallyasymptomatic

Investigations: Rare: Neutralising antibodies to calcitonin rarely develop. The development of these antibodies is notusually related to loss of clinical efficacy, although their presence in a small percentage of patientsfollowing long-term therapy with calcitonin may result in a reduced response to the product. Thepresence of antibodies appears to bear no relationship to allergic reactions, which are rare. Calcitoninreceptor down-regulation may also result in a reduced clinical response in a small percentage ofpatients following long-term therapy.

Immune system disorders:Very rare: serious allergic-type reactions, such as bronchospasm, swelling of the tongue and throat,and in isolated cases, anaphylaxis.

4.9 Overdose

Nausea, vomiting, flushing and dizziness are known to be dose dependent when calcitonin isadministered parenterally. Single doses (up to 10,000 I.U.) of injectable salmon calcitonin have beenadministered without adverse reactions, other than nausea and vomiting, and exacerbation ofpharmacological effects.Should symptoms of overdose appear, treatment should be symptomatic.

51

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antiparathyroid hormone, ATC code: H05BA01 (calcitonin, salmon).

The pharmacological properties of the synthetic and recombinant peptides have been demonstrated tobe qualitatively and quantitatively equivalent.

5.1 Pharmacodynamic properties

Calcitonin is a calciotropic hormone, which inhibits bone resorption by a direct action on osteoclasts.By inhibiting osteoclast activity via its specific receptors, salmon calcitonin decreases bone resorption.In pharmacological studies, calcitonin has been shown to have analgesic activity in animal models.

Calcitonin markedly reduces bone turnover in conditions with an increased rate of bone resorptionsuch as Paget ‘s disease and acute bone loss due to sudden immobilisation.The absence of mineralisation defect with calcitonin has been demonstrated by bonehistomorphometric studies both in man and in animals.Decreases in bone resorption as judged by a reduction in urinary hydroxyproline anddeoxypyridinoline are observed following calcitonin treatment in both normal volunteers and patientswith bone-related disorders, including Paget’s disease and osteoporosis.

The calcium-lowering effect of calcitonin is caused both by a decrease in the efflux of calcium fromthe bone to the ECF and inhibition of renal tubular reabsorption of calcium.

5.2 Pharmacokinetic properties

General characteristics of the active substanceSalmon calcitonin is rapidly absorbed and eliminated.Peak plasma concentrations are attained within the first hour of administration.Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidneyfollowing parenteral administration. The metabolites lack the specific biological activity of calcitonin.Bioavailability following subcutaneous and intramuscular injection in humans is high and similar forthe two routes of administration (71% and 66%, respectively).Calcitonin has short absorption and elimination half-lives of 10-15 minutes and 50-80 minutes,respectively. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, formingpharmacologically inactive fragments of the molecule. Therefore, the metabolic clearance is muchlower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevanceof this finding is not known.Plasma protein binding is 30 to 40%.

Characteristics in patientsThere is a relationship between the subcutaneous dose of calcitonin and peak plasma concentrations.Following parenteral administration of 100 I.U. calcitonin, peak plasma concentration lies betweenabout 200 and 400 pg/ml. Higher blood levels may be associated with increased incidence of nauseaand vomiting.

5.3 Preclinical safety data

Conventional long-term toxicity, reproduction, mutagenicity, and carcinogenicity studies have beenperformed in laboratory animals. Salmon calcitonin is devoid of embryotoxic, teratogenic andmutagenic potential.An increased incidence of pituitary adenomas has been reported in rats given synthetic salmoncalcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance.Salmon calcitonin does not cross the placental barrier.

In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin issecreted into the milk.

52

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

6.5 Nature and contents of container

6.6 Instructions for use and handling <and disposal>

7. MARKETING AUTHORISATION HOLDER

{Name and address}

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

53

INJECTABLE HUMAN CALCITONIN

54




Company- specific.



Powder and solvent for solution for injection (company specific).



Calcitonin is indicated for:





For subcutaneous, intramuscular or intravenous (product specific) use in individuals aged 18 years ormore.

Human calcitonin may be administered at bedtime to reduce the incidence of nausea or vomitingwhich may occur, especially at the initiation of therapy.

Prevention of acute bone loss:The recommended dosage is 0,5 mg. daily or 0,25 mg. twice daily for 2 to 4 weeks, administeredsubcutaneously or intramuscularly. The dose may be reduced to 0,25 mg. daily at the start ofremobilisation. The treatment should be maintained until patients are fully mobilized.

Paget’s disease:The dosage should be individually adapted to the patient's requirements. As a rule, it is recommendedthat treatment be initiated with a dose of 0.5 mg injected subcutaneously or intramuscularly once aday, for several weeks. Depending on the patient's response, this dosage may subsequently be raised to0.5 mg twice a day or reduced for maintenance therapy, e.g. to 0.25 mg daily or to 0.5 mg 2-3 times aweek.As an aid in evaluating the efficacy of human calcitonin determination of serum alkaline phosphataseand urinary hydroxyproline excretion should be performed prior to initiation of therapy, during thefirst three months, and at intervals (approximately 3-6 months) if treatment needs to be continued.Adjustments in dose should be guided by clinical and radiological evidence, as well as changes inserum alkaline phosphatase and urinary hydroxyproline excretion.The treatment should be continued for 6 months or more. If withdrawal of therapy is followed by arenewed exacerbation (marked by an increase in the biochemical parameters and recurrence ofsymptoms or radiological signs), the treatment should be resumed.

55

Hypercalcemia of malignancy:For acute treatment 0.5 mg of human calcitonin is administered every 6 hours by slow intravenousinjection, after previous rehydration.Serum calcium should be measured every 6 hours. Twelve hours after serum calcium levels havereturned to normal, treatment can be discontinued.The therapeutic effect is usually obtained within the first 24 hours of treatment. In patients withincomplete results, increasing the dosage does not result in a further reduction of serum calcium. Anew rise in serum calcium is observed a few days after treatment is discontinued.






Because calcitonin is a peptide, the possibility of systemic allergic reactions exists and allergic-typereactions including isolated cases of anaphylactic shock have been reported in patients receivingcalcitonin. Such reactions should be differentiated from generalised or local flushing, which arecommon non-allergic effects of calcitonin (see 4.8).


Serum calcium levels may be transiently decreased to below normal levels following administration ofcalcitonin, notably upon initiation of therapy in patients with abnormally high rates of bone turnover.This effect is diminished as osteoclastic activity is reduced. However, care should be exercised inpatients receiving concurrent treatment with cardiac glycosides or calcium channel blocking agents.Dosages of these drugs may require adjustment in view of the fact that their effects may be modifiedby changes in cellular electrolyte concentrations.

The use of calcitonin in combination with bisphosphonates may result in an additive calcium-loweringeffect.


Calcitonin has not been studied in pregnant women. There is no evidence from animal work thathuman calcitonin is free from either teratogenic potential or other adverse effects, on the embryoand/or the foetus. Calcitonin should be used during pregnancy only if treatment is consideredabsolutely essential by the physician.It is not known if the substance is excreted in human milk. Therefore, breast-feeding is notrecommended during treatment.


No data exist on the effects of injectable calcitonin on the ability to drive and use machines. Injectablecalcitonin may cause transient dizzines (see 4.8. Undesirable effects) which may impair the reaction ofthe patient. Patients must therefore be warned that transient dizzines may occur, in which case theyshould not drive or use machines.

56

4.8 Undesirable effects


Gastrointestinal disorder:Very common: Nausea with or without vomiting is noted in approximately 10% of patients treatedwith calcitonin. The effect is more evident on initiation of therapy and tends to decrease or disappearwith continued administration or a reduction in dose. An antiemetic may be administered, if required.Nausea/vomiting are less frequent when the injection is done in the evening and after meals.Uncommon: diarrhoea








Investigations:The risk of developing neutralising antibodies, even in the case of long-term therapy, is low becausethe amino acid sequence is identical to that of endogenous human calcitonin.

4.9 Overdose

Nausea, vomiting, flushing and dizziness are known to be dose dependent when calcitonin isadministered parenterally. However, no cases of overdosage have been reported.


Pharmacotherapeutic group: antiparathyroid hormone, ATC code: H05BA03 (calcitonin, humansynthetic).

57


Calcitonin is a calciotropic hormone, which inhibits bone resorption by a direct action on osteoclasts.By inhibiting osteoclast activity via its specific receptors, human calcitonin decreases bone resorption.In pharmacological studies, calcitonin has been shown to have analgesic activity in animal models.

Calcitonin markedly reduces bone turnover in conditions with an increased rate of bone resorptionsuch as Paget ‘s disease disease and acute bone loss due to sudden immobilisation.The absence of mineralisation defect with calcitonin has been demonstrated by bonehistomorphometric studies both in man and in animals.Decreases in bone resorption as judged by a reduction in urinary hydroxyproline anddeoxypyridinoline are observed following calcitonin treatment in both normal volunteers and patientswith bone-related disorders, including Paget’s disease and osteoporosis.

The calcium-lowering effect of calcitonin is caused both by a decrease in the efflux of calcium fromthe bone to the ECF and inhibition of renal tubular reabsorption of calcium.


Following single intramuscular and subcutaneous doses of synthetic human calcitonin, systemicuptake of exogenous calcitonin is rapid; mean peak serum levels are attained within 20 minutes afterboth routes. Peak serum concentrations average 4 ng/ml after i.m. and 3-5 ng/ml after subcutaneousinjection of 0.5 mg doses. The i.m. and s.c. doses (0.5 mg) are bioequivalent in terms of serum AUCs.Peak concentrations and AUC values of exogenous calcitonin in serum increases proportionally withsubcutaneous doses of 0.25 mg and 0.50 mg of synthetic human calcitonin. Exogenous calcitonin israpidly eliminated from the circulation, mean apparent half-lives being 1.1 hours after i.m. and 1.1 -1.4 hours after subcutaneous. administration.Under steady-state conditions, a mean metabolic clearance of about 600 ml/min was maintainedduring constant intravenous infusion of human calcitonin. After single intravenous injection, a meanvalue of 720 ml/min was observed. The apparent volume of distribution averages 11.4 l, whichcorresponds to 0.15 l/kg, calculated for a body weight of 75 kg.Following single intravenous injection of synthetic human I-calcitonin, 95% of the dose is excreted inthe 48-hour urine; 2.4% of the dose is accounted for by unchanged I-calcitonin and the rest byiodinated degradation products.Human calcitonin is primarily and almost exclusively degraded in the kidneys, formingpharmacologically inactive fragments of the molecule. Therefore, the metabolic clearance is muchlower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevanceof this finding is not known.


Human calcitonin is not directly mutagenic in bacterial or eukaryotic systems in vitro or inmammalian tests in vivo. It did give positive results in bacterial mutagenicity tests in the presence of ametabolic activating system. These findings are most probably a consequence of the oxidation ofamino acids released by hydrolysis or a reflection of an alteration of bacterial growth by hydrolysisproducts and are not considered an indication of human calcitonin mutagenicity.No long-term carcinogenicity studies have been conducted with human calcitonin.Animal reproduction studies have not been performed with human calcitonin.




6.3 Shelf life

58





{Name and address}




59

INJECTABLE ELCATONIN

60




Elcatonin is an analog of eel calcitonin

Company- specific.



Solution for injection



Elcatonin is indicated for:





For intramuscular or intravenous (product specific) use in individuals aged 18 years or more.

Elcatonin may be administered at bedtime to reduce the incidence of nausea or vomiting which mayoccur, especially at the initiation of therapy.

Prevention of acute bone loss:The recommended dosage is 40 I.U. daily for 2 to 4 weeks, administered intramuscularly. The dosemay be reduced to 40 I.U. every other day at the start of remobilisation. The treatment should bemaintained until patients are fully mobilized.

Paget’s disease:The recommended dosage is 40 IU per day administered intramuscularly, however, a minimumdosage regimen of 40 IU three times a week has achieved clinical and biochemical improvement.Dosage is to be adjusted to the individual patient’s needs. The effect of calcitonin may be monitoredby measurement of suitable markers of bone remodeling such as serum alkaline phosphatase orurinary hydroxyproline or deoxypyridinoline. The duration of treatment depends on the indication fortreatment and the patient´s response, but should be a minimum of 3 months. The dose may be reducedafter the condition of the patient has improved.

Hypercalcemia of malignancy:The recommended starting dose is 40 IU every 6 to 8 hours by intramuscular injection. In addition,elcatonin could be administered by intravenous injection after previous rehydration.

61

If the response is not satisfactory after one or two days, the dose may be increased to a maximum of80 IU every 6 to 8 hours.






Because calcitonin is a peptide, the possibility of systemic allergic reactions exists and allergic-typereactions including isolated cases of anaphylactic shock have been reported in patients receivingcalcitonin. Such reactions should be differentiated from generalised or local flushing, which arecommon non-allergic effects of calcitonin (see 4.8). Skin testing should be conducted in patients withsuspected sensitivity to calcitonin prior to their treatment with elcatonin.


Serum calcium levels may be transiently decreased to below normal levels following administration ofelcatonin, notably upon initiation of therapy in patients with abnormally high rates of bone turnover.This effect is diminished as osteoclastic activity is reduced. However, care should be exercised inpatients receiving concurrent treatment with cardiac glycosides or calcium channel blocking agents.Dosages of these drugs may require adjustment in view of the fact that their effects may be modifiedby changes in cellular electrolyte concentrations.

The use of calcitonin in combination with bisphosphonates may result in an additive calcium-loveringeffect.


Elcatonin has not been studied in pregnant women. Elcatonin should be used during pregnancy only iftreatment is considered absolutely essential by the physician. It is not known if the substance is excreted in human milk. Therefore, breast-feeding is notrecommended during treatment.


No data exist on the effects of injectable elcatonin on the ability to drive and use machines. Injectableelcatonin may cause transient dizzines (see 4.8. Undesirable effects) which may impair the reaction ofthe patient. Patients must therefore be warned that transient dizzines may occur, in which case theyshould not drive or use machines.

4.8 Undesirable effectsThe undesirable effects observed during treatment with elcatonin are similar to those reported afteradministration of salmon calcitonin.


Gastrointestinal disorder:

62

Very common: Nausea with or without vomiting is noted in approximately 10% of patients treatedwith calcitonin. The effect is more evident on initiation of therapy and tends to decrease or disappearwith continued administration or a reduction in dose. An antiemetic may be administered, if required.Nausea/vomiting are less frequent when the injection is done in the evening and after meals.Uncommon: diarrhoea







Investigations: Rare: Neutralising antibodies to calcitonin rarely develop. The development of these antibodies is notusually related to loss of clinical efficacy, although their presence in a small percentage of patientsfollowing long-term therapy with calcitonin may result in a reduced response to the product. Thepresence of antibodies appears to bear no relationship to allergic reactions, which are rare. Calcitoninreceptor down-regulation may also result in a reduced clinical response in a small percentage ofpatients following long-term therapy.


4.9 Overdose

Nausea, vomiting, flushing and dizziness are known to be dose dependent when calcitonin isadministered parenterally. Should symptoms of overdose appear, treatment should be symptomatic.


Pharmacotherapeutic group: antiparathyroid hormone, ATC code: H05B A04 (elcatonin).

The pharmacological properties of the synthetic and recombinant peptides have been demonstrated tobe qualitatively and quantitatively equivalent.

63


Calcitoinin is a calciotropic hormone, which inhibits bone resorption by a direct action on osteoclasts.By inhibiting osteoclast activity via its specific receptors, calcitoinin decreases bone resorption.In pharmacological studies, calcitonin has been shown to have analgesic activity in animal models.

Calcitoinin markedly reduces bone turnover in conditions with an increased rate of bone resorptionsuch as Paget ‘s disease and acute bone loss due to sudden immobilisation.The absence of mineralisation defect with calcitonin has been demonstrated by bonehistomorphometric studies both in man and in animals.Decreases in bone resorption as judged by a reduction in urinary hydroxyproline anddeoxypyridinoline are observed following calcitoinin treatment in both normal volunteers and patientswith bone-related disorders, including Paget’s disease and osteoporosis.

The calcium-lowering effect of calcitoinin is caused both by a decrease in the efflux of calcium fromthe bone to the ECF and inhibition of renal tubular reabsorption of calcium.


General characteristics of the active substanceElcatonin is rapidly absorbed and eliminated.Peak plasma concentrations are attained within the first hour of administration.Animal studies have shown that elcatonin is primarily metabolised via proteolysis in the kidneyfollowing parenteral administration. The metabolites lack the specific biological activity of elcatonin.Bioavailability following intramuscular injection in humans is high and similar to other calcitoninsElcatonin has short absorption and elimination half-lives of approx 4 hours. Entire elcatonin and itsmetabolites are excreted by the renal excretion (73%) and the biliar excretion 7%.


Conventional long-term toxicity, reproduction and mutagenicity, studies have been performed inlaboratory animals. Elcatonin is devoid of embryotoxic, teratogenic and mutagenic potential.

Elcatonin does not cross the placental barrier.

In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin issecreted into the milk.




6.3 Shelf life





{Name and address}

64




65

INTRANASAL SALMON CALCITONIN

66


Company-specific.


Company-specific.For excipients, see 6.1.


Nasal Spray, solution.


4.1. Therapeutic indications

Treatment of established post-menopausal osteoporosis in order to reduce the risk of vertebralfractures. A reduction in hip fractures has not been demonstrated.

4.2. Posology and method of administration

The recommended dosage of intranasal calcitonin for the treatment of established post-menopausalosteoporosis is 200 I.U. once a day. Use of intranasal calcitonin is recommended in conjunction withan adequate calcium and vitamin D intake. Treatment is to be administered on a long-term basis, (seepoint 5.1., Pharmacodynamic properties).

Use in elderly patients, in hepatic impairment and in renal insufficiencyExtensive experience with the use of intranasal calcitonin in the elderly has shown no evidence ofreduced tolerability or altered dosage requirements. The same applies to patients with altered renal orhepatic function.

Use in childrenAs intranasal calcitonin is indicated for post-menopausal women, its use in children is not appropriate.

NoteFull instructions for use by the patient are given in the package leaflet.

4.3. Contra-indications

Hypersensitivity to calcitonin (see section 4.8. Undesirable effects) or to any of the excipients of theformulation (see section 6.1. List of excipients).Calcitonin is also contra-indicated in patients with hypocalcaemia.

4.4. Special warnings and special precautions for use

Nasal examinations is to be performed before treatment begins and in the case of nasal complaints,medication should not be started. If severe ulceration of the nasal mucosa occurs (e.g. penetrationbelow the mucosa or association with heavy bleeding), intranasal calcitonin is to be discontinued. Incase of mild ulceration, medication is to be interrupted temporarily until healing occurs.

Because calcitonin is a peptide, the possibility of systemic allergic reactions exists and allergic-typereactions including isolated cases of anaphylactic shock have been reported in patients receiving

67

intranasal calcitonin. In patients with suspected sensitivity to calcitonin, skin testing is to be consideredprior to treatment.

The excipient benzalkonium chloride is an irritant and may cause irritation of the nasal mucosa(company-specific).

4.5. Interaction with other medicinal products and other forms of interaction

No drug interactions with intranasal salmon calcitonin have been reported.

4.6. Use during pregnancy and lactation

As intranasal calcitonin is indicated for postmenopausal women, no studies have been carried out inpregnant women or nursing mothers. Therefore, intranasal calcitonin is not to be administered to suchpatients. However, animal studies have shown no embryotoxic and teratogenic potential. It appearsthat salmon calcitonin does not cross the placental barrier in animals.It is not known whether salmon calcitonin is excreted into human breast milk. In animals, salmoncalcitonin has been shown to decrease lactation and to be excreted in milk.

4.7. Effects on ability to drive and use machinesNo data exist on the effects of intranasal calcitonin on the ability to drive and use machines. Intranasalcalcitonin may cause transient dizziness (see section 4.8. Undesirable effects) which may impair thereaction of the patient. Patients must therefore be warned that transient dizziness may occur, in whichcase they are not to drive or use machines.

4.8. Undesirable effectsFrequency estimates:Very common (>1/10); common (>1/100, �1/10); uncommon (>1/1,000, �1/100); rare (>1/10,000,<1/1,000); very rare (<1/10,000), including isolated reports.

Gastrointestinal disordersCommon: nausea, diarrhoea, abdominal painUncommon: vomiting

Vascular disordersCommon: flushingUncommon: hypertension

Respiratory disordersVery common: rhinitis (including dry nose, nasal oedema, nasal congestion, sneezing, allergicrhinitis), unspecified symptoms of the nose (e.g. nasal passage irritation, rash papular, parosmia,erythema, abrasion)Common: rhinitis ulcerative, sinusitis, epistaxis, pharyngitisUncommon: coughThese events are generally mild (in about 80% of reports) and require discontinuation of the treatmentin less than 5% of cases.

Nervous system disordersCommon: dizziness, headache, dysgeusia,

Sense Organ disordersUncommon: vision disturbance

Skin and subcutaneous tissue disordersUncommon: oedema (face oedema, oedema peripheral and ansarca)

Musculoskeletal disorders

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Common: musculoskeletal painUncommon: arthralgia

Immune system disordersUncommon: hypersensitivity reactions such as generalised skin reactions, flushing, oedema (faceoedema, oedema peripheral and ansarca), hypertension, arthralgia and pruritis

Very rare: allergic and anaphylactoid-like reactions such as tachycardia, hypotension, circulatorycollapse and anaphylactic shock

InvestigationsRare: development of neutralising antibodies to calcitonin. The development of these antibodies is notusually related to loss of clinical efficacy, although their presence in a small percentage of patientsfollowing long-term therapy with high doses of calcitonin may result in a reduced response to theproduct. The presence of antibodies appears to bear no relationship to allergic reactions, which arerare. Calcitonin receptor down-regulation may also result in a reduced clinical response in a smallpercentage of patients following long-term therapy with high doses.

General disordersCommon: fatigueUncommon: influenza-like illness

4.9. Overdose

Nausea, vomiting, flushing and dizziness are known to be dose dependent when calcitonin isadministered parenterally. Single doses (up to 10 000 I.U.) of salmon calcitonin have been administeredparenterally without adverse effects other than nausea and vomiting, and exacerbation ofpharmacological effects. Such events might therefore also be expected to occur in association with anoverdose of intranasal calcitonin. However, intranasal calcitonin has been administered at up to1600 I.U. as a single dose and up to 800 I.U. per day for three days without causing any serious adverseevent. If symptoms of overdose appear, treatment is to be symptomatic.


Pharmacotherapeutic group: antiparathyroid hormone, ATC code: H05BA01 (calcitonin, salmon).

5.1. Pharmacodynamic properties

Calcitonin is a calciotropic hormone, which inhibits bone resorption by a direct action on osteoclasts.By inhibiting osteoclast activity via its specific receptors, salmon calcitonin decreases bone resorption.Calcitonin markedly reduces bone turnover in conditions with an increased rate of bone resorptionsuch as osteoporosis.

The absence of mineralisation defect with calcitonin has been demonstrated by bonehistomorphometric studies both in man and in animals.

In pharmacological studies, calcitonin has been shown to have analgesic activity in animal models. Intranasal calcitonin produces a clinically relevant biological response in humans , as shown by anincrease in the urinary excretion of calcium, phosphorus, and sodium (by reducing their tubular re-uptake) and a decrease in the urinary excretion of hydroxyproline. Long-term administration ofintranasal calcitonin significantly suppresses biochemical markers of bone turnover such as serum C-telopeptides (sCTX) and skeletal isoenzymes of alkaline phosphatase . Intranasal calcitonin results in a statistically significant 1-2% increase in lumbar spine Bone MineralDensity (BMD), which is evident from year 1 and is sustained for up to 5 years. Hip BMD ispreserved.

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In a 5-year trial in postmenopausal women (PROOF study), administration of 200 IU intranasalsalmon calcitonin resulted in a reduction of 33% in the relative risk of developing vertebral fractures.The relative risk of developing vertebral fractures, compared to placebo (treatment with vitamin D andcalcium alone) in all patients treated with daily doses of 200 I.U. was 0.67 (95% CI: 0.47-0.97). Theabsolute risk of developing vertebral fractures over 5 years was reduced from 25.9% in the placebogroup to 17.8% in the 200 I.U. group. A reduction in hip fractures has not been demonstrated. The recommended dosage of intranasal salmon calcitonin for the treatment of established post-menopausal osteoporosis is 200 I.U. once a day. Higher dosages were not more effective. 5.2. Pharmacokinetic properties Pharmacokinetic parameters of intranasally administered salmon calcitonin are difficult to quantitatedue to the inadequate sensitivity and uncertain specificity of the available immunoassay methods usedin the studies performed to date. The bioavailability of a 200 I.U. dose relative to parenteraladministration is between 2 and 15%. Intranasal calcitonin is absorbed rapidly through the nasalmucosa and peak plasma concentrations are attained within the first hour of administration. The half-life of elimination has been calculated to be approximately 16 to 43 minutes and no evidence ofaccumulation was observed with multiple dosing. Doses higher than the recommended dose result inhigher blood levels (as shown by an increase in AUC) but relative bioavailability does not increase. Asis the case with other polypeptide hormones, there is very little value in monitoring plasma levels ofsalmon calcitonin since these are not directly predictive of the therapeutic response. Hence, calcitoninactivity is to be evaluated by using clinical parameters of efficacy. Plasma protein binding is 30 to 40%. 5.3. Preclinical safety data

Conventional long-term toxicity, reproduction, mutagenicity and carcinogenicity studies have beenperformed in laboratory animals. In addition, nasal tolerance was investigated in dogs and monkeys.Salmon calcitonin is devoid of embryotoxic, teratogenic and mutagenic potential. Daily intranasaladministration of high doses of a calcitonin formulation containing 0.01% benzalkonium chloride for26 weeks was well tolerated by monkeys.An increased incidence of pituitary adenomas has been reported in rats given synthetic salmoncalcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance.Salmon calcitonin does not cross the placental barrier.In lactating animals given calcitonin, suppression of milk production has been observed. Calcitoninsare secreted into the milk.


6.1. List of excipients

6.2. Incompatibilities

6.3. Shelf life

6.4. Special precautions for storage

6.5. Nature and content of container

6.6. Instructions for use/handling


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8. MARKETING AUTHORISATION NUMBER

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION


71

INTRANASAL ELCATONIN

72


Company-specific.


Elcatonin is an analog of eel calcitoninCompany-specific.For excipients, see 6.1.


Nasal Spray, solution.


4.1. Therapeutic indications

Treatment of established post-menopausal osteoporosis in order to reduce the risk of vertebralfractures. A reduction in hip fractures has not been demonstrated.

4.2. Posology and method of administration

The recommended dosage of intranasal calcitonin for the treatment of established post-menopausalosteoporosis is 80 I.U. once a day. Use of intranasal calcitonin is recommended in conjunction with anadequate calcium and vitamin D intake. Treatment is to be administered on a long-term basis, (see point5.1., Pharmacodynamic properties).

Use in elderly patients, in hepatic impairment and in renal insufficiencyExperience with the use of intranasal calcitonin in the elderly has shown no evidence of reducedtolerability or altered dosage requirements. The same applies to patients with altered renal or hepaticfunction.

Use in childrenAs intranasal calcitonin is indicated for post-menopausal women, its use in children is not appropriate.

NoteFull instructions for use by the patient are given in the package leaflet.

4.3. Contra-indications

Hypersensitivity to calcitonin (see section 4.8. Undesirable effects) or to any of the excipients of theformulation (see section 6.1. List of excipients).Calcitonin is also contra-indicated in patients with hypocalcaemia.

4.4. Special warnings and special precautions for use

Nasal examinations is to be performed before treatment begins and in the case of nasal complaintsmedication should not be started. If severe ulceration of the nasal mucosa occurs (e.g. penetrationbelow the mucosa or association with heavy bleeding), intranasal calcitonin is to be discontinued. Incase of mild ulceration, medication is to be interrupted temporarily until healing occurs.Because calcitonin is a peptide, the possibility of systemic allergic reactions exists and allergic-typereactions including isolated cases of anaphylactic shock have been reported in patients receiving

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intranasal calcitonin. In patients with suspected sensitivity to calcitonin, skin testing is to be consideredprior to treatment.

4.5. Interaction with other medicinal products and other forms of interaction

No drug interactions with intranasal elcatonin have been reported.

4.6. Use during pregnancy and lactation

As intranasal calcitonin is indicated for postmenopausal women, no studies have been carried out inpregnant women or nursing mothers. Therefore, intranasal calcitonin is not to be administered to suchpatients. However, animal studies have however shown no embryotoxic and teratogenic potential. Itappears that elcatonin does not cross the placental barrier in animals.It is not known whether elcatonin is excreted into human breast milk. Therefore, breast-feeding is notrecommended during treatment.

4.7. Effects on ability to drive and use machines

No data exist on the effects of intranasal calcitonin on the ability to drive and use machines. Intranasalcalcitonin may cause transient dizziness (see section 4.8. Undesirable effects) which may impair thereaction of the patient. Patients must therefore be warned that transient dizziness may occur, in whichcase they are not to drive or use machines.

4.8. Undesirable effects

The undesirable effects observed during treatment with elcatonin are similar to dose reported afteradministration of salmon calcitoninFrequency estimates:Very common ( >1/10); common (>1/100, <1/10); uncommon (>1/1,000, < 1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports.

Gastrointestinal disordersCommon: nausea, diarrhoea, abdominal painUncommon: vomiting

Vascular disordersCommon: flushingUncommon: hypertension

Respiratory disordersVery common: rhinitis (including dry nose, nasal oedema, nasal congestion, sneezing, allergicrhinitis), unspecified symptoms of the nose (e.g. nasal passage irritation, rash papular, parosmia,erythema, abrasion)Common: rhinitis ulcerative, sinusitis, epistaxis, pharyngitisUncommon: coughThese events are generally mild (in about 80% of reports) and require discontinuation of the treatmentin less than 5% of cases.

Nervous system disordersCommon: dizziness, headache, dysgeusia,

Sense Organ disordersUncommon: vision disturbance

Skin and subcutaneous tissue disordersUncommon: oedema (face oedema, oedema peripheral and ansarca)

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Musculoskeletal disordersCommon: musculoskeletal painUncommon: arthralgia

Immune system disordersUncommon: hypersensitivity reactions such as generalised skin reactions, flushing, oedema (faceoedema, oedema peripheral and ansarca), hypertension, arthralgia and pruritisVery rare: allergic and anaphylactoid-like reactions such as tachycardia, hypotension, circulatorycollapse and anaphylactic shock

InvestigationsRare: development of neutralising antibodies to calcitonin. The development of these antibodies is notusually related to loss of clinical efficacy, although their presence in a small percentage of patientsfollowing long-term therapy with high doses of calcitonin may result in a reduced response to theproduct. The presence of antibodies appears to bear no relationship to allergic reactions, which arerare. Calcitonin receptor down-regulation may also result in a reduced clinical response in a smallpercentage of patients following long-term therapy with high doses.

General disordersCommon: fatigueUncommon: influenza-like illness

4.9. Overdose

Nausea, vomiting, flushing and dizziness are known to be dose dependent when calcitonin isadministered parenterally. However, no cases of overdosage have been reported. If symptoms ofoverdose appear, treatment is to be symptomatic.


Pharmacotherapeutic group: antiparathyroid hormone, ATC code: H05BA04 (elcatonin).

5.1. Pharmacodynamic properties

Calcitonin is a calciotropic hormone, which inhibits bone resorption by a direct action on osteoclasts.By inhibiting osteoclast activity via its specific receptors, elcatonin decreases bone resorption.Calcitonin markedly reduces bone turnover in conditions with an increased rate of bone resorptionsuch as osteoporosis.

The absence of mineralisation defect with calcitonin has been demonstrated by bonehistomorphometric studies both in man and in animals.

In pharmacological studies, calcitonin has been shown to have analgesic activity in animal models. Intranasal calcitonin produces a clinically relevant biological response in humans as shown by anincrease in the urinary excretion of calcium, phosphorus, and sodium (by reducing their tubular re-uptake) and a decrease in the urinary excretion of hydroxyproline. Long-term administration ofintranasal calcitonin significantly suppresses biochemical markers of bone turnover such as serum C-telopeptides (sCTX) and skeletal isoenzymes of alkaline phosphatase.

Intranasal calcitonin results in a statistically significant 1-2% increase in lumbar spine Bone MineralDensity (BMD), which is evident from year 1 and is sustained for up to 5 years. Hip BMD ispreserved.

In a 5-year trial using intranasal salmon calcitonin in postmenopausal women (PROOF study),administration of 200IU resulted in a reduction of 33% in the relative risk of developing vertebralfractures. The relative risk of developing vertebral fractures, compared to placebo (treatment with

75

vitamin D and calcium alone) in all patients treated with daily doses of 200 I.U. was 0.67 (95% CI:0.47-0.97). The absolute risk of developing vertebral fractures over 5 years was reduced from 25.9%in the placebo group to 17.8% in the 200 I.U. group. A reduction in hip fractures has not beendemonstrated. The recommended dosage of elcatonin for the treatment of established post-menopausal osteoporosisis 80 I.U. once a day. Higher dosages were not more effective.

5.2. Pharmacokinetic properties Pharmacokinetic parameters of intranasally administered elcatonin are difficult to quantitate due to theinadequate sensitivity and uncertain specificity of the available immunoassay methods used in thestudies performed to date. The bioavailability of a 40 I.U. dose relative to parenteral administration isbetween 45 and 53 %. Intranasal calcitonin is absorbed rapidly through the nasal mucosa and peakplasma concentrations are attained within the first hour of administration. Doses higher than therecommended dose result in higher blood levels (as shown by an increase in AUC) but relativebioavailability does not increase. As is the case with other polypeptide hormones, there is very littlevalue in monitoring plasma levels of elcatonin since these are not directly predictive of the therapeuticresponse. Hence, calcitonin activity is to be evaluated by using clinical parameters of efficacy. 5.3. Preclinical safety data

Conventional long-term toxicity, reproduction and mutagenicity studies have been performed inlaboratory animals. In addition, nasal tolerance was investigated in dogs and rats.

Elcatonin is devoid of embryotoxic, teratogenic and mutagenic potential. Daily intranasaladministration of high doses of elcatonin formulation containing 2% of ammonium glycyrrhizinate for12 weeks was well tolerated by .rats and dogs.

Elcatonin does not cross the placental barrier.

In lactating animals given calcitonin, suppression of milk production has been observed. Calcitoninsare secreted into the milk.


6.1. List of excipients

6.2. Incompatibilities

6.3. Shelf life

6.4. Special precautions for storage

6.5. Nature and content of container

6.6. Instructions for use/handling


8. MARKETING AUTHORISATION NUMBER

76

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION


Documents

ANNEX I LIST OF THE NAMES, PHARMACEUTICAL FORMS, … · 2010. 6. 3. · Italy Molteni Farmaceutici L. Molteni E C. Dei F .Lli Alitti Societa' di Esercizio S.P.A. Strada Statale 67