DOCSLIB.ORG

WO 2010/096820 Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
WO 2010/096820 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 26 August 2010 (26.08.2010) WO 2010/096820 Al (51) International Patent Classification: (74) Agents: DEO, Sandhya et al; Cooley LLP, 777 6th A61K 9/22 (2006.01) A61K 9/52 (2006.01) Street, NW, Suite 1100 , Washington, DC 20001 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US20 10/025083 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (22) Date: International Filing CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, 23 February 2010 (23.02.2010) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (26) Publication Language: English ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (30) Priority Data: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, 61/154,504 23 February 2009 (23.02.2009) US SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US): EU- RAND, INC. [US/US]; 845 Center Drive, Vandalia, Ohio (84) Designated States (unless otherwise indicated, for every 45377 (US). kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (72) Inventors; and ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (75) Inventors/Applicants (for US only): VENKATESH, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Gopi [US/US]; 780 Waldsmith Way, Vandalia, Ohio ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 45377 (US). PARRINO, Vincent [US/US]; 1307 White MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, hall Drive, Doylestown, Pennsylvania 18901 (US). GAT- TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, TL Paolo [YT/YT]; Via Ludovico Ariosto 123, 1-20099 ML, MR, NE, SN, TD, TG). Sesto San Giovanni (MI) (IT). FABIANI, Flavio [IT/IT]; Published: Via S. Francesco d'Asssisi, 50, 1-20050 Ronco Briantino (MI) (IT). — with international search report (Art. 21(3)) (54) Title: CONTROLLED RELEASE COMPOSITIONS COMPRISING ANTI-CHOLINERGIC DRUGS (57) Abstract: The present invention provides compositions comprising dicy Schematic of CR beads clomine, or salts, and/or solvates and methods of making and using the com positions to treat intestinal hypermotility or Irritable Bowel Syndrome (IBS). The present invention also provides once-a- day orally disintegrating dosage forms comprising compositions of the present invention. Figure 1 CONTROLLED RELEASE COMPOSITIONS COMPRISING ANTI CHOLINERGIC DRUGS CROSS REFERENCE TO RELATED APPLICATIONS The present application claims priority to U.S. Provisional Application No. 61/154,504 filed February 23, 2009, which is incorporated herein by reference in its entirety for all purposes. FIELD OF THE INVENTION This invention relates to compositions comprising anti-cholinergic drugs such as dicyclomine, and methods of making and using such compositions. BACKGROUND OF THE INVENTION Anti-cholinergic drugs block the activity of acetylcholine on cholinergic receptors on the surface of smooth muscle cells, and as a class have utility for a variety of clinical applications, e.g., as smooth muscle relaxants, antispasmodics, anti-motion sickness agents, antihistamines, bronchodilators, etc. Anti-cholinergic drugs can be difficult to formulate into controlled release dosage forms which provide therapeutic levels of the drug over a 24 hour period using a once-a-day dosing schedule, while minimizing dose related side affects. The difficulty in designing extended release once-a-day dosage forms can be further complicated by the pharmacokinetic properties and physical properties of the drug itself. For example, bicyclohexyl-1-carboxylic acid, 2-diethylamino ethyl ester (dicyclomine, also known as dicycloverine) is an exemplary anti-cholinergic drug known to have smooth muscle relaxant properties. The currently marketed formulation of dicyclomine has a very rapid dissolution profile that results in a rapid rise in blood plasma concentrations of the drug shortly after administration (T013x of approximately 1.5-3 hours) and is eliminated quickly with a short half-life ( / ) of 1.8 hours. The combination of this rapid Tmax and short half life requires that conventional dicyclomine dosage forms be administered multiple times a day in order to maintain, tolerable, therapeutic serum levels over a 24 hour period. Anti-cholinergic drugs such as dicyclomine HCl are indicated for managing abdominal spasms and pain associated with moderate-to-severe irritable bowel syndrome. Dicyclomine, a muscarinic Ml acetylcholine receptor antagonist, acts as a smooth muscle relaxant and is used as an antispasmodic to alleviate abdominal pain and bloating caused by colonic spasms associated with irritable bowel syndrome (IBS). IBS may be attributed to autonomic neuropathy; decreased vagal tone will lead to constipation while an increase in sympathetic stimulus is associated with diarrhea. The majority of IBS cases are a result of the interrelation between psychological morbidity and visceral hypersensitivity. IBS patients have higher incidences of anxiety, depression and sleep disturbance. Typical anti-cholinergic side effects, such as dry mouth, dizziness, blurred vision and nausea, are problematic for moderate-to-severe IBS patients taking an immediate release therapeutic agent several times a day on an extended basis. Severe symptoms are frequent, intense, and chronically interfere with daily functioning. Moderate-to-severe symptoms also impact social well-being, as patients will tend to avoid long journeys or going out (Drossman, D. 2006 Gastroenterology 20 (5): 121-132 and Smith, D.G. 2005 Am J Manag Care 11: S43-S50). According to the Bentyl® (immediate release dicyclomine HCl capsules) package insert, 46 out of 100 patients in a clinical trial could not take the recommended 160 mg daily dose due to side effects. The prevalence rate of IBS in the U.S. is 15-20% of the general population. As such, conventional dosage forms of dicyclomine are far from clinically optimal, not only for patient compliance reasons, but also because a rapid serum level rise to Cmax is associated with common side effects such as dry mouth, dizziness, blurred vision, nausea, etc. Thus, there is a need for controlled release formulations of anti-cholinergic drugs which can provide clinically usefully effects with a single, once-a-day administration schedule. More particularly there is a need for dosage forms of anti-cholinergic drugs which maintain clinically effective and therapeutic serum levels of the drug over a 24 hour period to allow for once-a-day dosing, for example to treat intestinal hypermotility disorders. SUMMARY OF THE INVENTION In one embodiment, the present invention is directed to a controlled release composition comprising a plurality of anti-cholinergic drug-containing particles, the particles comprising: (a) a core comprising an anti-cholinergic drug; (b) a first coating disposed over the core comprising at least one water-insoluble polymer; and (c) a second coating disposed over the first coating comprising an enteric polymer optionally in combination with a water-insoluble polymer. In another embodiment, the present invention is directed to a dosage form comprising: (a) a core comprising an anti-cholinergic drug; (b) a first coating disposed over the core comprising at least one water-insoluble polymer; (c) a second coating disposed over the first coating comprising an enteric polymer optionally in combination with a water-insoluble polymer; and (d) a plurality of rapidly-dispersing microgranules each having an average particle size of not more than about 400 µm and comprising (i) a disintegrant and (ii) a sugar alcohol and/or a saccharide, wherein said sugar alcohol and/or saccharide each have an average particle size of not more than about 30 µm; wherein said dosage form is an orally disintegrating tablet. In yet another embodiment, the present invention is directed to a method of preparing a controlled release composition comprising: (a) preparing a plurality of cores comprising an anti-cholinergic drug; (b) coating said cores with a first coating comprising at least one water-insoluble polymer optionally in combination with an enteric polymer; (c) applying a second coating, disposed over said coated cores from step (b) wherein the second coating comprises an enteric polymer optionally in combination with a water-insoluble polymer; and (d) filling said cores comprising an anti-cholinergic drug of step (a) and said coated cores of step (c) in clinically effective quantities into capsules. In still yet another embodiment, the present invention is directed to a method of preparing a controlled release composition comprising: (a) preparing a plurality of cores comprising an anti-cholinergic drug; (b) coating said cores with a first coating comprising at least one water-insoluble polymer; (c) applying a second coating, disposed over said coated cores from step (b) wherein the second coating comprises an enteric polymer optionally in combination with a water-insoluble polymer; (d) preparing rapidly-dispersing microgranules each having an average particle size of not more than about 400 µm and comprising (i) a disintegrant and (ii) a sugar alcohol and/or a saccharide, wherein said sugar alcohol and/or saccharide each have an average particle size of not more than about 30 µm; and (e) compressing a blend comprising clinically effective amounts of said cores of step (a) and said coated said drug particles of step (c), together with said rapidly-dispersing microgranules of (d) into orally disintegrating tablets. In still another embodiment, the present invention is directed to a method of treating intestinal hypermotility or irritable bowel syndrome, comprising administering a therapeutic amount of the composition of the present invention to a patient in need thereof.
Load more

Recommended publications
  • Appendix A: Potentially Inappropriate Prescriptions (Pips) for Older People (Modified from ‘STOPP/START 2’ O’Mahony Et Al 2014)
    Appendix A: Potentially Inappropriate Prescriptions (PIPs) for older people (modified from ‘STOPP/START 2’ O’Mahony et al 2014) Consider holding (or deprescribing - consult with patient): 1. Any drug prescribed without an evidence-based clinical indication 2. Any drug prescribed beyond the recommended duration, where well-defined 3. Any duplicate drug class (optimise monotherapy) Avoid hazardous combinations e.g.: 1. The Triple Whammy: NSAID + ACE/ARB + diuretic in all ≥ 65 year olds (NHS Scotland 2015) 2. Sick Day Rules drugs: Metformin or ACEi/ARB or a diuretic or NSAID in ≥ 65 year olds presenting with dehydration and/or acute kidney injury (AKI) (NHS Scotland 2015) 3. Anticholinergic Burden (ACB): Any additional medicine with anticholinergic properties when already on an Anticholinergic/antimuscarinic (listed overleaf) in > 65 year olds (risk of falls, increased anticholinergic toxicity: confusion, agitation, acute glaucoma, urinary retention, constipation). The following are known to contribute to the ACB: Amantadine Antidepressants, tricyclic: Amitriptyline, Clomipramine, Dosulepin, Doxepin, Imipramine, Nortriptyline, Trimipramine and SSRIs: Fluoxetine, Paroxetine Antihistamines, first generation (sedating): Clemastine, Chlorphenamine, Cyproheptadine, Diphenhydramine/-hydrinate, Hydroxyzine, Promethazine; also Cetirizine, Loratidine Antipsychotics: especially Clozapine, Fluphenazine, Haloperidol, Olanzepine, and phenothiazines e.g. Prochlorperazine, Trifluoperazine Baclofen Carbamazepine Disopyramide Loperamide Oxcarbazepine Pethidine
    [Show full text]
  • Pain Management 101
    PAIN MANAGEMENT 101 By: Vicki McCulloch RN, NP & DeAnna Looper RN, CHPN, CHPCA Expect more from us. We do. Objectives • Identify a step-wise approach to pain management. • Identify the WHO Pain Ladder. • Identify non-pharmacological pain control measures. • Identify adjuvant treatment measures. • Identify common myths and truths • Identify common side effects and treatment options. Expect more from us. We do. Pain Management Principles • Use Multi-Treatment and Multi-Discipline Approach • Combine opioids with non-opioid medications • Non-pharmaceutical approaches • Include family and caregiver in planning • Include the patient! • Coordinate with facility • Coordinate with all providers- • Primary Care Provider • Nursing Home Physician • Hospice IDG Members Expect more from us. We do. Utilize the WHO Ladder World Health Organization • (WHO) “analgesic ladder” • Follow the steps as indicated. • Determine if adjuvants are necessary. Expect more from us. We do. WHO Pain Ladder STEP 3 “Strong” opioid for severe pain +/- non-opioid +/- adjuvant STEP 2 “Mild” opioid for mild- moderate pain +/- non- opioid +/- adjuvant STEP 1 Non-opioid + / - adjuvant Expect more from us. We do. Step 1-Mild Pain NON-OPIOID MEDICATION OPTIONS • Acetaminophen (Tylenol)-(Paracetamol)-(Panadol) • Non-steroidal anti-inflammatory drugs (NSAIDs) Traditional NSAIDS Ibuprofen-(Motrin) Aspirin-(Bayer) Naproxen- (Aleve) Nabumetone-(Relafen) Cox-2 Inhibitors Celecoxib-(Celebrex) Rofecoxib-(Vioxx) Valdecoxib-(Bextra) Expect more from us. We do. Adjuvants • Antidepressants
    [Show full text]
  • Department of Health
    DEPARTMENT OF HEALTH National Drug Policy - Pharmaceutical Management Unit 50 National Formulary Committee Philippine National Drug Formulary EssentialEssential MedicinesMedicines ListList Volume I, 7th Edition ( 2008 ) Published by: The National Formulary Committee National Drug Policy ‐ Pharmaceutical Management Unit 50 DEPARTMENT OF HEALTH Manila, Philippines All rights reserved 2008 The National Formulary Committee National Drug Policy‐Pharmaceutical Management Unit 50 (NDP‐PMU 50) Department of Health San Lazaro Cmpd., Rizal Ave., Sta. Cruz, Manila, Philippines 1003 ISBN 978‐971‐91620‐7‐0 Any part or the whole book may be reproduced or transmitted without any alteration, in any form or by any means, with permission from DOH provided it is not sold commercially. ii PHILIPPINE NATIONAL DRUG FORMULARY Volume I, 7th Edition 2 0 0 8 Francisco T. Duque III, MD, MSc Secretary of Health Alexander A. Padilla Undersecretary of Health, Office for External Affairs Robert Louie P. So, MD Program Manager, NDP-PMU 50 Dennis S. Quiambao, MD Proj. Mgmt. Operating Officer & Coordinator (PMOOC) NDP-PMU 50 NATIONAL FORMULARY COMMITTEE Estrella B. Paje-Villar, MD, DTM & H Chairperson Jose M. Acuin, MD, MSc Alma L. Jimenez, MD Alejandro C. Baroque II, MD Marieta B. de Luna, MD Bu C. Castro, MD Nelia P. Cortes-Maramba, MD Dina V. Diaz, MD Yolanda R. Robles, PhD Pharm Mario R. Festin, MD, MS, MHPEd Isidro C. Sia, MD BFAD Representative SECRETARIAT Luzviminda O. Marquez, RPh, RMT Mary Love C. Victoria, RPh Michael D. Junsay, RPh Ermalyn M. Magturo iii Republic of the Philippines DEPARTMENT OF HEALTH OFFICE OF THE SECRETARY 2/F Bldg. 1, San Lazaro Cmpd., Rizal Avenue, Sta.
    [Show full text]
  • Pcf5 Palliative Care Formulary
    PCF5 PALLIATIVE CARE FORMULARY Published by palliativedrugs.com Ltd. Palliativedrugs.com Ltd Hayward House Study Centre Nottingham University Hospitals NHS Trust, City Campus Nottingham NG5 1PB United Kingdom www.palliativedrugs.com # palliativedrugs.com Ltd 2014 The moral rights of the editors have been asserted. PCF4þ ePDF 2013 PCF4þ ePDF 2012 PCF4 2011, reprinted 2012 (twice), 2013 PCF3 2007, reprinted 2008, 2009 PCF2 2002, reprinted 2003 PCF1 1998 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise without the prior permission in writing of palliativedrugs.com Ltd or as expressly permitted by law, or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to [email protected] or by ordinary mail to the above address. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library. ISBN 978-0-9552547-9-6 Typeset by OKS Prepress Services Private Ltd, Chennai, India Printed by Halstan Printing Group, Amersham, UK DISCLAIMER Every effort has been made to ensure the accuracy of this text, and that the best information available has been used. However, palliativedrugs.com Ltd neither represents nor guarantees that the practices described herein will, if followed, ensure safe and effective patient care. The recommendations contained in this book reflect the editors’ judgement regarding the state of general knowledge and practice in the field as of the date of publication. Information in a book of this type can never be all-inclusive, and therefore will not cover every eventuality.
    [Show full text]
  • Composition Colicon ® Tablet: Each Tablet Contains Dicycloverine Hydrochloride BP 10 Mg
    Composition Colicon ® Tablet: Each tablet contains Dicycloverine Hydrochloride BP 10 mg. Colicon ® Syrup: Each 5 ml syrup contains Dicycloverine Hydrochloride BP 10 mg. Colicon ® Injection: Each 2 ml ampoule contains Dicycloverine Hydrochloride BP 20 mg. Description Colicon ® (Dicycloverine Hydrochloride) is an antispasmodic and anticholinergic (antimuscarinic) agent. Colicon ® relieves smooth muscle spasm of the gastrointestinal tract, urinary bladder & ureter. It works at specific receptors, called cholinergic (or muscarinic) receptors, located on the involuntary muscle in the walls of the gut. As antispasmodic drug Colicon ® causes the gut muscle to relax, relieving the pain of colic produced by gut muscle contraction and spasm. Also it has direct musculotropic action. Indication and usage Irritable bowel syndrome (Diarrhea Predominant) Infantile colic GIT spasm Diverticulitis Abdominal colic Diarrhea Dysentery Dosage and administration Adults : 10 to 20 mg three to four times a day. Maximum recommended oral dose is 160 mg daily in divided dose. Children : Children over 6 months of age- 5 to 10 mg three times a day. IM injection: Usual recommended injectable dose is 80 mg daily by IM route in 4 divided dose. Side-Effects Insomnia, headache, weakness, confusion, increased ocular tension, urinary hesitancy, palpitations etc. Precaution Use with caution in patients with autonomic neuropathy, hepatic or renal disease, ulcerative colitis, coronary heart disease, congestive heart failure, cardiac tachyarrhythmia, known or suspected prostatic hypertrophy. Contraindication Obstructive uropathy Obstruction disorder in GIT Severe ulcerative colitis Unstable cardiovascular status in acute hemorrhage Glucoma Myasthenia gravis Patients with hypersensitivity to dicycloverine hydrochloride Infants less than 6 months of age Use in Pregnancy and Lactation Pregnancy Category B.
    [Show full text]
  • 1. What Panadol Night Does 2. Check Before You Take Panadol Night
    GSK LOCisresponsibletoapprovethechangedocumentation, artworkbrief and finalartwork,ensuringthatitisaccurate,consistent complete. GSK MarketisresponsibletoadviseSDCwhenchanges GSK SDCisresponsibleforsitetechnicalrequirements Storage conditions andShelfLife Formulation, Tablet embossing, Formulation, Tablet IMPORTANT required impactthefollowing: and pre-presssuitability. Local approversmustensurethattrademarkand NOTE TO MARKET NOTE TO copyright statementsincludedinthebrief comply withguidanceprovidedby Legal: Global Trade Marks. Legal: GlobalTrade PATIENT INFORMATION LEAFLET 2. Check before you take Panadol Night Do not take Panadol Night: • if you have ever had an allergic reaction to paracetamol, diphenhydramine hydrochloride or to any of the other ingredients (listed in Section 6) • if you have porphyria (too much of the pigment called porphyrin which may discolour the urine) • if you have taken another medicine containing paracetamol in the last 4 hours. Contains paracetamol. Do not take with any other antihistamine-containing products, including those used Night on your skin or in cough and cold medicines. Paracetamol + Diphenhydramine Ask your doctor before you take this medicine: Please read right through this leaflet before you start using this medicine. • if you have liver or kidney problems, including alcoholic liver disease, are This medicine is available without prescription, but you still need to use underweight or malnourished or regularly drink alcohol. You may need to avoid Panadol Night carefully to get the best results from them. using this product altogether or limit the amount of paracetamol that you take. • Keep this leaflet you may need to read it again. • if you have epilepsy, or seizure disorders • If you have any questions, or if there is anything you do not understand, • if you have an obstruction in your stomach or gut (for example, because of an ulcer) ask your pharmacist.
    [Show full text]
  • Drug Tariff Price Changes
    Drug tariff September 2018 Top 10 price reductions since August 2018 Medicine Pack size Basic price August 2018 Difference Pergolide 1mg tablets 100 tablet £116.86 £131.66 -£14.80 Ropinirole 5mg tablets 84 tablet £170.16 £175.32 -£5.16 Olanzapine 20mg orodispersible tablets sugar free 28 tablet £57.20 £62.20 -£5.00 Naproxen 250mg/5ml oral suspension 100 ml £48.75 £52.50 -£3.75 Telmisartan 80mg / Hydrochlorothiazide 25mg tablets 28 tablet £14.98 £17.00 -£2.02 Yellow soft paraffin solid 500 gram £6.24 £8.02 -£1.78 Cefadroxil 500mg capsules 20 capsule £5.87 £7.61 -£1.74 Etoricoxib 120mg tablets 28 tablet £17.03 £18.59 -£1.56 Gabapentin 800mg tablets 100 tablet £24.86 £25.50 -£0.64 Felodipine 2.5mg modified-release tablets 28 tablet £5.68 £6.31 -£0.63 Top 10 price increases since August 2018 Medicine Pack size Basic price August 2018 Difference Anagrelide 500microgram capsules 100 capsule £378.98 £350.70 £28.28 Macrogol 3350 oral powder 8.5g sachets sugar free 28 sachet £29.85 £3.89 £25.96 Linezolid 600mg tablets 10 tablet £305.44 £283.32 £22.12 Famciclovir 125mg tablets 10 tablet £53.45 £36.72 £16.73 Sevelamer 2.4g oral powder sachets sugar free 60 sachet £214.65 £198.78 £15.87 Diamorphine 500mg powder for solution for injection ampoules 5 ampoule £199.00 £187.70 £11.30 Dicycloverine 20mg tablets 84 tablet £269.84 £259.39 £10.45 Meloxicam 15mg orodispersible tablets sugar free 30 tablet £25.50 £15.50 £10.00 Meloxicam 7.5mg orodispersible tablets sugar free 30 tablet £25.50 £15.50 £10.00 Dicycloverine 10mg tablets 100 tablet £252.78 £242.99
    [Show full text]
  • Smecta®) in the Symptomatic Treatment of Acute Diarrhoea in Adults
    IPSEN GROUP F-FR-00250-105 CONFIDENTIAL PROTOCOL: FINAL (WITH AMENDMENT NO. 4): 07 JANUARY 2019 PAGE 1/89 PROTOCOL TITLE: EFFICACY OF DIOSMECTITE (SMECTA®) IN THE SYMPTOMATIC TREATMENT OF ACUTE DIARRHOEA IN ADULTS. A MULTICENTRE, RANDOMISED, DOUBLE BLIND, PLACEBO-CONTROLLED, PARALLEL GROUPS STUDY STUDY PROTOCOL STUDY number: F-FR-00250-105 (Diosmectite- BN 00250) EudraCT number: n° 2015-001138-10 Final Version (with Amendment No. 4): 07 January 2019 Sponsor’s Medically Responsible Person: Study Sponsor: PPD Ipsen Pharma SAS PPD 65 quai Georges Gorse Ipsen Pharma SAS 92100 Boulogne-Billancourt, France 65 quai Georges Gorse Tel: PPD 92100 Boulogne-Billancourt, France Fax: PPD Tel: PPD Fax: PPD Monitoring Office: and/or CRO Co-ordinating Investigator: PPD PPD PPD Délégation à la Recherche Ipsen Pharma SAS Centre Hospitalier Régional Universitaire 65 quai Georges Gorse de Lille 92100 Boulogne-Billancourt, France 2, avenue Oscar Lambret, Tel: PPD 59037 Lille, France Cedex Fax: PPD Tel: PPD Fax: PPD Pharmacovigilance/Emergency Contact: PPD Ipsen Innovation, ZI de Courtaboeuf - 5 avenue du Canada - 91940 Les Ulis - France Tel: PPD Tel: PPD – PPD For SAEs reporting: Fax: PPD Email: PPD Persons supplied with this information must understand that it is strictly confidential. Information contained herein cannot be disclosed, submitted for publication or used for any purpose other than that contemplated herein without the sponsor’s prior written authorisation. IPSEN GROUP F-FR-00250-105 CONFIDENTIAL PROTOCOL: FINAL (WITH AMENDMENT NO. 4): 07 JANUARY 2019 PAGE 2/89 INVESTIGATOR’S AGREEMENT Investigator Agreement and Signature: I have read and agree to Protocol F-FR-00250-105 entitled Efficacy of the diosmectite (Smecta®) in the symptomatic treatment of acute diarrhoea in adults.
    [Show full text]
  • Multi-Discipline Review/Summary, Clinical, Non-Clinical
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210868Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA Multi-disciplinary Review and Evaluation NDA 210868 Lorlatinib NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 210868 Priority or Standard Priority Submit Date(s) December 5, 2017 Received Date(s) December 5, 2017 PDUFA Goal Date November 5, 2018 Division/Office OHOP/DOP2 Review Completion Date November 2, 2018 Established Name Lorlatinib (Proposed) Trade Name LORBRENA Pharmacologic Class Kinase inhibitor Code name PF-06463922 Applicant Pfizer, Inc. Formulation(s) 100 mg and 25 mg tablets Dosing Regimen 100 mg orally once daily Applicant Proposed For the treatment of patients with anaplastic lymphoma kinase Indication(s)/Population(s) (ALK)-positive metastatic non-small cell lung cancer (NSCLC) previously treated with one or more ALK tyrosine kinase inhibitors (TKIs). Recommendation on Accelerated Approval Regulatory Action Recommended For the treatment of patients with anaplastic lymphoma kinase Indication(s)/Population(s) (ALK)-positive metastatic non-small celling cancer (NSCLC) (if applicable) whose disease has progressed on: • crizotinib and at least one other ALK inhibitor for metastatic disease; or • alectinib as the first ALK inhibitor therapy for metastatic disease; or • ceritinib as the first ALK inhibitor therapy for metastatic disease 1 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4344794 NDA Multi-disciplinary Review and Evaluation NDA 210868 Lorlatinib Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 13 Additional Reviewers of Application ............................................................................................
    [Show full text]
  • OUH Formulary Approved for Use in Breast Surgery
    Oxford University Hospitals NHS Foundation Trust Formulary FORMULARY (Y): the medicine can be used as per its licence. RESTRICTED FORMULARY (R): the medicine can be used as per the agreed restriction. NON-FORMULARY (NF): the medicine is not on the formulary and should not be used unless exceptional approval has been obtained from MMTC. UNLICENSED MEDICINE – RESTRICTED FORMULARY (UNR): the medicine is unlicensed and can be used as per the agreed restriction. SPECIAL MEDICINE – RESTRICTED FORMULARY (SR): the medicine is a “special” (unlicensed) and can be used as per the agreed restriction. EXTEMPORANEOUS PREPARATION – RESTRICTED FORMULARY (EXTR): the extemporaneous preparation (unlicensed) can be prepared and used as per the agreed restriction. UNLICENSED MEDICINE – NON-FORMULARY (UNNF): the medicine is unlicensed and is not on the formulary. It should not be used unless exceptional approval has been obtained from MMTC. SPECIAL MEDICINE – NON-FORMULARY (SNF): the medicine is a “special” (unlicensed) and is not on the formulary. It should not be used unless exceptional approval has been obtained from MMTC. EXTEMPORANEOUS PREPARATION – NON-FORMULARY (EXTNF): the extemporaneous preparation (unlicensed) cannot be prepared and used unless exceptional approval has been obtained from MMTC. CLINICAL TRIALS (C): the medicine is clinical trial material and is not for clinical use. NICE TECHNOLOGY APPRAISAL (NICETA): the medicine has received a positive appraisal from NICE. It will be available on the formulary from the day the Technology Appraisal is published. Prescribers who wish to treat patients who meet NICE criteria, will have access to these medicines from this date. However, these medicines will not be part of routine practice until a NICE TA Implementation Plan has been presented and approved by MMTC (when the drug will be given a Restricted formulary status).
    [Show full text]
  • West Essex CCG Anticholinergic Side-Effects and Prescribing Guidance
    Anticholinergic side-effects and prescribing guidance . Anticholinergic (antimuscarinic) medications: associated with increased risks of impaired cognition and falls in patients over the age of 65 years. Recent research also points to a link to mortality increasing with the number and potency of anticholinergic agents prescribed. Anticholinergic Syndrome: is a state of confusion with characteristic features related to dysfunction of the autonomic parasympathetic (cholinergic) nervous system. Symptoms classified into systemic and CNS manifestations: o Systemic (peripheral) symptoms: Blurred vision, photophobia, non-reactive mydriasis, loss of accommodation response, flushed and dry skin, dry mouth, tachycardia, hypertension and fever. Gastrointestinal and urinary motility are frequently reduced o CNS symptoms: Delirium, agitation, disorientation, and visual hallucinations. Ataxia, choreoathetosis, myoclonus and seizures may also occur without peripheral symptoms. Medication Issues: several commonly prescribed medications that may not be thought of as anticholinergic have significant anticholinergic effects, which when taken with known anticholinergic medication can increase the risk of adverse effects. Many medication groups e.g. antihistamines, tricyclic antidepressants, drugs for asthma and COPD, cold preparations, hyoscine have varying degrees of anticholinergic activity and have the potential to cause Anticholinergic Syndrome . Clinicians should be aware of the risk for chronic anticholinergic toxicity and the fact that not all the symptoms may manifest in patients and if they do suffer some symptoms they could be wrongly attributed to another diagnosis Evidence . A study of patients over 65 found that 20% of participants who scored four or more had died by the end of the two year study period compared with 7% of patients with a score of zero.
    [Show full text]
  • Polypharmacy Guidance 2018
    3rd Edition, 2018 If using any content from this document, please acknowledge the Scottish Government Polypharmacy Model of Care Group, 2018. When referencing this document, please use the following format: Scottish Government Polypharmacy Model of Care Group. Polypharmacy Guidance, Realistic Prescribing 3rd Edition, 2018. Scottish Government Cover images courtesy of jk1991 at FreeDigitalPhotos.net Infographics courtesy of SIMPATHY consortium Key words and search terms: polypharmacy, appropriate polypharmacy, inappropriate polypharmacy, deprescribing, 7-Steps, Drug Efficacy (NNT), Anticholinergic Burden, Cumulative Toxicity, Polypharmacy Indicators, Case Finding Indicators, Outcomes Indicators 2 3 Foreword The care of patients with multi-morbidities (multiple medical conditions) is the greatest challenge now faced by the health service, as it can create overly complex health care for some of the most vulnerable in society. The vast majority of medical research, guidelines and contractual agreements have focussed on single targets for single disease states, whereas in reality most patients have multi-morbidities, requiring multiple treatments.1 The resulting polypharmacy (use of multiple medicines) can be appropriate or inappropriate and the key healthcare aim for the individual patient is to ensure the safe and effective use of their multiple medicines. Despite research into this area being in relative infancy there exists a requirement to produce guidance for both patients and healthcare providers, based on the best evidence to date. Polypharmacy becomes inappropriate when the medication risks begin to outweigh benefits for an individual patient. The aim of addressing this is to identify those patients at greatest risk of harm and to agree a medication regimen that is tailored to their changing needs and expectations.
    [Show full text]