NEVIRAPINE

1. NEVIRAPINE THE CONCERNS REGISTRAR OF MEDICINES 15 AUGUST 2002

2. ARV Retrovir (AZT) Videx (ddI) Hivid (ddC) Zerit (d4T) Epivir(3TC) Invirase (INV) Norvir(RTV) Crixivan (IDV) Viramune (NVP) Viracept (NFV) Combivir(AZT/3TC) Sustiva (EFV) USA EU RSA 1987 1987 1989 1991 1992 1992 1992 1992 1994 1994 1996 1998 1995 1996 - 1995 1996 1997 1996 1996 1997 1996 1996 1996 1996 - 1998 1997 1998 1999 1997 1998 1998 1998 DATES OF FIRST REGULATORY APPROVAL OF ARV’s IN US,EU,RSA

3. GCP- South Africa & ICH • Clinical trials conducted according to sound scientific and ethical standards (good clinical practice) • Safety monitoring of participants during a clinical trials an ethical requirement • Written and verbal consent should be obtained - countersigning by literate person where required • Lack of adherence to standards of GCP (Shalala D. New England Journal of Medicine Sep 2000, Vol. 343, No. 11

4. GCP-TRIAL DRUG • Maintenance of records • Inventory at the site • Return of unused records • Reconciliation of doses • List of essential documents and detail on how they are handled and stored

5. GCP-DATA MANAGEMENT • Collection of data, quality recording, maintenance, retrieval of source data • Source documentation validity • Documentation of all data changes • Maintenance of a security system to prevent unauthorized access to the data • Source document verification integral to GCP (DIA, Journal 1999) • Retention of essential documents for not less than 5 years

6. Nevirapine-HIVNET012 • A study conducted in Uganda • Published in Lancet September 1999 • Involving 626 women & a pivotal study • submitted to MCC for the indication reduction of risk of transmission from mother to child

7. ISSUE-1 • CONDITIONS OF APPROVAL • Submission South African cases of lack of efficacy and other serious adverse reactions • submission of 6 monthly periodic safety update reports & information on resistance • new local and international information particularly information on resistance • information on local utilisation patterns • information on resistance from selected pilot sites and SAINT study • inclusion of the statement that safety and efficacy in subsequent pregnancy has not been established

8. Package Insert information • Appropriate wording for the indication MTCT- “ to reduce the risk of intrapartum transmission of HIV_1 from mother to child in pregnant women who are not taking antiretroviral therapy at the time of labour • Viramune should be only prescribed for the reduction of the risk of intrapartum transmission, of HIV-1 from mother to child for patients who have been tested for HIV and appropriately counseled

9. Package Insert Information • Safety and efficacy has not been established in neonates with birth weight of less than 2,5 kg is contraindicated, should be under the Heading “Contraindicated” • Breastfeeding is not recommended if the benefits of the medication in achieving HIV-1 free survival are to be maintained

10. ISSUE-2 • PROBLEMS WITH HIVNET012 STUDY RESULTS IN UGANDA • According to company • a) reporting and documentation • b) deficiencies revealed by the Audit in source documentation • c) withdrawal of application from FDA

11. ISSUE-3 • COMMUNICATION WITH FDA,NIH, BI, • Confirmation of concerns by FDA • EMEA,TGA, MCA- (NVP not a drug of choice other regimens used) • NIH (Report confidentiality) • BI ( Data ownership rests with NIH) • Offer from NIH to see report and wait for September Re-monitoring plan report

12. Adverse Drug Reaction Reporting Rates in S. Africa No. of Reports Reporting Year

13. National DRAs and Pharmacovigilance Centres Ministry of Health Complementary Medicines Clinical Trials Uppsala Monitoring Centre Inspectorate MCC Industry Enforcement NADEMC UCT teaching hospital Public health Clinical Consulting Pharmnet SAMJ/SAPJ Health providers Medunsa(ARV) Natal (ARV)

14. RESISTANCE • Ongoing trials on ARV resistance including NVP • MCC stakeholder congress- regulatory challenges of antimicrobial resistance & public health implications • Organizing Committee and call for papers

15. MCC provincial visits- findings • Protocol contradicts Package insert information in terms of paediatric dosing, and breastfeeding • Stability profile of the suspension 2 months after opening container • Availability of Patient Information Leaflet • No process for reporting safety • Unresolved breastfeeding issues

16. MCC-RESPONSE • Review of all data (Copy of full submission filed with FDA & Copy of full SAINT report) • Evaluation of audit report referred in (March 2002) • Provincial visits by MCC team (summary later) • Establishment of special MCC team to review all documents submitted • Re-monitoring plan report awaited from NIH • Ongoing Communication with BI, NIH,FDA • Strengthening of Pharmacovigilance • New ARV pharmacovigilance established in Medunsa Upgrading of UCT (All medicines) Future unit for ARV in KZN • ARV Pregnancy registry (project proposal) for ARV-safety monitoring in pregnant women & babies

17. IN CONCLUSION • Nevirapine is still registered for treatment of HIV/AIDS • Nevirapine is not banned • Nevirapine is still approved for the indication of “reduction of the risk of intrapartum transmission, of HIV-1 from mother to child” • Nevirapine like AZT is one of the available options for the treatment of this indication • Review of HIVNET 012 is ongoing