Application for the Deletion of Saquinavir (Invirase®) on the WHO Model List of Essential Medicines

21st Expert Committee on the Selection and Use of Essential Medicines

Application for the deletion of saquinavir (Invirase®) on the WHO Model List of Essential Medicines

Submitted by

F. Hoffmann-La Roche Ltd.

2 December 2016

F. Hoffmann-La Roche Ltd. Grenzacherstrasse 124 4070 Basel, Switzerland

Table of Contents

1. Summary Statement of the proposal for inclusion, change or deletion 3

2. Name of the focal point in WHO submitting or supporting the application 3

3. Name of organization(s) consulted and/or supporting the application 3

4. International Nonproprietary Name (INN) and ATC code of the medicine 3

5. Formulation and strength proposed for inclusion 3

6. Whether listing is requested as an individual medicine or a pharmacological class 3

7. Treatment details (requirements for diagnosis, treatment and monitoring). 3

8. Information support the public health relevance 3-4

9. Summary of comparative effectiveness in a variety of clinical settings 4

10. Summary of evidence on safety 4

11. Summary of available data on comparative cost and cost-effectiveness 4

12. Summary of regulatory status of the medicine 4

13. Availability of pharmacopoeial standards 4

14. Reference List 5

1. Summary statement of the proposal for inclusion, change or deletion.

F. Hoffmann-La Roche Ltd. (Hereafter referred to as Roche) proposes the deletion of saquinavir from the WHO Model List of Essential Medicines (EML) under the category of 6.4.2 Antiretrovirals.

Saquinavir is indicated for the treatment of HIV-1 in adults.

2. Name of the WHO technical department and focal point supporting the application (where relevant).

Not applicable

3. Name of organization(s) consulted and/or supporting the application.

F. Hoffmann-La Roche Ltd.

4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine.

INN: saquinavir mesylate ATC: J05A E01

5. Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate).

Roche proposes the deletion of saquinavir (200mg and 500mg) from the WHO EML.

6. Whether listing is requested as an individual medicine or as representative of a pharmacological class.

The WHO EML lists under section 6.4.2.3 five Protease inhibitor medicines in total including saquinavir

7. Treatment details (requirements for diagnosis, treatment and monitoring). N/A

8. Information supporting the public health relevance.

Saquinavir (Invirase®) was the first protease inhibitor (PI) approved for marketing in 1995. It was listed in many clinical HIV guidelines during 1998-2002 as the preferred PI for initial ART treatment of HIV. In the 21 years of marketing experience since approval of saquinavir, 1.77 million people have been treated to saquinavir (both boosted and unboosted) in combination with other antiretrovirals.

In recent years, the clinical use of saquinavir has declined substantially due to the development of other newer HIV agents with less pill burden and equal or more effectiveness(1). Current HIV treatment guidelines no longer recommend saquinavir as an initial therapy for the treatment of HIV-1 infected patients, for example saquinavir/ritonavir is not listed as a preferred or alternative option in the British HIV guidelines for the treatment of ART naïve patients because of a higher pill burden and the availability of alternative PI/r’s with more convenient dosing (2). The standard recommended dosage regimen in adults for saquinavir is 1000mg two times daily with ritonavir 100mg two times daily in combination with other antiviral agents. Film coated tablets of saquinavir contain 500mg or hard capsules contain 200mg of saquinavir.

For treatment- naïve patients the saquinavir product label now requires dose escalation and careful ECG monitoring due to an association with QT prolongation, which is unique to saquinavir in the class of PIs. Saquinavir is a potent inhibitor of CYP3A, significantly increasing the exposure of drugs primarily

3 metabolized by CYP3A and drug -drug adverse reactions. Many of the current HIV guidelines (USA [3]), EU [4]) have therefore removed saquinavir from their recommendations due to this extra burden..

Alternative PIs to saquinavir include: lopinivir/r, atazanivir/r, darunivir/r: the dosage strengths and number of tablets are compared in table below. A number of PI alternatives use less tablets/day to reach the recommended dose compared to saquinavir. DRUG Dosage Strengths Standard recommended Number of tablets of Available dose PI ( mg strength) required per day Invirase (Saqunavir) 200mg, 500mg, 1000 mg two times per 4 using 500mg or 8 day/100mg r using 200mg Reyataz (Atazanavir) 150mg, 200mg, 300mg 300mg /100mg r once daily 1 using 300mg Prezista (Darunavir) 800mg, 600mg, 400mg 800mg/100mg r once daily 1 using 800mg once daily Kaletra (Lopinivir) 100mg, 200mg 400mg two times per day 4 using 200mg ( but co- formulated with ritonavir 50mg )

A number of PIs are currently in use. Boosting refers to the use of a small dose of ritonavir (Norvir) in combination with another PI. Most ART regimens are boosted, although some patients cannot tolerate the adverse gastrointestinal effects of ritonavir. PIs are metabolized by the CYP450 system and are associated with the most drug-drug interactions (5). Common adverse effects of PIs include gastrointestinal effects, lipohypertrophy, glucose intolerance or diabetes mellitus, and lipid disorders. It is difficult to differentiate on the basis of adverse events between PI’s.

9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings. Some important clinical HIV guidelines no longer specifically recommend saquinavir/ritonavir as an alternative in HIV-1 patients. The removal of saquinavir/ritonavir reflects the fact that clinical guideline committees consider all evidence and remove agents which are more complicated to use and/or less well tolerated in favor of newer agents offering an enhanced convenience of single dose combinations. Although no direct comparison studies between saquinavir/ritonavir and these newer agents have been conducted, the newer agents are generally perceived to have a better tolerability or greater response rates in treatment-experienced patients.

10. Review of harms and toxicity: summary of evidence on safety. The key risk associated with saquinavir/ritonavir treatment is related to the potential for QT prolongation which may result in Torsade de Pointes (TdP) and sudden death. Cases of TdP or sudden death attributable to saquinavir/ritonavir have not been reported in either clinical trials of HIV-infected adults or in postmarketing experience. Reducing the initial dosing regimen for treatment-naïve patients to 500 mg minimized the risk. Treatment-naïve patients with a QT within the normal range should undergo on- treatment ECGs to exclude an increased risk.

11. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group. N/A

12. Summary of regulatory status of the medicine. Saquinavir was approved in approximately 74 countries worldwide. Generic versions are available in some countries such as Russia, Germany, Denmark, Finland, and the Netherlands.

13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia). N/A

14. Reference list. 1. Nachega et al; Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection; a meta analyses of randomized controlled trials. Clin Inf Disease 2014; 58;1297-1307 2. British HIV guidelines: HIV Medicine (2014), 15 (Suppl. 4), 1–77

3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. on accessed [24.11.16]

4. European HIV EACS guidelines version 8.1 October 2016 available at: http://www.eacsociety.org/files/guidelines_8.1-english.pdf

5. Reust C.E; Common adverse events of antiretroviral therapy for HIV disease. Am Family Physician 83;12;1443-51