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10.5.2 informed consent of non-english

If there is an unexpected enrollment of a research participant for whom there is no translated extant IRB approved consent document, the principal investigator and/or those authorized to obtain informed consent will use the Short Form Oral Consent Process as described in MAS Policy M772, OHSRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2). The summary that will be used is the English version of the extant IRB approved consent document. Signed copies of both the English version of the consent and the translated short form will be given to the subject or their legally authorized representative and the signed original will be filed in the medical record. Unless the PI is fluent in the prospective subject's language, an interpreter will be present to facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a family member) will assist in presenting information and obtaining consent. Whenever possible, interpreters will be provided copies of the relevant consent documents well before the consent conversation with the subject (24 to 48 hours if possible). We request prospective IRB approval of the use of the short form process and will notify the IRB at the time of continuing review of the frequency of the use of the Short Form.
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11 pharmaceutical information 11.1 anetumab

Anetumab ravtansine will be supplied by the manufacturer, Bayer Healthcare Pharmaceuticals under a CRADA agreement between the manufacturer and the Thoracic and GI Oncology Branch.
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11.1.2 toxicity

The clinical experience with anetumab ravtansine available to date comes from the ongoing Study 15051 entitled "An open label Phase 1 dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and MTD of the anti-mesothelin ADC anetumab ravtansine in subjects with advanced solid tumors." (NCT01439152) Data are available from 147 subjects evaluated on this study, including: 10 dose escalation cohorts (45 subjects), two expansion cohorts in mesothelioma and ovarian cancer at a dose of 6.5 mg/kg every 3 weeks (32 subjects); two further expansion cohorts in mesothelioma and ovarian cancer at doses of 1.8 mg/kg weekly (35 subjects, but data from 1 individual was not available) and 2.2 mg/kg weekly (36 subjects). One hundred nine subjects (74.1%) had treatment emergent adverse events (TEAEs) considered to be at least possibly related to the study drug. The most common TEAEs at least possibly related to anetumab ravtansine are presented in Table 11 by the number of subjects who reported an event in decreasing order. A total of 16 subjects died within 30 days of the drug being stopped and none of these events were related to the study drug.  
| Number of subjects with drug related TEAE   |                         |                                     |                                     |                           |                         |                         |               |
|---------------------------------------------|-------------------------|-------------------------------------|-------------------------------------|---------------------------|-------------------------|-------------------------|---------------|
| MedDRA  Preferred Term                      | Escalation  1-8A (n=35) | Escalation  9  6.5 mg/kg  Q3W (n=6) | Escalation  10 7.5 mg/kg  Q3W (n=4) | Exp 6.5 mg/kg Q3W  (n=32) | Exp 1.8 mg/kg QW (n=34) | Exp 2.2 mg/kg QW (n=36) | Total (n=147) |
| All                                         | 29  (64.4%)             | n/a                                 | n/a                                 | 30                        | 26                      | 24                      | 109           |
| (93.8%)                                     | (76.5%)                 | (66.7%)                             | (74.1%)                             |                           |                         |                         |               |
| Nausea                                      | 8 (22.8%)               | 3 (50.0%)                           | 2 (50.0%)                           | 19 (59.4%)                | 10 (29.4%)              | 8 (22.2%)               | 50 (34.0%)    |
| Fatigue                                     | 10 (28.6%)              | 2 (33.3%)                           | 1 (25.0%)                           | 16 (50.0%)                | 9 (26.5%)               | 11 (30.6%)              | 49 (33.3%)    |
| Diarrhea                                    | 1 (2.9%)                | 3 (50.0%)                           | 0                                   | 10 (31.3%)                | 6 (17.6%)               | 5 (13.9%)               | 25 (17.0%)    |
| Vomiting                                    | 5 (14.3%)               | 3 (50.0%)                           | 1 (25.0%)                           | 9 (28.1%)                 | 2 (5.9%)                | 4 (11.1%)               | 24 (16.3%)    |
| Decreased  appetite                         | 4 (11.4%)               | 2 (33.3%)                           | 0                                   | 10 (31.3%)                | 2 (5.9%)                | 3 (8.3%)                | 21 (14.3%)    |
| AST  increase                               | 0                       | 1 (16.7%)                           | 2 (50.0%)                           | 7 (21.9%)                 | 5 (14.7%)               | 5 (13.9%)               | 20 (13.6%)    |  
Table 11: Treatment-emergent adverse events at least possibly related to anetumab ravtansine,
>5% by cohort (with separation of higher and lower dose-escalation cohorts)  
| MedDRA  Preferred Term Neuropath y  peripheral ALT  Vision  Platelet  Alk phos  Lymphocy te  decrease Corneal  Non  cardiac  chest pain Peripheral  sensory  neuropath y Hypothyro Lipase   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Escalation  1-8A (n=35)   |
|---------------------------|  
Neuropath  
y  
peripheral  
3 (8.6%) 0 1 (25.0%) 9 (28.1%) 3 (8.8%) 3 (8.3%) 19 (12.9%)  
ALT  
increase 1 (2.9%) 1 (16.7%) 1 (25.0%) 5 (15.6%) 2 (5.9%) 6 (16.7%) 16 (10.9%)  
Vision  
blurred 0 0 2 (50.0%) 6 (18.8%) 2 (5.9%) 4 (11.1%) 14 (9.5%)  
Platelet  
decrease 0 1 (16.7%) 1 (25.0%) 6 (18.8%) 2 (5.9%) 3 (8.3%) 13 (8.8%)  
Alk phos  
increase 0 0 1 (25.0%) 4 (12.5%) 0 5 (13.9%) 10 (6.8%)  
Lymphocy  
te  
decrease  
2 (5.7%) 1 (16.7%) 0 2 (6.3%) 2 (5.9%) 1 (2.8%) 8 (5.4%)  
Corneal  
disorder 0 0 2 (50.0%) 5 (15.6%) 0 0 7 (4.8%)  
Dry eye 0 0 0 2 (6.3%) 2 (5.9%) 3 (8.3%) 7 (4.8%) Asthenia 2 (5.7%) 0 0 5 (15.6%) 0 0 7 (4.8%) Non  
cardiac  
chest pain  
1 (2.9%) 0 1 (25.0%) 2 (6.3%) 1 (2.9%) 0 5 (3.4%)  
Flushing 1 (2.9%) 1 (16.7%) 1 (25.0%) 1 (3.1%) 1 (2.9%) 0 5 (3.4%) Dyspepsia 1 (2.9%) 1 (16.7%) 0 1 (3.1%) 2 (5.9%) 0 5 (3.4%) Pyrexia 1 (2.9%) 0 1 (25.0%) 0 1 (2.9%) 2 (5.6%) 5 (3.4%) Anemia 0 0 0 1 (3.1%) 3 (8.8%) 1 (2.8%) 5 (3.4%) Hypothyro  
idism 0 0 0 0 2 (5.9%) 3 (8.3%) 5 (3.4%)  
Lipase  
increase 0 0 1 (25.0%) 2 (6.3%) 1 (2.9%) 1 (2.8%) 5 (3.4%)  
Rash 1 (2.9%) 0 0 1 (3.1%) 2 (5.9%) 0 4 (2.7%) Chills 2 (5.7%) 0 1 (25.0%) 0 0 1 (2.8%) 4 (2.7%)  
| Escalation  9  6.5 mg/kg  Q3W (n=6)   |
|---------------------------------------|  
0 0 0 1 (3.1%) 3 (8.8%) 1 (2.8%) 5 (3.4%)  
| Escalation  10 7.5 mg/kg  Q3W (n=4)   |
|---------------------------------------|  
| Exp 6.5 mg/kg Q3W  (n=32)   |
|-----------------------------|  
| Exp 1.8 mg/kg QW (n=34)   |
|---------------------------|  
| Exp 2.2 mg/kg QW (n=36)   |
|---------------------------|  
| Total (n=147)   |
|-----------------|  
| Number of subjects with drug related TEAE   |                         |                                     |                                     |                           |                         |                         |               |
|---------------------------------------------|-------------------------|-------------------------------------|-------------------------------------|---------------------------|-------------------------|-------------------------|---------------|
| MedDRA  Preferred Term                      | Escalation  1-8A (n=35) | Escalation  9  6.5 mg/kg  Q3W (n=6) | Escalation  10 7.5 mg/kg  Q3W (n=4) | Exp 6.5 mg/kg Q3W  (n=32) | Exp 1.8 mg/kg QW (n=34) | Exp 2.2 mg/kg QW (n=36) | Total (n=147) |
| Corneal  epithelial                         | 0                       | 0                                   | 0                                   | 2 (6.3%)                  | 2 (5.9%)                | 3 (8.3%)                | 7 (4.8%)      |
| microcysts Hyponatre mia                    | 1 (2.9%)                | 0                                   | 0                                   | 2 (6.3%)                  | 0                       | 1 (2.8%)                | 4 (2.7%)      |
| Dyspnea                                     | 0                       | 0                                   | 0                                   | 1 (3.1%)                  | 2 (5.9%)                | 1 (2.8%)                | 4 (2.7%)      |
| Arthralgia                                  | 0                       | 0                                   | 0                                   | 2 (6.3%)                  | 1 (2.9%)                | 1 (2.8%)                | 4 (2.7%)      |
| Cholestero l increased                      | 0                       | 1 (16.7%)                           | 0                                   | 0                         | 0                       | 0                       | 1 (0.7%)      |
| Exp = expansion cohort                      |                         |                                     |                                     |                           |                         |                         |               |  
Exp = expansion cohort Cohorts 1 - 8A were dosed every 3 weeks. The doses were as follows: cohort 1 (n=3) - 0.15 mg/kg; cohort 2 (n=3) - 0.3 mg/kg; cohort 3 (n=4) - 0.6 mg/kg; cohort 4 (n=4) - 1.2 mg/kg; cohort 5 (n=4) - 2.4 mg/kg; cohort 6 (n=4)
- 3.6 mg/kg, cohort 7 (n=4) - 4.5 mg/kg; cohorts 8+8A* (n=9) - 5.5 mg/kg
* including cohort 8A (anetumab ravtansine produced from a new cell line)
Describe all toxicities observed in patients and/or relevant animal studies
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11.1.3 formulation and preparation

The drug product is available as a lyophilizate. Each vial contains 62.5 mg of anetumab ravtansine; the amount available for administration, based on retractable volume of reconstituted solution, is 60 mg of anetumab ravtansine. It should be reconstituted in water for injection and diluted in 0.9% sodium chloride solution (normal saline) or dextrose 5% solution prior to administration as IV infusion. The drug product is to be stored at 2°C to 8°C (36°F to 46°F). The reconstitution and dilution of the anetumab ravtansine solution and the associated stability information is described in detail in a separate manual "Anetumab ravtansine storage and handling instructions".
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11.1.5 incompatibilities

None have been confirmed in a clinical study.  
11.1.5.1 Chemical Structure  
  
Anetumab ravtansine is an ADC consisting of a fully human IgG1 antibody (MF-T, BAY 86-1903) directed at the mesothelin antigen and conjugated to a synthetic cytotoxic anticancer agent, maytansine derivative (DM4, BAY 100-6640) as toxophore through an SPDB.  
Based on the reference by Davis et al.23, DM4 is a substrate of metabolizing enzymes CYP3A4, 3A5, and 2D6. Further the package insert of ado-trastuzumab emtansine, which also uses maytansine (referred to as DM1) conjugated to trastuzumab, indicates that the cytotoxic component is mainly metabolized by 3A4 and to a lesser extent by 3A5. Therefore, concomitant administration of strong inhibitors and inducers of CYP3A4 are prohibited in patients receiving anetumab ravtansine. DM4-Me is a substrate of P-gp transporter and it is possible that medications that are potent inhibitors of P-gp transporter could alter the pharmacokinetic profile of DM4-Me in plasma.
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12 references

1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global Cancer Statistics. CaCancer J Clin 2011;61:69-90.  
2. Reck M, Heigener DF, Mok T, Soria JC, Rabe KF. Management of non-small-cell lung cancer: recent developments. Lancet 2013;382:709-19. 3. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. New Engl J Med 2002;346:92-8. 4. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57.  
5. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in nonsmall-cell lung cancer. N Engl J Med 2010;363:1693-703.  
6. Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 2015;372:1700-9. 7. Li S, Qi X, Huang Y, Liu D, Zhou F, Zhou C. Ceritinib (LDK378): a potent alternative to crizotinib for ALK-rearranged non-small-cell lung cancer. Clin Lung Cancer 2015;16:86-91. 8. Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 2014;15:1119-28. 9. Chang K, Pastan I. Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. P Natl Acad Sci USA 1996;93:136-40. 10. Ordonez NG. Application of mesothelin immunostaining in tumor diagnosis. Am J Surg Pathol 2003;27:1418-28. 11. Pastan I, Hassan R. Discovery of Mesothelin and Exploiting It as a Target for Immunotherapy. Cancer Res 2014;74:2907-12. 12. Thomas A, Chen Y, Steinberg SM, et al. High mesothelin expression in advanced lung adenocarcinoma is associated with KRAS mutations and a poor prognosis. Oncotarget 2015;6:11694-703. 13. Kachala SS, Bograd AJ, Villena-Vargas J, et al. Mesothelin Overexpression Is a Marker of Tumor Aggressiveness and Is Associated with Reduced Recurrence-Free and Overall Survival in Early-Stage Lung Adenocarcinoma. Clin Cancer Res 2014;20:1020-8.  
14. Ho M, Bera TK, Willingham MC, et al. Mesothelin expression in human lung cancer. Clin Cancer Res 2007;13:1571-5. 15. Golfier S, Kopitz C, Kahnert A, et al. Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Molecular cancer therapeutics 2014;13:1537-48. 16. Hassan R, Bendell JC, Blumenschein Jr. G, et al. Phase I Study of Anti-Mesothelin Antibody Drug Conjugate Anetumab Ravtansine. World Conference on Lung Cancer; 2015; Denver, CO. 17. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2006;24:3187-205. 18. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European journal of cancer 2009;45:228-47. 19. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the  
Version Date: *01-11-18* Prostate Cancer Clinical Trials Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008;26:1148-59. 20. Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). Journal of the National Cancer Institute 2004;96:4878. 21. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II
clinical trials in androgen-independent prostate cancer: recommendations from the ProstateSpecific Antigen Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1999;17:3461-7. 22. Vergote I, Rustin GJ, Eisenhauer EA, et al. Re: new guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup. Journal of the National Cancer Institute 2000;92:1534-5. 23. Davis JA, Rock DA, Wienkers LC, Pearson JT. In vitro characterization of the drug-drug interaction potential of catabolites of antibody-maytansinoid conjugates. Drug metabolism and disposition: the biological fate of chemicals 2012;40:1927-34.  
Abbreviated Title: Anetumab ravtansine in lung CA
Version Date: 01-11-18
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13 appendices

13.1
APPENDIX A: NON SIGNIFICANT RISK REQUEST AND DETERMINATION FOR MESOTHELIN  
EXPRESSION TESTING
13.1.1  NSR Determination Request to FDA  
  
240ct2015 BAY 94-9343 / 17631, An open label Phase Ib dose escalation study to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and maximum tolerated dose of anetumab ravtansine in combination with pemetrexed 500 mg/m² and cisplatin 75 mg/m² in subjects with mesothelin-expressing predominantly epithelial mesothelioma or nonsquamous non-small-cell lung cancer Dear Insitutional Review Board Members, The companion diagnostic device used in this research has been assessed by the Sponsor as Non-
Significant Risk.  The populations enrolled are receiving standard of care in addition to the investigational product can may be chemotherapy naive or previously treated  to be eligible for BY 94-9343 / 17631:  
Subjects must have histologically confirmed, unresectable, locally advanced or metastatic
(1)
pleural or peritoneal predominantly (>50% of tumor component) epithelial mesothelioma or nonsquamous non-small-cell lung cancer (NSCLC).  Both chemotherapy-naive and previously treated subjects will be eligible; however, newly diagnosed NSCLC subjects eligible for FDA-approved therapies should have received the same before enrollment
(e.g. subjects with epidermal growth factor receptor [EGFR]-mutated and anaplastic lymphoma kinase [ALK]-translocated NSCLC should have received FDA-approved targeted therapies).
Further, there is no significant risk incurred by the subjects to obtain the required specimens for  mesothelin expression testing on archival tissue.  Therefore, it is the opinion of the Sponsor that the use of this diagnostic device does not pose a serious risk to the health, safety, or welfare of a subject and therefore is considered Non-Significant Risk under 21 CFR 812.3(m).  Further, the Sponsor has sought confirmation from the FDA regarding the assessment.  FDA's response is pending, and can be provided upon receipt. If you have any questions or concerns, please do not hesitate to contract our team.  
Thank you for your thorough and expert review of this study.  
Sincerely, Katie Andrews Katie Andrews INC Research Project Manager Version Date: 01-11-18
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13.1.2 nsr designation from fda

| Public Health Service               |
|-------------------------------------|
| Food and Drug Administration        |
| 10903 New Hampshire Aven            |
| Document Control Conter - WO66-G609 |
| DOCUMON CONTROL                     |  
Pauline Shand, Regulatory Affairs Manager, Companion Diagnostics Ventana Medical Systems, Inc. 1910 E Innovation Park Drive, Tucson, AZ  85755 Re:
Q151839– Study Risk Determination for the use of the VENTANA PD-L1 MSLN (SP74)
Immunohistochemistry Assay in the proposed study titled "An Open Label, Phase Ib Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity and Maximum Tolerated Dose of Anetumab Ravtansine in Combination with Pemetrexed 500 Mg/M2 and Cisplatin 75 Mg/M2 in Subjects with Mesothelin-Expressing Predominantly Epithelial Mesothelioma or Nonsquamous Non-Small-Cell Lung Cancer."
Dated: Nov 12, 2015 Received: Nov 13, 2015
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dear ms. shand

The Food and Drug Administration (FDA) has reviewed your submission, dated Nov 12, 2015, requesting a risk determination for the use of the Ventana MSLN (SP74) Immunohistochemistry Assay in the proposed study titled, "An Open Label Phase Ib Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity and Maximum Tolerated Dose of Anetumab Ravtansine in Combination with Pemetrexed 500 mg/m 2 and Cisplatin 75 mg/m 2 in Subjects with Mesothelin-Expressing Predominantly Epithelial Mesothelioma or Nonsquamous Non-Small-Cell Lung Cancer.  
FDA has determined that your proposed clinical investigation is a non-significant risk (NSR)
device study because it does not meet the definition of a significant risk (SR) device under §
812.3(m) of the investigational device exemptions (IDE) regulation (21 CFR 812).  
An IDE application is not required to be submitted to, or approved by, FDA for a NSR study.  A
NSR study is, however, subject to the abbreviated requirements described in § 812.2(b) of the IDE regulation. The abbreviated requirements stipulate that the sponsor of the investigation must label the device in accordance with § 812.5; obtain institutional review board approval of the investigation as a NSR study; ensure that each investigator obtains informed consent from each subject under the investigator's care; comply with the monitoring requirements of § 812.46; maintain records required under § 812.140(b)(4) and (5) and file the reports required under § 812.150(b)(1) through (3) and (5) through (10); and ensure that participating investigators maintain the records required by § 812.140(a)(3)(i) and file the reports required under
§ 812.150(a)(1), (2), (5) and (7).  
Version Date: 01-11-18
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page 2 -pauline shand

Under the abbreviated IDE requirements, a sponsor must also comply with the prohibitions against promotion and other practices as identified in § 812.7. According to this section of the regulation, the sponsor of a NSR study, investigator, or any person acting for or on behalf of the sponsor or investigator is prohibited from promoting or test marketing the investigational device util after FDA has approved the device for commercial distribution; commercializing the device by charging a price greater than that necessary to recover the cost of manufacture, research, development, and handling, unduly prolonging the investigation; and representing the investigational device as being safe or effective for the purposes for which it is being investigated.  
Title VIII of FDAAA amended the PHS Act by adding new section 402(j) (42 USC § 282(j),
which expanded the current database known as ClinicalTrials.gov to include mandatory registration and reporting of results for applicable clinical trials of human drugs (including biological products) and devices. Please note that, if in the future you submit an application uder sections 505, 515, or 520(m) of the FDCA (21 USC §§ 355, 360(e), or 360(j)(m)), or uder section 351 of the PHS Act (21 U.S.C. § 262), or you submit a report under section 510(k)
of the FDCA (21 USC § 360(k)), the application or submission must be accompanied by a certification that all applicable requirements of section 402(j) of the PHS Act (42 USC § 282(j)) have been met. Where available, such certification must include the appropriate National Clinical Trial (NCT) control numbers.  42 USC § 282(j)(5)(B).  Additional information regarding the certification is available at:
http://ww.fda.gov/downloads/RegulatoryInformation/Guidances/UCM164819.pdf Additional information regarding Title VIII of FDAAA is available at:
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-014.html . Additional information on registering your clinical trial(s) is available at the Protocol Registration System website ( http://prsinfo.clinicaltrials.gov/ ). If you have any questions, please contact Janaki Veeraraghavan at (240) 402-6634.  
Sincerely yours, Reena Philip, Ph.D.  
Director Division of Molecular Genetics and Pathology Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health  
Version Date: *01-11-18*
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13.2 appendix b performance status

| ECOG Performance Status Scale     |                                                                                                                                                                                    |                      |                                |
|-----------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|--------------------------------|
| Grade                             | Descriptions                                                                                                                                                                       |                      |                                |
| 0                                 | Normal activity. Fully active, able to carry on all pre-disease performance  without restriction. Symptoms, but ambulatory. Restricted in physically strenuous activity, but       |                      |                                |
| 1                                 | ambulatory and able to carry out work of a light or sedentary nature (e.g.,  light housework, office work).  In bed <50% of the time. Ambulatory and capable of all self-care, but |                      |                                |
| 2                                 | unable to carry out any work activities. Up and about more than 50% of  waking hours.                                                                                              |                      |                                |
| 3                                 | In bed >50% of the time. Capable of only limited self-care, confined to bed  or chair more than 50% of waking hours.                                                               |                      |                                |
| 4                                 | 100% bedridden.                                                                                                                                                                    | Completely disabled. | Cannot carry on any self-care. |
| Totally confined to bed or chair. |                                                                                                                                                                                    |                      |                                |
| 5                                 | Dead.                                                                                                                                                                              |                      |                                |  
Version Date: *01-11-18*
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13.3 appendix c cyp3a4 inhibitors

| 13.3                                                                                                                                                                                                                                       | APPENDIX C: CYP3A4 INHIBITORS AND INDUCERS   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------|
| Strong CYP3A4 inhibitors                                                                                                                                                                                                                   | Strong CYP3A4 inducers                       |
| Boceprevir                                                                                                                                                                                                                                 | Avasimibe                                    |
| Clarithromycin                                                                                                                                                                                                                             | Carbamazepine                                |
| Conivaptan                                                                                                                                                                                                                                 | Phenytoin                                    |
| Grapefruit juice                                                                                                                                                                                                                           | Rifampin                                     |
| Indinavir                                                                                                                                                                                                                                  | St. John's wort                              |
| Itraconazole Ketoconazole Lopinavir / Ritonavir Mibefradil (withdrawn in US) Nefazodone  Nelfinavir Posaconazole Ritonavir Saquinavir Telaprevir Telithromycin Voriconazole CYP3A4 = Cytochrome P450, family 3, subfamily A, polypeptide 4 |                                              |  
71