Product Use Management: Grade 1 and Grade 2 Adverse Events AE addressed in protocol section 9.5? no CONTINUE product. yes Follow relevant protocol section Protocol Reference: Section 9.4

Product Use Management: Grade 3 Adverse Events START AE addressed in protocol sections 9.5? Assess AE relationship to product no not related CONTINUE product. yes related Follow relevant protocol section HOLD product. Re-evaluate at least weekly for up to 2 weeks. RESUME product. If same grade 3 AE recurs, regardless of relationship to product, HOLD product and CONSULT PSRT. grade ≤2 within 2 weeks after initiating hold grade >2 through 2 weeks after initiating hold Consult PSRT Protocol Reference: Section 9.4

Product Use Management: Grade 4 Adverse Events AE addressed in protocol section 9.5? HOLD product. CONSULT PSRT. no yes Follow relevant protocol section Protocol Reference: Section 9.4

Product Use Management for ORAL Study Product: Decreased Creatinine Clearance START Assess creatinine clearance rate  60 mL/min CONTINUE product. < 60 mL/min HOLD product and consult the PSRT. Re-test within 1 week of receipt of result. Continue HOLD and CONSULT PSRT. 60 mL/min on re-test No re-test within 1 week < 60 mL/min on re-test Continue HOLD and CONSULT PSRT. PERMANENTLY DISCONTINUE product. Protocol Reference: Section 9.5

CONTINUE product, unless permanent discontinuation guidelines apply. Product Use Management: Sexually Transmitted Infections and Reproductive Tract Infections CONTINUE product, unless permanent discontinuation guidelines apply. Consult the PSRT if a permanent discontinuation is deemed necessary and instituted by the IoR/designee. Vaginally applied medications should not be used. Whenever possible, oral or parenteral medications should be used instead. *Treat per WHO guidelines, using observed single dose regimens whenever possible. Protocol Reference: Section 9.5

Re-evaluate by speculum exam in 3-5 days. Product Use Management VAGINAL RING Study Product: Superficial epithelial disruption (abrasion/peeling) Re-evaluate by speculum exam in 3-5 days. Is it worse? CONTINUE product. Perform naked eye exam. HOLD product and consult the PSRT. Yes No CONTINUE product. Protocol Reference: Section 9.5

Product Use Management VAGINAL RING Study Product: Deep epithelial disruption (ulceration) Re-evaluate by speculum exam in 3-5 days. Has it resolved? Re-evaluate by speculum exam in 2-3 days. Has it resolved? If confirmed by investigator, HOLD Product CONTINUEHOLD consult the PSRT. No No Yes Yes CONTINUE product. CONTINUE product. If reoccurrence with no identified etiology, hold product and consult the PSRT regarding permanent discontinuation Protocol Reference: Section 9.5

Re-evaluate by speculum exam in 3-5 days. Product Use Management VAGINAL RING Study Product: Localized erythema or edema (area less than 50%) Re-evaluate by speculum exam in 3-5 days. Is it worse? CONTINUE product. Perform naked eye exam. HOLD product and consult the PSRT. Symptomatic? Yes No Asymptomatic? CONTINUE product. Re-evaluate at next scheduled visit Protocol Reference: Section 9.5

Product Use Management VAGINAL RING Study Product: Generalized Erythema or Severe Edema (area more than 50%) Re-evaluate by speculum exam in 3-5 days. Has it resolved? Re-evaluate by speculum exam in 2-3 days. Has it resolved? HOLD Product and perform naked eye examination CONTINUEHOLD consult the PSRT. No No Yes Yes CONTINUE product. CONTINUE product. If reoccurrence with no identified etiology, hold product and consult the PSRT regarding permanent discontinuation Protocol Reference: Section 9.5

CONTINUE product and perform naked eye pelvic examination Product Use Management VAGINAL RING Study Product: Unexpected genital bleeding Follow guidance for deep epithelial disruption CONTINUE product and perform naked eye pelvic examination Due to deep epithelial disruption? yes no Continue Product use Protocol Reference: Section 9.5

Re-evaluate by speculum exam in 3-5 days. Product Use Management VAGINAL RING Study Product: Cervicitis (including inflammation and/or friability) Re-evaluate by speculum exam in 3-5 days. Has it resolved? HOLD Product and evaluate for GC/CT; provide treatment as indicated CONTINUEHOLD consult the PSRT. No Yes CONTINUE product. Protocol Reference: Section 9.5

Product Use Management VAGINAL RING Study Product: Genital petechia(e)/ genital ecchymosis CONTINUE product and perform naked eye exam; treat per clinician discretion Protocol Reference: Section 9.5