Doravirine, Islatravir

1 INDICATIONS AND USAGE IDVYNSO™ is indicated as a complete two-drug regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of virologic treatment failure and no known substitutions associated with resistance to doravirine [see Microbiology (12.4) and Clinical Studies (14) ]. IDVYNSO is a two-drug combination of doravirine, a HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI), and islatravir, a nucleoside analog reverse transcriptase inhibitor (NRTI), and is indicated as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of virologic treatment failure and no known substitutions associated with resistance to doravirine. ( 1 )

6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in other sections of the labeling: Skin and Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Most common adverse reactions (incidence greater than or equal to 2%, all grades): diarrhea, dizziness, fatigue, abdominal distension, headache, and weight increased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Virologically-Suppressed Adults Living with HIV-1 Who Switched to IDVYNSO The safety assessment of IDVYNSO in virologically-suppressed (HIV-1 RNA less than 50 copies/mL) participants living with HIV was based on Week 48 data from two Phase 3, randomized trials, Trial 051 and Trial 052. A total of 708 participants received once-daily IDVYNSO [see Clinical Studies (14) ] . In Trial 051, an open-label trial with 551 participants, 366 participants were switched to IDVYNSO and 185 participants continued their baseline antiretroviral therapy (ART). By Week 48, 0.5% in the IDVYNSO group and 2% in the baseline ART group had adverse events leading to discontinuation of study medication. In Trial 052, a double-blinded trial with 513 participants, 342 participants were switched to IDVYNSO and 171 participants continued on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). By Week 48, 3% in the IDVYNSO group and 2% in the BIC/FTC/TAF group had adverse events leading to discontinuation of study medication. Among participants who received IDVYNSO and experienced at least one adverse event in Trial 051 or Trial 052, 88% experienced only adverse events that were mild (Grade 1) or moderate (Grade 2). The most common adverse reactions (all grades) reported in greater than or equal to 2% of participants in any treatment group from Trial 051 and Trial 052 through Week 48 are presented in Table 1 . Table 1: Adverse Reactions Frequencies based on all adverse events attributed to study drugs by the investigator (All Grades) Reported in ≥2% of Participants in Any Treatment Group in Trials 051 and 052 in HIV-1 Virologically-Suppressed Adults (Week 48) Adverse Reactions Trial 051 Trial 052 IDVYNSO N=366 Baseline ART N=185 IDVYNSO N=342 BIC/FTC/TAF N=171 Diarrhea 3% 0 1% 1% Dizziness 2% 1% 1% 0 Fatigue Fatigue includes fatigue and asthenia. 2% 1% 1% 1% Abdominal distension 2% 0 1% 0 Headache 2% 1% 1% 0 Weight increased The mean change in weight from baseline at Week 48 was 0.94 kg in the IDVYNSO group vs. -0.15 kg in the baseline ART group in Trial 051, and -0.03 kg in the IDVYNSO group vs. 0.28 kg in the BIC/FTC/TAF group in Trial 052. 2% 4 of the 6 participants with adverse reactions of weight increased switched from a baseline ART regimen containing efavirenz and/or tenofovir disoproxil fumarate in Trial 051. 0 <1% 0 A single case of severe immune thrombocytopenia (platelet count nadir of 2 x10 9 /L) characterized by abrupt onset of subcutaneous hematoma, petechiae, and hematuria was reported in a participant 32 days after initiating IDVYNSO in Trial 052. This serious adverse reaction resolved with discontinuation of IDVYNSO, in conjunction with treatments including corticosteroids and IVIG. Among all participants in Trial 051 and Trial 052, there were no patterns of platelet decreases over time with IDVYNSO and no differences between treatment arms in mean change from baseline in platelet count. Less Common Adverse Reactions The following select adverse reactions were observed in less than 2% of participants administered IDVYNSO: Gastrointestinal disorders : Abdominal pain (includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort), flatulence, nausea Psychiatric disorders: Abnormal dreams, Insomnia (includes insomnia, initial insomnia, middle insomnia and terminal insomnia) Skin and Subcutaneous Tissue Disorders : Pruritus, Rash (includes rash, rash papular, rash maculo-papular and rash pruritic) In an ongoing clinical trial, a participant developed Grade 4 DRESS syndrome ten weeks after starting IDVYNSO that was characterized by a diffuse pruritic maculopapular rash covering 60% of the body, lymphadenopathy, eosinophilia (peak 20,000 cells/µL), and an episode of hypotension. This serious adverse reaction resolved with discontinuation of IDVYNSO [see Warnings and Precautions (5.1) ]. Laboratory Abnormalities Hepatic laboratory data from Trials 051 and Trial 052 are presented in Table 2 . The hepatic laboratory abnormalities were generally asymptomatic and resolved without discontinuation of IDVYNSO. Table 2: Hepatic Laboratory Abnormalities (Grades 2-4) Worsened from Baseline Reported in Adults Receiving IDVYNSO in Trial 051 and Trial 052 Laboratory Parameter Trial 051 Trial 052 IDVYNSO N=366 Baseline ART N=185 IDVYNSO N=340 BIC/FTC/TAF N=171 Alanine Aminotransferase Grade 2: 2.5 - <5.0 x ULN 2% 1% 1% 1% Grade 3: 5.0 - <10.0 x ULN <1% 0 0 0 Grade 4: ≥10.0 x ULN 0 1% 1% 0 Aspartate Aminotransferase Grade 2: 2.5 - <5.0 x ULN 2% 2% 2% 1% Grade 3: 5.0 - <10.0 x ULN 0 0 <1% 0 Grade 4: ≥10.0 x ULN 0 1% 1% 1% Total Bilirubin Grade 2: 1.6 - <2.6 x ULN 1% 1% 1% 1% Grade 3: 2.6 - <5.0 x ULN <1% 0 1% 0 Grade 4: ≥5.0 x ULN 0 0 0 0 Across the clinical development program for the combination of doravirine and islatravir, there were 3 participants with elevations in alanine aminotransferase and/or aspartate aminotransferase greater than 10X ULN attributed to study drug that resolved with discontinuation of treatment. Of the 3 participants, one received doravirine 100 mg with islatravir 0.75 mg (three times the recommended dosage of islatravir) and had transient elevation in total bilirubin 2X ULN and Grade 1 (mild) nausea. The other 2 participants received IDVYNSO and were asymptomatic. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving doravirine-containing regimens. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Doravirine: Hepatobiliary Disorders: hepatitis Investigations: hepatic enzyme increased Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)