Doravirine for HIV

INDICATIONS AND USAGE PIFELTRO ® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg: with no prior antiretroviral treatment history; OR 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 treatment failure and no known substitutions associated with resistance to doravirine [see Clinical Studies (14) ] . PIFELTRO, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg: with no prior antiretroviral treatment history, OR 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 treatment failure and no known substitutions associated with resistance to doravirine. ( 1 )

DOSAGE AND ADMINISTRATION Recommended dosage: One tablet taken orally once daily with or without food in adults. ( 2.1 ) Dosage adjustment with rifabutin: Take one tablet of IDVYNSO once daily, followed by one tablet of doravirine (PIFELTRO) 100 mg approximately 12 hours after the dose of IDVYNSO. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of IDVYNSO is one tablet taken orally once daily with or without food [see Clinical Pharmacology (12.3) ] . One tablet of IDVYNSO contains 100 mg doravirine and 0.25 mg islatravir. 2.2 Dosage Adjustment with Rifabutin If IDVYNSO is co-administered with rifabutin, take one tablet of IDVYNSO once daily as recommended, followed by one tablet of doravirine (PIFELTRO) 100 mg approximately 12 hours after the dose of IDVYNSO for the duration of rifabutin co-administration [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ].

WARNINGS AND PRECAUTIONS Severe skin reactions, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine-containing regimens. Discontinue PIFELTRO, and other medications known to be associated with severe skin reactions, immediately if a painful rash with mucosal involvement or a progressive severe rash develops, and closely monitor clinical status. ( 5.1 ) Monitor for Immune Reconstitution Syndrome. ( 5.3 ) 5.1 Severe Skin Reactions Severe skin reactions, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine-containing regimens [see Adverse Reactions (6.2) ]. Discontinue PIFELTRO, and other medications known to be associated with severe skin reactions, immediately if a painful rash with mucosal involvement or a progressive severe rash develops. Clinical status should be closely monitored, and appropriate therapy should be initiated. 5.2 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of PIFELTRO and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of PIFELTRO and possible development of resistance [see Dosage and Administration (2.2) , Contraindications (4) and Drug Interactions (7.1) ]. See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during PIFELTRO therapy, review concomitant medications during PIFELTRO therapy, and monitor for adverse reactions. 5.3 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

DRUG INTERACTIONS Because IDVYNSO is a complete regimen, co-administration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. ( 7.1 ) Consult the full prescribing information prior to and during treatment for important potential drug-drug interactions. ( 2.2 , 4 , 5.2 , 7 , 12.3 ) 7.1 Concomitant Use with Other Antiretroviral Medications Because IDVYNSO is a complete regimen for the treatment of HIV-1 infection, co-administration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. 7.2 Effects of Other Drugs on IDVYNSO Doravirine Co-administration of IDVYNSO with a CYP3A inducer decreases doravirine plasma concentrations, which may reduce the efficacy of IDVYNSO [see Contraindications (4) , Warnings and Precautions (5.2) , and Clinical Pharmacology (12.3) ] . Co-administration of IDVYNSO and drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine. Islatravir Islatravir requires phosphorylation by cellular kinases to form the pharmacologically active ISL-TP. Co-administration of IDVYNSO and drugs that are substrates of dCK (e.g., certain nucleoside antiviral agents and nucleoside antimetabolites) may result in a decrease in ISL-TP concentrations and may reduce the therapeutic effect of islatravir [see Contraindications (4) , Warnings and Precautions (5.2) , and Clinical Pharmacology (12.3) ] . Islatravir is subject to ADA-mediated metabolism (approximately 53%). Co-administration of IDVYNSO and drugs that are ADA inhibitors (e.g., pentostatin) may result in increased plasma concentrations of islatravir and may increase the risk of adverse reactions [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . The drug interactions described in Table 3 are based on studies conducted with IDVYNSO, its components, or are predicted drug interactions that may occur with IDVYNSO. Table 3: Drug Interactions with IDVYNSO This table is not all inclusive. Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment ↑ = increase, ↓ = decrease Strong CYP3A Inducers ↓ doravirine Co-administration with strong CYP3A inducers is contraindicated At least a 4-week cessation period is recommended prior to initiation of IDVYNSO. Moderate CYP3A Inducers ↓ doravirine If IDVYNSO is co-administered with rifabutin Interactions were evaluated in clinical studies. All other drug-drug interactions are predicted. , one tablet of doravirine (PIFELTRO) should be taken approximately 12 hours after the dose of IDVYNSO [see Dosage and Administration (2.2) ] . Co-administration with other moderate CYP3A inducers is not recommended. dCK Substrates May include other nucleoside drugs Anti-virals lamivudine emtricitabine ↓ ISL-TP Co-administration is contraindicated with lamivudine or emtricitabine. Nucleoside Antimetabolites cladribine clofarabine cytarabine fludarabine gemcitabine ↓ ISL-TP Co-administration with these nucleoside antimetabolites is not recommended as dCK substrates may cause a decrease in the intracellular concentration of ISL-TP. ADA Inhibitors pentostatin ↑ islatravir Co-administration with pentostatin is not recommended as it may cause an increase in plasma concentrations of islatravir.

ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Immune Reconstitution Syndrome [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence greater than or equal to 5%, all grades) are nausea, dizziness, headache, fatigue, diarrhea, abdominal pain, and abnormal dreams. ( 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 Adults with No Antiretroviral Treatment History The safety assessment of PIFELTRO used in combination with other antiretroviral agents is based on Week 96 data from two Phase 3, randomized, international, multicenter, double-blind, active-controlled trials (DRIVE-FORWARD (Protocol 018) and DRIVE-AHEAD (Protocol 021)). In DRIVE-FORWARD, 766 adult participants received either PIFELTRO 100 mg (n=383) or darunavir 800 mg + ritonavir 100 mg (DRV+r) (n=383) once daily, each in combination with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC). By Week 96, 2% in the PIFELTRO group and 3% in the DRV+r group had adverse events leading to discontinuation of study medication. In DRIVE-AHEAD, 728 adult participants received either DELSTRIGO [doravirine (DOR)/3TC/TDF] (n=364) or efavirenz (EFV)/FTC/TDF once daily (n=364). By Week 96, 3% in the DELSTRIGO group and 7% in the EFV/FTC/TDF group had adverse events leading to discontinuation of study medication. Adverse reactions reported in greater than or equal to 5% of participants in any treatment group in DRIVE-FORWARD and DRIVE-AHEAD are presented in Table 1. Table 1: Adverse Reactions Frequencies of adverse reactions are based on all adverse events attributed to trial drugs by the investigator. (All Grades) Reported in ≥5% No adverse reactions of Grade 2 or higher (moderate or severe) occurred in ≥ 2% of participants treated with doravirine. of Participants in Any Treatment Group in Adults with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 96) DRIVE-FORWARD DRIVE-AHEAD PIFELTRO+2 NRTIs NRTI = nucleoside reverse transcriptase inhibitor. Once Daily N=383 DRV+r+2 NRTIs Once Daily N=383 DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 NRTIs = FTC/TDF or ABC/3TC. Fatigue: includes fatigue, asthenia, malaise Abdominal Pain: includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, epigastric discomfort Rash: includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular Nausea 7% 8% 5% 7% Headache 6% 3% 4% 5% Fatigue 6% 3% 4% 4% Diarrhea 6% 13% 4% 6% Abdominal Pain 5% 2% 1% 2% Dizziness 3% 2% 7% 32% Rash 2% 3% 2% 12% Abnormal Dreams 1% <1% 5% 10% Insomnia 1% 2% 4% 5% Somnolence 0% <1% 3% 7% The majority (77%) of adverse reactions associated with doravirine occurred at severity Grade 1 (mild). Neuropsychiatric Adverse Events For DRIVE-AHEAD, the analysis of participants with neuropsychiatric adverse events by Week 48 is presented in Table 2. The proportion of participants who reported one or more neuropsychiatric adverse events was 24% and 57% in the DELSTRIGO and EFV/FTC/TDF groups, respectively. A statistically significantly lower proportion of DELSTRIGO-treated participants compared to EFV/FTC/TDF-treated participants reported neuropsychiatric adverse events by Week 48 in the three pre-specified categories of dizziness, sleep disorders and disturbances, and altered sensorium. Table 2: DRIVE-AHEAD - Analysis of Participants with Neuropsychiatric Adverse Events All causality and all grade events were included in the analysis. (Week 48) DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 Treatment Difference DELSTRIGO - EFV/FTC/TDF Estimate (95% CI) The 95% CIs were calculated using Miettinen and Nurminen's method. Categories pre-specified for statistical testing were dizziness (p <0.001), sleep disorders and disturbances (p <0.001), and altered sensorium (p=0.033). Sleep disorders and disturbances Predefined using MedDRA preferred terms, including: abnormal dreams, hyposomnia, initial insomnia, insomnia, nightmare, sleep disorder, somnambulism. 12% 26% -13.5 (-19.1, -7.9) Dizziness 9% 37% -28.3 (-34.0, -22.5) Altered sensorium Predefined using MedDRA preferred terms, including: altered state of consciousness, lethargy, somnolence, syncope. 4% 8% -3.8 (-7.6, -0.3) Neuropsychiatric adverse events in the pre-defined category of depression and suicide/self-injury were reported in 4% and 7% of participants, in the DELSTRIGO and EFV/FTC/TDF groups, respectively. In DRIVE-AHEAD through 48 weeks of treatment, the majority of participants who reported neuropsychiatric adverse events reported events that were mild to moderate in severity (97% [83/86] and 96% [198/207], in the DELSTRIGO and EFV/FTC/TDF groups, respectively) and the majority of participants reported these events in the first 4 weeks of treatment (72% [62/86] in the DELSTRIGO group and 86% [177/207] in the EFV/FTC/TDF group). Neuropsychiatric adverse events led to treatment discontinuation in 1% (2/364) and 1% (5/364) of participants in the DELSTRIGO and EFV/FTC/TDF groups, respectively. The proportion of participants who reported neuropsychiatric adverse events through Week 4 was 17% (62/364) in the DELSTRIGO group and 49% (177/364) in the EFV/FTC/TDF group. At Week 48, the prevalence of neuropsychiatric adverse events was 12% (44/364) in the DELSTRIGO group and 22% (81/364) in the EFV/FTC/TDF group. At Week 96, the prevalence of neuropsychiatric adverse events was 13% (47/364) in the DELSTRIGO group and 23% (82/364) in the EFV/FTC/TDF group. Laboratory Abnormalities The percentages of participants with selected laboratory abnormalities (that represent a worsening from baseline) who were treated with PIFELTRO or DRV+r in DRIVE-FORWARD, or DELSTRIGO or EFV/FTC/TDF in DRIVE-AHEAD are presented in Table 3. Table 3: Selected Laboratory Abnormalities Reported in Adult Participants with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 96) DRIVE-FORWARD DRIVE-AHEAD Laboratory Parameter Preferred Term (Unit)/Limit PIFELTRO+2 NRTIs Once Daily N=383 DRV+r+2 NRTIs Once Daily N=383 DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 Blood Chemistry Each participant is only counted once per parameter at the highest toxicity grade. Only participants with a baseline value and at least one on-treatment value for a given laboratory parameter are included. ULN = Upper limit of normal range. Note: NRTIs = FTC/TDF or ABC/3TC. Total bilirubin (mg/dL) 1.1 - < 1.6 × ULN 6% 2% 5% 0% 1.6 - <2.6 × ULN 2% <1% 2% 0% ≥2.6 × ULN <1% 0% 1% <1% Creatinine (mg/dL) >1.3 - 1.8 × ULN or Increase of >0.3 mg/dL above baseline 4% 6% 3% 2% >1.8 × ULN or Increase of ≥1.5 × above baseline 4% 4% 3% 2% Aspartate aminotransferase (IU/L) 2.5 - <5.0 × ULN 5% 4% 3% 3% ≥5.0 × ULN 2% 2% 1% 4% Alanine aminotransferase (IU/L) 2.5 - <5.0 × ULN 4% 2% 4% 4% ≥5.0 × ULN 2% 3% 1% 3% Alkaline phosphatase (IU/L) 2.5 - <5.0 × ULN <1% 1% <1% 1% ≥5.0 × ULN 0% <1% 0% <1% Lipase 1.5 - <3.0 × ULN 7% 6% 6% 4% ≥3.0 × ULN 3% 4% 2% 3% Creatine kinase (IU/L) 6.0 - <10.0 × ULN 3% 3% 3% 3% ≥10.0 × ULN 5% 6% 4% 6% Cholesterol, fasted (mg/dL) ≥300 mg/dL 0% 1% 1% <1% LDL cholesterol, fasted (mg/dL) ≥190 mg/dL <1% 4% <1% 2% Triglycerides, fasted (mg/dL) >500 mg/dL 1% 2% 1% 3% Change in Lipids from Baseline For DRIVE-FORWARD and DRIVE-AHEAD, changes from baseline at Week 48 in LDL-cholesterol, non-HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol are shown in Table 4. Changes from baseline at Week 96 were similar to those seen