{"id":"doravirine","rwe":[{"pmid":"41847923","year":"2026","title":"A 48-week, Randomized Controlled Trial of Doravirine for Individuals with HIV and Obesity on Integrase Inhibitors and Tenofovir Alafenamide: The Do IT Study (ACTG A5391).","finding":"","journal":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","studyType":"Clinical Study"},{"pmid":"30372003","year":"2006","title":"Doravirine.","finding":"","journal":"","studyType":"Clinical Study"},{"pmid":"41818070","year":"2026","title":"Drug Resistance in HIV Following First-line ART Failure: Insights from a Cross-sectional Study in India.","finding":"","journal":"The Journal of the Association of Physicians of India","studyType":"Clinical Study"},{"pmid":"41811386","year":"2026","title":"Virological Failure on Long-Acting Injectable Cabotegravir and Rilpivirine: An Analysis of Subtypes, Drug Levels, Resistance, and Therapeutic Implications.","finding":"","journal":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","studyType":"Clinical Study"},{"pmid":"41808663","year":"2026","title":"Prioritization of adverse events related to integrase inhibitors and NNRTIs: a disproportionality analysis using data from the FAERS database.","finding":"","journal":"The Journal of antimicrobial chemotherapy","studyType":"Clinical Study"}],"_fda":{"id":"20dc2455-4d48-4183-b1ad-29a2686dcd2a","set_id":"76ce1f00-28c0-4314-bd2c-d473fe3d0970","openfda":{"nui":["N0000175463","N0000009948","N0000175460"],"upc":["0300063069014"],"unii":["913P6LK81M"],"route":["ORAL"],"rxcui":["2055760","2055766"],"spl_id":["20dc2455-4d48-4183-b1ad-29a2686dcd2a"],"brand_name":["PIFELTRO"],"spl_set_id":["76ce1f00-28c0-4314-bd2c-d473fe3d0970"],"package_ndc":["0006-3069-01"],"product_ndc":["0006-3069"],"generic_name":["DORAVIRINE"],"product_type":["HUMAN PRESCRIPTION DRUG"],"substance_name":["DORAVIRINE"],"pharm_class_epc":["Human Immunodeficiency Virus 1 Non-Nucleoside Analog Reverse Transcriptase Inhibitor [EPC]"],"pharm_class_moa":["Non-Nucleoside Reverse Transcriptase Inhibitors [MoA]"],"manufacturer_name":["Merck Sharp & Dohme LLC"],"application_number":["NDA210806"],"is_original_packager":[true]},"version":"20","pregnancy":["8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary No adequate human data are available to establish whether or not PIFELTRO poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when doravirine was administered at exposures ≥8 times the exposure in humans at the recommended human dose (RHD) of PIFELTRO ( see Data ). The background rate of major birth defects is 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates individuals and infants from the limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation. Data Animal Data Doravirine was administered orally to pregnant rabbits (up to 300 mg/kg/day on gestation days (GD) 7 to 20) and rats (up to 450 mg/kg/day on GD 6 to 20 and separately from GD 6 to lactation/postpartum day 20). No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed at exposures (AUC) approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the RHD. Doravirine was transferred to the fetus through the placenta in embryo-fetal studies, with fetal plasma concentrations of up to 40% (rabbits) and 52% (rats) that of maternal concentrations observed on GD 20."],"description":["11 DESCRIPTION PIFELTRO is a film-coated tablet containing doravirine for oral administration. Doravirine is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI). Each tablet contains 100 mg of doravirine as the active ingredient. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are film coated with a coating material containing the following inactive ingredients: hypromellose, lactose monohydrate, titanium dioxide, and triacetin. The coated tablets are polished with carnauba wax. The chemical name for doravirine is 3-chloro-5-[[1-[(4,5-dihydro-4-methyl-5-oxo-1 H -1,2,4-triazol-3-yl)methyl]-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy]benzonitrile. It has a molecular formula of C 17 H 11 ClF 3 N 5 O 3 and a molecular weight of 425.75. It has the following structural formula: Doravirine is practically insoluble in water. Chemical Structure"],"how_supplied":["16 HOW SUPPLIED/STORAGE AND HANDLING Each PIFELTRO tablet contains 100 mg of doravirine, is white, oval-shaped and film-coated, and is debossed with the corporate logo and 700 on one side and plain on the other side. Each bottle contains 30 tablets (NDC 0006-3069-01) with silica gel desiccant and is closed with a child-resistant closure. Store PIFELTRO in the original bottle. Keep the bottle tightly closed to protect from moisture. Do not remove the desiccant. Store PIFELTRO at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]."],"microbiology":["12.4 Microbiology Mechanism of Action Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). The inhibitory concentration at 50% (IC 50 ) of doravirine for RNA-dependent DNA polymerization of recombinant wild-type HIV-1 RT in a biochemical assay was 12.2±2.0 nM (n=3). Doravirine does not inhibit the human cellular DNA polymerases α, β, and mitochondrial DNA polymerase γ. Antiviral Activity in Cell Culture Doravirine exhibited an EC 50 value of 12.0±4.4 nM against wild-type laboratory strains of HIV-1 when tested in the presence of 100% normal human serum (NHS) using MT4-GFP reporter cells and a median EC 50 value for HIV-1 subtype B primary isolates (n=118) of 4.1 nM (range: 1.0 nM-16.0 nM). Doravirine demonstrated antiviral activity against a broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC 50 values ranging from 1.2 nM to 10.0 nM. Antiviral Activity in Combination with other HIV Antiviral Agents The antiviral activity of doravirine in cell culture was not antagonistic when combined with the NNRTIs delavirdine, efavirenz, etravirine, nevirapine, or rilpivirine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, or zidovudine; the PIs darunavir or indinavir; the gp41 fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir. Resistance In Cell Culture Doravirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes, as well as NNRTI-resistant HIV-1. Observed emergent amino acid substitutions in RT included: V106A, V106I, V106M, V108I, H221Y, F227C, F227I, F227L, F227V, M230I, L234I, P236L, and Y318F. The V106A, V106M, V108I, H221Y, F227C, M230I, P236L, and Y318F substitutions conferred 3.4-fold to 70-fold reductions in susceptibility to doravirine. Y318F in combination with V106A, V106M, V108I, or F227C conferred greater decreases in susceptibility to doravirine than Y318F alone, which conferred a 10-fold reduction in susceptibility to doravirine. In Clinical Trials Clinical Trial Results in Adults with No Antiretroviral Treatment History In the doravirine treatment arms of the DRIVE-FORWARD and DRIVE-AHEAD trials (n=747) through Week 96, 13 participants showed the emergence of doravirine resistance-associated substitutions in their HIV among 36 (36%) participants in the resistance analysis subset (participants with HIV-1 RNA greater than 400 copies per mL at virologic failure or early study discontinuation and having post-baseline resistance samples). Emergent doravirine resistance-associated substitutions in RT included one or more of the following: V90G/I, A98G, V106A, V106I, V106M/T, V108I, E138G, Y188L, H221Y, P225H, P225L, P225P/S, F227C, F227C/R, Y318Y/F and Y318Y/S. Eight of 13 (62%) participants with emergent doravirine resistance-associated substitutions showed doravirine phenotypic resistance and most of them had at least a 100-fold reduction in doravirine susceptibility (range >95- to >211–fold reduction in doravirine susceptibility). The other 5 virologic failures who had only amino acid mixtures of NNRTI resistance substitutions showed doravirine phenotypic fold-changes of less than 2-fold. Of the 36 participants in the resistance analysis subset, 10 participants (28%) developed genotypic and/or phenotypic resistance to the other drugs (abacavir, emtricitabine, lamivudine, or tenofovir) in the regimens of the DRIVE-FORWARD and DRIVE-AHEAD trials. The resistance-associated substitutions that emerged were RT M41L (n=1), A62A/V (n=1), K65R (n=2), T69T/A (n=1), V75V/I (n=1), and M184I or V (n=7). In the DRV/r treatment arm of the DRIVE-FORWARD trial (n=383) through Week 96, no participants showed the emergence of darunavir resistance-associated substitutions among 15 participants with resistance data and 2 of the participants had emergent genotypic or phenotypic resistance to lamivudine or tenofovir. In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364) through Week 96, 15 participants showed the emergence of efavirenz resistance-associated substitutions among 25 (60%) participants in the resistance analysis subset and genotypic resistance to emtricitabine or tenofovir developed in 5 evaluable participants; emergent resistance-associated substitutions were RT K65R (n=1), D67G/K70E (n=1), L74V/V75M/V118I (n=1), M184I or V (n=5), and K219K/E (n=1). Clinical Trial Results in Virologically-Suppressed Adults In the DRIVE-SHIFT clinical trial [see Clinical Studies (14.2) ] , there were 6 participants in the immediate switch group (n=447) and 2 participants in the delayed switch group (n=209) who met the protocol-defined virologic failure criteria (confirmed HIV-1 RNA ≥ 50 copies/mL). Two of the 6 virologic failure participants in the immediate switch group had available resistance data and neither developed detectable genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir during treatment with DELSTRIGO. One of the two virologic failure participants in the delayed switch group who had available resistance data developed the RT M184M/I substitution and phenotypic resistance to emtricitabine and lamivudine during treatment with their baseline regimen. Cross-Resistance Cross-resistance has been observed among NNRTIs. Treatment-emergent doravirine resistance-associated substitutions can confer cross-resistance to efavirenz, etravirine, nevirapine, and rilpivirine. Of the 8 virologic failure participants who developed doravirine phenotypic resistance, all had phenotypic resistance to nevirapine, 6 had phenotypic resistance to efavirenz, 4 had phenotypic resistance to rilpivirine, and 4 had resistance to etravirine in the Monogram PhenoSense assay. Of the 11 virologic failure participants in DRIVE-AHEAD phenotypically resistant to efavirenz, 2 (18%) had decreased susceptibility to doravirine (18- and 36-fold). The treatment-emergent doravirine resistance-associated substitution Y318F did not confer reduced susceptibility to efavirenz, etravirine, or rilpivirine. A panel of 96 diverse clinical isolates containing NNRTI resistance-associated substitutions was evaluated for susceptibility to doravirine. Clinical isolates containing the Y188L substitution alone or in combination with K103N or V106I, V106A in combination with G190A and F227L, or E138K in combination with Y181C and M230L showed greater than 100-fold reduced susceptibility to doravirine."],"geriatric_use":["8.5 Geriatric Use Clinical trials of PIFELTRO did not include sufficient numbers of participants aged 65 years and over to determine whether they respond differently from younger participants. In general, caution should be exercised in the administration of PIFELTRO in elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) ] ."],"pediatric_use":["8.4 Pediatric Use The safety and efficacy of PIFELTRO for the treatment of HIV-1 infection have been established in pediatric patients weighing at least 35 kg [see Indications and Usage (1) and Dosage and Administration (2.1) ]. Use of PIFELTRO in this group is supported by evidence from adequate and well-controlled trials in adults and an open-label trial in virologically-suppressed or treatment-naïve pediatric participants 12 to less than 18 years of age. The safety, efficacy, and exposure of doravirine in these pediatric participants were similar to that in adults [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.3) ]. Safety and efficacy of PIFELTRO in pediatric patients weighing less than 35 kg have not been established."],"effective_time":"20251029","clinical_studies":["14 CLINICAL STUDIES 14.1 Clinical Trial Results in Adults with No Antiretroviral Treatment History The efficacy of PIFELTRO is based on the analyses of 96-week data from two randomized, multicenter, double-blind, active controlled Phase 3 trials (DRIVE-FORWARD, NCT02275780 and DRIVE-AHEAD, NCT02403674) in participants living with HIV with no antiretroviral treatment history (n=1494). In DRIVE-FORWARD, 766 participants were randomized and received at least 1 dose of either PIFELTRO once daily or darunavir 800 mg + ritonavir 100 mg (DRV+r) once daily each in combination with emtricitabine/tenofovir DF (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator. At baseline, the median age of participants was 33 years, 16% were female, 27% were Non-White, 4% had hepatitis B and/or C virus co-infection, 10% had a history of AIDS, 20% had HIV-1 RNA greater than 100,000 copies/mL, 86% had CD4+ T-cell count greater than 200 cells/mm 3 , 13% received ABC/3TC, and 87% received FTC/TDF; these characteristics were similar between treatment groups. In DRIVE-AHEAD, 728 participants were randomized and received at least 1 dose of either DELSTRIGO (DOR/3TC/TDF) or EFV 600 mg/FTC 200 mg/TDF 300 mg once daily. At baseline, the median age of participants was 31 years, 15% were female, 52% were Non-White, 3% had hepatitis B or C co-infection, 14% had a history of AIDS, 21% had HIV-1 RNA greater than 100,000 copies/mL, and 88% had CD4+ T-cell count greater than 200 cells/mm 3 ; these characteristics were similar between treatment groups. Week 96 outcomes for DRIVE-FORWARD and DRIVE-AHEAD are provided in Table 10. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. In DRIVE-FORWARD, the mean CD4+ T-cell counts in the PIFELTRO and DRV+r groups increased from baseline by 224 and 207 cells/mm 3 , respectively. In DRIVE-AHEAD, the mean CD4+ T-cell counts in the DELSTRIGO and EFV/FTC/TDF groups increased from baseline by 238 and 223 cells/mm 3 , respectively. Table 10: Virologic Outcome in DRIVE-FORWARD and DRIVE-AHEAD at Week 96 in HIV-1 Adults with No Antiretroviral Treatment History Outcome DRIVE-FORWARD DRIVE-AHEAD PIFELTRO + 2 NRTIs Once Daily DRV+r + 2 NRTIs Once Daily DELSTRIGO Once Daily EFV/FTC/TDF Once Daily N=383 N=383 N=364 N=364 Note: NRTIs = FTC/TDF or ABC/3TC. HIV-1 RNA <50 copies/mL 72% 65% 77% 74% Treatment Differences (95% CI) The 95% CIs for the treatment differences were calculated using stratum-adjusted Mantel-Haenszel method. 7.5% (1.0%, 14.1%) 3.8% (-2.4%, 10.0%) HIV-1 RNA ≥ 50 copies/mL Includes participants who discontinued study drug or study before Week 96 for lack or loss of efficacy and participants with HIV-1 RNA equal to or above 50 copies/mL in the Week 96 window. 17% 20% 15% 12% No Virologic Data at Week 96 Window 11% 15% 7% 14% Discontinued study due to AE or Death Includes participants who discontinued because of adverse event (AE) or death if this resulted in no virologic data in the Week 96 window. 2% 4% 3% 8% Discontinued study for Other Reasons Other Reasons include: lost to follow-up, non-compliance with study drug, physician decision, pregnancy, protocol deviation, screen failure, withdrawal by participant. 7% 9% 4% 5% On study but missing data in window 2% 3% 1% 1% Proportion (%) of Participants With HIV-1 RNA <50 copies/mL at Week 96 by Baseline and Demographic Category Gender Male 72% (N = 319) 67% (N = 326) 78% (N = 305) 73% (N = 311) Female 73% (N = 64) 54% (N = 57) 75% (N = 59) 75% (N = 53) Race White 78% (N = 280) 68% (N = 280) 80% (N = 176) 74% (N = 170) Non-White 58% (N = 103) 57% (N = 102) 76% (N = 188) 74% (N = 194) Ethnicity Does not include participants whose ethnicity or viral subtypes were unknown. Hispanic or Latino 76% (N = 93) 63% (N = 86) 81% (N = 126) 77% (N = 119) Not Hispanic or Latino 71% (N = 284) 66% (N = 290) 76% (N = 238) 72% (N = 239) NRTI Background Therapy FTC/TDF 71% (N = 333) 64% (N = 335) - - ABC/3TC 80% (N = 50) 67% (N = 48) - - Baseline HIV-1 RNA (copies/mL) ≤100,000 copies/mL 75% (N = 300) 66% (N = 309) 80% (N = 291) 77% (N = 282) >100,000 copies/mL 61% (N = 83) 59% (N = 73) 67% (N = 73) 62% (N = 82) CD4+ T-cell Count (cells/mm 3 ) ≤200 cells/mm 3 62% (N = 42) 51% (N = 67) 59% (N = 44) 70% (N = 46) >200 cells/mm 3 74% (N = 341) 68% (N = 316) 80% (N = 320) 74% (N = 318) Viral Subtype Subtype B 71% (N = 266) 66% (N = 272) 80% (N = 232) 72% (N = 253) Subtype Non-B 75% (N = 117) 62% (N = 111) 73% (N = 130) 77% (N = 111) 14.2 Clinical Trial Results in Virologically-Suppressed Adults The efficacy of switching from a baseline regimen consisting of two NRTIs in combination with a PI plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI to DELSTRIGO was evaluated in a randomized, open-label trial (DRIVE-SHIFT, NCT02397096), in virologically-suppressed adults living with HIV. Participants must have been virologically-suppressed (HIV-1 RNA < 50 copies/mL) on their baseline regimen for at least 6 months prior to trial entry, with no history of virologic failure. Participants were randomized to either switch to DELSTRIGO at baseline (n = 447, Immediate Switch Group (ISG)), or stay on their baseline regimen until Week 24, at which point they switched to DELSTRIGO (n = 223, Delayed Switch Group (DSG)). At baseline, the median age of participants was 43 years, 16% were female, and 24% were Non-White, 21% were of Hispanic or Latino ethnicity, 3% had hepatitis B and/or C virus co-infection, 17% had a history of AIDS, 96% had CD4+ T-cell count greater than or equal to 200 cells/mm 3 , 70% were on a regimen containing a PI plus ritonavir, 24% were on a regimen containing an NNRTI, 6% were on a regimen containing elvitegravir plus cobicistat, and 1% were on a regimen containing a PI plus cobicistat; these characteristics were similar between treatment groups. Virologic outcome results are shown in Table 11. Table 11: Virologic Outcomes in DRIVE-SHIFT in HIV-1 Virologically-Suppressed Participants Who Switched to DELSTRIGO Outcome DELSTRIGO Once Daily ISG Week 48 N=447 Baseline Regimen DSG Week 24 N=223 HIV-1 RNA ≥ 50 copies/mL Includes participants who discontinued study drug or study before Week 48 for ISG or before Week 24 for DSG for lack or loss of efficacy and participants with HIV-1 RNA ≥50 copies/mL in the Week 48 window for ISG and in the Week 24 window for DSG. 2% 1% ISG-DSG, Difference (95% CI) The 95% CI for the treatment difference was calculated using stratum-adjusted Mantel-Haenszel method. , Assessed using a non-inferiority margin of 4%. 0.7% (-1.3%, 2.6%) HIV-1 RNA <50 copies/mL 91% 95% No Virologic Data Within the Time Window 8% 4% Discontinued study due to AE or Death Includes participants who discontinued because of adverse event (AE) or death if this resulted in no virologic data on treatment during the specified window. 3% <1% Discontinued study for Other Reasons Other reasons include: lost to follow-up, non-compliance with study drug, physician decision, protocol deviation, withdrawal by participant. 4% 4% On study but missing data in window 0 0 Proportion (%) of Participants With HIV-1 RNA <50 copies/mL by Baseline and Demographic Category Age (years) < 50 90% (N = 320) 95% (N = 157) ≥ 50 94% (N = 127) 94% (N = 66) Gender Male 91% (N = 372) 94% (N = 194) Female 91% (N = 75) 100% (N = 29) Race White 90% (N = 344) 95% (N = 168) Non-White 93% (N = 103) 93% (N = 55) Ethnicity Hispanic or Latino 88% (N = 99) 91% (N = 45) Not Hispanic or Latino 91% (N = 341) 95% (N = 175) CD4+ T-cell Count (cells/mm 3 ) <200 cells/mm 3 85% (N = 13) 75% (N = 4) ≥200 cells/mm 3 91% (N = 426) 95% (N = 216) Baseline Regimen Baseline Regimen = PI plus either ritonavir or cobicistat (specifically atazanavir, darunavir, or lopinavir), or elvitegravir plus cobicistat, or NNRTI (specifically efavirenz, nevirapine, or rilpivirine), each administered with two NRTIs. PI plus either ritonavir or cobicistat 90% (N=316) 94% (N=156) elvitegravir plus cobicistat or NNRTI 93% (N=131) 96% (N=67) 14.3 Clinical Trial Results in Pediatric Participants The efficacy of DELSTRIGO (DOR/3TC/TDF) was evaluated in cohort 2 of an open-label, single-arm 2-cohort trial in pediatric participants 12 to less than 18 years of age living with HIV (IMPAACT 2014 (Protocol 027), NCT03332095). In cohort 1, virologically-suppressed participants (n=9) received a single 100 mg dose of PIFELTRO followed by intensive PK sampling. In cohort 2, virologically-suppressed participants (n=43) were switched to DELSTRIGO and treatment-naïve participants (n=2) were started on DELSTRIGO. In cohort 2, at baseline the median age of participants was 15 years (range: 12 to 17), the median weight was 52 kg (range: 45 to 80), 58% were female, 78% were Asian and 22% were Black, and the median CD4+ T-cell count was 713 cells per mm 3 (range 84 to 1397). After switching to DELSTRIGO, 95% (41/43) of virologically-suppressed participants remained suppressed (HIV-1 RNA <50 copies/mL) at Week 24. One of the two treatment-naïve participants achieved HIV-1 RNA <50 copies/mL at Week 24. The other treatment-naïve participant met the protocol-defined virologic failure criteria (defined as 2 consecutive plasma HIV-1 RNA test results ≥200 copies/mL at or after Week 24) and was evaluated for the development of resistance; no emergence of genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir was detected."],"pharmacodynamics":["12.2 Pharmacodynamics In a Phase 2 trial evaluating doravirine over a dose range of 0.25 to 2 times the recommended dose of PIFELTRO, (in combination with FTC/TDF) in participants living with HIV with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine. Cardiac Electrophysiology At a doravirine dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose of PIFELTRO, doravirine does not prolong the QT interval to any clinically relevant extent."],"pharmacokinetics":["12.3 Pharmacokinetics Doravirine pharmacokinetics are similar in healthy participants and participants living with HIV. Doravirine pharmacokinetics are provided in Table 7. Table 7: Pharmacokinetic Properties of Doravirine Parameter Doravirine Abbreviations: AUC=area under the time concentration curve; C max =maximum concentration; C 24 =concentration at 24 hours; T max time to C max ; V dss = volume of distribution at steady state, t 1/2 =elimination half-life; CL/F=apparent clearance; CL renal =apparent renal clearance General Steady State Exposure Doravirine 100 mg once daily to participants living with HIV , Presented as geometric mean (%CV: geometric coefficient of variation) AUC 0-24 (mcg∙h/mL) 16.1 (29) C max (mcg/mL) 0.962 (19) C 24 (mcg/mL) 0.396 (63) Time to Steady State (Days) 2 Accumulation Ratio 1.2 to 1.4 Absorption Absolute Bioavailability 64% T max (h) 2 Effect of Food Geometric mean ratio [high-fat meal/fasting] and (90% confidence interval) for PK parameters. High fat meal is approximately 1,000 kcal, 50% fat. The effect of food is not clinically relevant. AUC Ratio 1.16 (1.06, 1.26) C max Ratio 1.03 (0.89, 1.19) C 24 Ratio 1.36 (1.19, 1.55) Distribution V dss (L) Based on IV dose 60.5 Plasma Protein Binding 76% Elimination t 1/2 (h) 15 CL/F (mL/min) 106 (35.2) CL renal (mL/min) 9.3 (18.6) Metabolism Primary Pathway(s) CYP3A Excretion Major Route of Elimination Metabolism Urine (unchanged) 6% Biliary/Fecal (unchanged) Minor Specific Populations In adults, no clinically significant difference on the pharmacokinetics of doravirine were observed based on age (18 to 78 years of age), sex, and race/ethnicity, mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault), or moderate hepatic impairment (Child-Pugh B). The pharmacokinetics of doravirine in patients with end-stage renal disease or undergoing dialysis, or severe hepatic impairment (Child-Pugh C) is unknown. Patients with Renal Impairment In a study comparing 8 participants with severe renal impairment to 8 participants without renal impairment, the single dose exposure of doravirine was 43% higher in participants with severe renal impairment. In a population pharmacokinetic analysis, renal function did not have a clinically relevant effect on doravirine pharmacokinetics. Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis [see Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment No clinically significant difference in the pharmacokinetics of doravirine was observed in participants with moderate hepatic impairment (Child-Pugh score B) compared to participants without hepatic impairment. Doravirine has not been studied in participants with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations (8.7) ] . Pediatric Patients Mean doravirine exposures were similar in 54 pediatric participants aged 12 to less than 18 years and weighing at least 35 kg who received doravirine or DELSTRIGO in IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine or DELSTRIGO (Table 8). For pediatric participants weighing ≥ 35 kg and < 45 kg who received doravirine 100 mg or DELSTRIGO, the population pharmacokinetic model-predicted mean C 24 of doravirine was comparable to that achieved in adults, whereas mean AUC 0-24 and C max of doravirine were 25% and 36% higher than adult values, respectively. However, the predicted AUC 0-24 and C max increases are not considered clinically significant. Table 8: Steady State Pharmacokinetics for Doravirine Following Administration of Doravirine or DELSTRIGO in Pediatric Participants Living with HIV Aged 12 to Less than 18 Years and Weighing at Least 35 kg Parameter Presented as geometric mean (%CV: geometric coefficient of variation) Doravirine From population PK analysis (n=53 weighing ≥45 kg, n=1 weighing ≥35 kg to <45 kg) Abbreviations: AUC=area under the time concentration curve; C max =maximum concentration; C 24 =concentration at 24 hours AUC 0-24 (mcg∙h/mL) 16.4 (24) C max (mcg/mL) 1.03 (16) C 24 (mcg/mL) 0.379 (42) Drug Interaction Studies Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine. Co-administration of doravirine and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine. Co-administration of doravirine and drugs that inhibit CYP3A may result in increased plasma concentrations of doravirine. Doravirine is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Doravirine did not inhibit major drug metabolizing enzymes in vitro , including CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and UGT1A1 and is not likely to be an inducer of CYP1A2, 2B6, or 3A4. Based on in vitro assays, doravirine is not likely to be an inhibitor of OATP1B1, OATP1B3, P-glycoprotein, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2K. Drug interaction studies were performed with doravirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration with other drugs on the exposure (C max , AUC, and C 24 ) of doravirine are summarized in Table 9. A single doravirine 100 mg dose was administered in these studies unless otherwise noted. Table 9: Drug Interactions: Changes in Pharmacokinetic Parameter Values of Doravirine in the Presence of Co-administered Drug Co-administered Drug Regimen of Co-administered Drug N Geometric Mean Ratio (90% CI) of Doravirine Pharmacokinetics with/without Co-administered Drug (No Effect=1.00) AUC AUC 0-∞ for single-dose, AUC 0-24 for once daily. C max C 24 CI = confidence interval; QD = once daily; BID = twice daily Azole Antifungal Agents ketoconazole Changes in doravirine pharmacokinetic values are not clinically relevant. 400 mg QD 10 3.06 (2.85, 3.29) 1.25 (1.05, 1.49) 2.75 (2.54, 2.98) Antimycobacterials rifampin 600 mg QD 10 0.12 (0.10, 0.15) 0.43 (0.35, 0.52) 0.03 (0.02, 0.04) rifabutin 300 mg QD 12 0.50 (0.45, 0.55) 0.99 (0.85, 1.15) 0.32 (0.28, 0.35) 300 mg QD Doravirine 100 mg BID resulted in similar pharmacokinetic values when compared to 100 mg QD without rifabutin. 15 1.03 (0.94, 1.14) 0.97 (0.87, 1.08) 0.98 (0.88, 1.10) HIV Antiviral Agents ritonavir , A single doravirine 50 mg dose (0.5 times the recommended approved dose) was administered. 100 mg BID 8 3.54 (3.04, 4.11) 1.31 (1.17, 1.46) 2.91 (2.33, 3.62) efavirenz 600 mg QD The first day following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD. 17 0.38 (0.33, 0.45) 0.65 (0.58, 0.73) 0.15 (0.10, 0.23) 600 mg QD 14 days following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD. 17 0.68 (0.58, 0.80) 0.86 (0.77, 0.97) 0.50 (0.39, 0.64) Based on drug interaction studies conducted with doravirine, no clinically significant drug interactions have been observed following the co-administration of doravirine and the following drugs: dolutegravir, ritonavir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam."],"adverse_reactions":["6 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 at Week 48. The LDL and non-HDL comparisons were pre-specified and are summarized in Table 4. The differences were statistically significant, showing superiority for doravirine for both parameters. The clinical benefit of these findings has not been demonstrated. Table 4: Mean Change from Baseline in Fasting Lipids in Adult Participants with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 48) Participants on lipid-lowering agents at baseline were excluded from these analyses (in DRIVE-FORWARD: PIFELTRO n=12 and DRV+r n=14; in DRIVE-AHEAD: DELSTRIGO n=15 and EFV/FTC/TDF n=10). Participants initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (in DRIVE-FORWARD: PIFELTRO n=6 and DRV+r n=4; in DRIVE-AHEAD: DELSTRIGO n=3 and EFV/FTC/TDF n=8). DRIVE-FORWARD PIFELTRO+2 NRTIs Once Daily N=320 DRV+r+2 NRTIs Once Daily N=311 Laboratory Parameter Preferred Term Baseline Change Baseline Change Difference Estimates (95% CI) LDL-Cholesterol (mg/dL) p-values for the pre-specified hypothesis testing for treatment difference were <0.0001 in both DRIVE-FORWARD and DRIVE-AHEAD. 91.4 -4.6 92.3 9.5 -14.4 (-18.0, -10.8) Non-HDL Cholesterol (mg/dL) 113.6 -5.4 114.5 13.7 -19.4 (-23.4, -15.4) Total Cholesterol (mg/dL) Not pre-specified for hypothesis testing. 157.2 -1.4 157.8 18.0 - Triglycerides (mg/dL) 111.0 -3.1 113.7 24.5 - HDL-Cholesterol (mg/dL) 43.6 4.0 43.3 4.3 - DRIVE-AHEAD DELSTRIGO Once Daily N=320 EFV/FTC/TDF Once Daily N=307 Laboratory Parameter Preferred Term Baseline Change Baseline Change Difference Estimates (95% CI) LDL-Cholesterol (mg/dL) 91.7 -2.1 91.3 8.3 -10.2 (-13.8, -6.7) Non-HDL Cholesterol (mg/dL) 114.7 -4.1 115.3 12.7 -16.9 (-20.8, -13.0) Total Cholesterol (mg/dL) 156.8 -2.2 156.8 21.1 - Triglycerides (mg/dL) 118.7 -12.0 122.6 21.6 - HDL-Cholesterol (mg/dL) 42.1 1.8 41.6 8.4 - Adverse Reactions in Virologically-Suppressed Adults The safety of DELSTRIGO in virologically-suppressed adults was based on Week 48 data from 670 participants in the DRIVE-SHIFT trial (Protocol 024), a randomized, international, multicenter, open-label trial in which virologically-suppressed participants were switched from a baseline regimen consisting of two NRTIs in combination with a protease inhibitor (PI) plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or a non-nucleoside reverse transcriptase inhibitor (NNRTI) to DELSTRIGO. Overall, the safety profile in virologically-suppressed adult participants was similar to that in participants with no antiretroviral treatment history. Laboratory Abnormalities Serum ALT and AST Elevations: In the DRIVE-SHIFT trial, 22% and 16% of participants in the immediate switch group experienced ALT and AST elevations greater than 1.25 × ULN, respectively, through 48 weeks on DELSTRIGO. For these ALT and AST elevations, no apparent patterns with regard to time to onset relative to switch were observed. One percent of participants had ALT or AST elevations greater than 5 × ULN through 48 weeks on DELSTRIGO. The ALT and AST elevations were generally asymptomatic and not associated with bilirubin elevations. In comparison, 4% and 4% of participants in the delayed switch group experienced ALT and AST elevations of greater than 1.25 × ULN through 24 weeks on their baseline regimen. Change in Lipids from Baseline Changes from baseline at Week 24 in LDL-cholesterol, non-HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol in participants on a PI plus ritonavir-based regimen at baseline are shown in Table 5. The LDL and non-HDL comparisons were pre-specified, and the differences were statistically significant, showing superiority for an immediate switch to DELSTRIGO for both parameters. The clinical benefit of these findings has not been demonstrated. Table 5: Mean Change from Baseline in Fasting Lipids in Adult Virologically-Suppressed Participants on a PI plus Ritonavir-based Regimen at Baseline in DRIVE-SHIFT (Week 24) Laboratory Parameter Preferred Term DELSTRIGO (Week 0-24) Once Daily N=244 PI+ritonavir (Week 0-24) Once Daily N=124 Difference Estimates Baseline Change Baseline Change Difference (95% CI) Participants on lipid-lowering agents at baseline were excluded from these analyses (DELSTRIGO n=26 and PI+ritonavir n=13). Participants initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (DELSTRIGO n=4 and PI+ritonavir n=2). LDL-Cholesterol (mg/dL) p-value for the pre-specified hypothesis testing for treatment difference was <0.0001. 108.7 -16.3 110.5 -2.6 -14.5 (-18.9, -10.1) Non-HDL Cholesterol (mg/dL) 138.6 -24.8 138.8 -2.1 -22.8 (-27.9, -17.7) Total Cholesterol (mg/dL) Not pre-specified for hypothesis testing. 188.5 -26.1 187.4 -0.2 - Triglycerides (mg/dL) 153.1 -44.4 151.4 -0.4 - HDL-Cholesterol (mg/dL) 50.0 -1.3 48.5 1.9 - Adverse Reactions in Pediatric Participants The safety of doravirine as a component of DELSTRIGO was evaluated in 45 virologically-suppressed or treatment-naïve pediatric participants 12 to less than 18 years of age living with HIV through Week 24 in an open-label trial (IMPAACT 2014 (Protocol 027)) [see Clinical Studies (14.3) ] . The safety profile in pediatric participants was similar to that in adults. There were no serious or Grade 3 or 4 adverse reactions. No participants discontinued due to an adverse event. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving doravirine-containing regimens. Because postmarketing 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. Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) Hepatobiliary Disorders : hepatitis Investigations : hepatic enzyme increased"],"contraindications":["4 CONTRAINDICATIONS PIFELTRO is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of PIFELTRO [see Warnings and Precautions (5.2) , Drug Interactions (7.1) , and Clinical Pharmacology (12.3) ] . These drugs include, but are not limited to, the following: the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin the androgen receptor inhibitor enzalutamide the antimycobacterials rifampin, rifapentine the cytotoxic agent mitotane St. John's wort ( Hypericum perforatum) PIFELTRO is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of PIFELTRO. ( 4 )"],"drug_interactions":["7 DRUG INTERACTIONS Consult the full prescribing information prior to and during treatment for important potential drug-drug interactions. ( 4 , 5.2 , 7 ) 7.1 Effect of Other Drugs on PIFELTRO Co-administration of PIFELTRO with a CYP3A inducer decreases doravirine plasma concentrations, which may reduce PIFELTRO efficacy [see Contraindications (4) , Warnings and Precautions (5.2) , and Clinical Pharmacology (12.3) ] . Co-administration of PIFELTRO and drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine. Table 6 shows significant drug interactions with PIFELTRO. Table 6: Drug Interactions with PIFELTRO This table is not all inclusive. Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment ↑ = increase, ↓ = decrease All other drug-drug interactions shown are anticipated based on the known metabolic and elimination pathways. Androgen Receptors enzalutamide ↓ doravirine Co-administration is contraindicated with enzalutamide. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO. Anticonvulsants carbamazepine oxcarbazepine phenobarbital phenytoin ↓ doravirine Co-administration is contraindicated with these anticonvulsants. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO. Antimycobacterials rifampin The interaction between PIFELTRO and the concomitant drug was evaluated in a clinical study. rifapentine ↓ doravirine Co-administration is contraindicated with rifampin or rifapentine . At least a 4-week cessation period is recommended prior to initiation of PIFELTRO. rifabutin ↓ doravirine Increase PIFELTRO dosage to one tablet twice daily when co-administered with rifabutin [see Dosage and Administration (2.2) ] . Cytotoxic Agents mitotane ↓ doravirine Co-administration is contraindicated with mitotane. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO. HIV Antiviral Agents efavirenz etravirine nevirapine ↓ doravirine Use with efavirenz, etravirine, or nevirapine is not recommended. Herbal Products St. John's wort ↓ doravirine Co-administration is contraindicated with St. John's wort. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO. No clinically significant changes in concentration were observed for doravirine when co-administered with the following agents: dolutegravir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ritonavir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, and methadone [see Clinical Pharmacology (12.3) ]. 7.2 Effect of PIFELTRO on Other Drugs No clinically significant changes in concentration were observed for the following agents when co-administered with doravirine: dolutegravir, lamivudine, TDF, elbasvir and grazoprevir, ledipasvir and sofosbuvir, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam [see Clinical Pharmacology (12.3) ] ."],"mechanism_of_action":["12.1 Mechanism of Action Doravirine is an antiretroviral drug [see Microbiology (12.4) ]."],"recent_major_changes":["Warnings and Precautions, Severe Skin Reactions ( 5.1 ) 11/2024"],"storage_and_handling":["Store PIFELTRO in the original bottle. Keep the bottle tightly closed to protect from moisture. Do not remove the desiccant. Store PIFELTRO at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]."],"clinical_pharmacology":["12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Doravirine is an antiretroviral drug [see Microbiology (12.4) ]. 12.2 Pharmacodynamics In a Phase 2 trial evaluating doravirine over a dose range of 0.25 to 2 times the recommended dose of PIFELTRO, (in combination with FTC/TDF) in participants living with HIV with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine. Cardiac Electrophysiology At a doravirine dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose of PIFELTRO, doravirine does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Doravirine pharmacokinetics are similar in healthy participants and participants living with HIV. Doravirine pharmacokinetics are provided in Table 7. Table 7: Pharmacokinetic Properties of Doravirine Parameter Doravirine Abbreviations: AUC=area under the time concentration curve; C max =maximum concentration; C 24 =concentration at 24 hours; T max time to C max ; V dss = volume of distribution at steady state, t 1/2 =elimination half-life; CL/F=apparent clearance; CL renal =apparent renal clearance General Steady State Exposure Doravirine 100 mg once daily to participants living with HIV , Presented as geometric mean (%CV: geometric coefficient of variation) AUC 0-24 (mcg∙h/mL) 16.1 (29) C max (mcg/mL) 0.962 (19) C 24 (mcg/mL) 0.396 (63) Time to Steady State (Days) 2 Accumulation Ratio 1.2 to 1.4 Absorption Absolute Bioavailability 64% T max (h) 2 Effect of Food Geometric mean ratio [high-fat meal/fasting] and (90% confidence interval) for PK parameters. High fat meal is approximately 1,000 kcal, 50% fat. The effect of food is not clinically relevant. AUC Ratio 1.16 (1.06, 1.26) C max Ratio 1.03 (0.89, 1.19) C 24 Ratio 1.36 (1.19, 1.55) Distribution V dss (L) Based on IV dose 60.5 Plasma Protein Binding 76% Elimination t 1/2 (h) 15 CL/F (mL/min) 106 (35.2) CL renal (mL/min) 9.3 (18.6) Metabolism Primary Pathway(s) CYP3A Excretion Major Route of Elimination Metabolism Urine (unchanged) 6% Biliary/Fecal (unchanged) Minor Specific Populations In adults, no clinically significant difference on the pharmacokinetics of doravirine were observed based on age (18 to 78 years of age), sex, and race/ethnicity, mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault), or moderate hepatic impairment (Child-Pugh B). The pharmacokinetics of doravirine in patients with end-stage renal disease or undergoing dialysis, or severe hepatic impairment (Child-Pugh C) is unknown. Patients with Renal Impairment In a study comparing 8 participants with severe renal impairment to 8 participants without renal impairment, the single dose exposure of doravirine was 43% higher in participants with severe renal impairment. In a population pharmacokinetic analysis, renal function did not have a clinically relevant effect on doravirine pharmacokinetics. Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis [see Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment No clinically significant difference in the pharmacokinetics of doravirine was observed in participants with moderate hepatic impairment (Child-Pugh score B) compared to participants without hepatic impairment. Doravirine has not been studied in participants with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations (8.7) ] . Pediatric Patients Mean doravirine exposures were similar in 54 pediatric participants aged 12 to less than 18 years and weighing at least 35 kg who received doravirine or DELSTRIGO in IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine or DELSTRIGO (Table 8). For pediatric participants weighing ≥ 35 kg and < 45 kg who received doravirine 100 mg or DELSTRIGO, the population pharmacokinetic model-predicted mean C 24 of doravirine was comparable to that achieved in adults, whereas mean AUC 0-24 and C max of doravirine were 25% and 36% higher than adult values, respectively. However, the predicted AUC 0-24 and C max increases are not considered clinically significant. Table 8: Steady State Pharmacokinetics for Doravirine Following Administration of Doravirine or DELSTRIGO in Pediatric Participants Living with HIV Aged 12 to Less than 18 Years and Weighing at Least 35 kg Parameter Presented as geometric mean (%CV: geometric coefficient of variation) Doravirine From population PK analysis (n=53 weighing ≥45 kg, n=1 weighing ≥35 kg to <45 kg) Abbreviations: AUC=area under the time concentration curve; C max =maximum concentration; C 24 =concentration at 24 hours AUC 0-24 (mcg∙h/mL) 16.4 (24) C max (mcg/mL) 1.03 (16) C 24 (mcg/mL) 0.379 (42) Drug Interaction Studies Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine. Co-administration of doravirine and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine. Co-administration of doravirine and drugs that inhibit CYP3A may result in increased plasma concentrations of doravirine. Doravirine is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Doravirine did not inhibit major drug metabolizing enzymes in vitro , including CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and UGT1A1 and is not likely to be an inducer of CYP1A2, 2B6, or 3A4. Based on in vitro assays, doravirine is not likely to be an inhibitor of OATP1B1, OATP1B3, P-glycoprotein, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2K. Drug interaction studies were performed with doravirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration with other drugs on the exposure (C max , AUC, and C 24 ) of doravirine are summarized in Table 9. A single doravirine 100 mg dose was administered in these studies unless otherwise noted. Table 9: Drug Interactions: Changes in Pharmacokinetic Parameter Values of Doravirine in the Presence of Co-administered Drug Co-administered Drug Regimen of Co-administered Drug N Geometric Mean Ratio (90% CI) of Doravirine Pharmacokinetics with/without Co-administered Drug (No Effect=1.00) AUC AUC 0-∞ for single-dose, AUC 0-24 for once daily. C max C 24 CI = confidence interval; QD = once daily; BID = twice daily Azole Antifungal Agents ketoconazole Changes in doravirine pharmacokinetic values are not clinically relevant. 400 mg QD 10 3.06 (2.85, 3.29) 1.25 (1.05, 1.49) 2.75 (2.54, 2.98) Antimycobacterials rifampin 600 mg QD 10 0.12 (0.10, 0.15) 0.43 (0.35, 0.52) 0.03 (0.02, 0.04) rifabutin 300 mg QD 12 0.50 (0.45, 0.55) 0.99 (0.85, 1.15) 0.32 (0.28, 0.35) 300 mg QD Doravirine 100 mg BID resulted in similar pharmacokinetic values when compared to 100 mg QD without rifabutin. 15 1.03 (0.94, 1.14) 0.97 (0.87, 1.08) 0.98 (0.88, 1.10) HIV Antiviral Agents ritonavir , A single doravirine 50 mg dose (0.5 times the recommended approved dose) was administered. 100 mg BID 8 3.54 (3.04, 4.11) 1.31 (1.17, 1.46) 2.91 (2.33, 3.62) efavirenz 600 mg QD The first day following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD. 17 0.38 (0.33, 0.45) 0.65 (0.58, 0.73) 0.15 (0.10, 0.23) 600 mg QD 14 days following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD. 17 0.68 (0.58, 0.80) 0.86 (0.77, 0.97) 0.50 (0.39, 0.64) Based on drug interaction studies conducted with doravirine, no clinically significant drug interactions have been observed following the co-administration of doravirine and the following drugs: dolutegravir, ritonavir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam. 12.4 Microbiology Mechanism of Action Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). The inhibitory concentration at 50% (IC 50 ) of doravirine for RNA-dependent DNA polymerization of recombinant wild-type HIV-1 RT in a biochemical assay was 12.2±2.0 nM (n=3). Doravirine does not inhibit the human cellular DNA polymerases α, β, and mitochondrial DNA polymerase γ. Antiviral Activity in Cell Culture Doravirine exhibited an EC 50 value of 12.0±4.4 nM against wild-type laboratory strains of HIV-1 when tested in the presence of 100% normal human serum (NHS) using MT4-GFP reporter cells and a median EC 50 value for HIV-1 subtype B primary isolates (n=118) of 4.1 nM (range: 1.0 nM-16.0 nM). Doravirine demonstrated antiviral activity against a broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC 50 values ranging from 1.2 nM to 10.0 nM. Antiviral Activity in Combination with other HIV Antiviral Agents The antiviral activity of doravirine in cell culture was not antagonistic when combined with the NNRTIs delavirdine, efavirenz, etravirine, nevirapine, or rilpivirine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, or zidovudine; the PIs darunavir or indinavir; the gp41 fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir. Resistance In Cell Culture Doravirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes, as well as NNRTI-resistant HIV-1. Observed emergent amino acid substitutions in RT included: V106A, V106I, V106M, V108I, H221Y, F227C, F227I, F227L, F227V, M230I, L234I, P236L, and Y318F. The V106A, V106M, V108I, H221Y, F227C, M230I, P236L, and Y318F substitutions conferred 3.4-fold to 70-fold reductions in susceptibility to doravirine. Y318F in combination with V106A, V106M, V108I, or F227C conferred greater decreases in susceptibility to doravirine than Y318F alone, which conferred a 10-fold reduction in susceptibility to doravirine. In Clinical Trials Clinical Trial Results in Adults with No Antiretroviral Treatment History In the doravirine treatment arms of the DRIVE-FORWARD and DRIVE-AHEAD trials (n=747) through Week 96, 13 participants showed the emergence of doravirine resistance-associated substitutions in their HIV among 36 (36%) participants in the resistance analysis subset (participants with HIV-1 RNA greater than 400 copies per mL at virologic failure or early study discontinuation and having post-baseline resistance samples). Emergent doravirine resistance-associated substitutions in RT included one or more of the following: V90G/I, A98G, V106A, V106I, V106M/T, V108I, E138G, Y188L, H221Y, P225H, P225L, P225P/S, F227C, F227C/R, Y318Y/F and Y318Y/S. Eight of 13 (62%) participants with emergent doravirine resistance-associated substitutions showed doravirine phenotypic resistance and most of them had at least a 100-fold reduction in doravirine susceptibility (range >95- to >211–fold reduction in doravirine susceptibility). The other 5 virologic failures who had only amino acid mixtures of NNRTI resistance substitutions showed doravirine phenotypic fold-changes of less than 2-fold. Of the 36 participants in the resistance analysis subset, 10 participants (28%) developed genotypic and/or phenotypic resistance to the other drugs (abacavir, emtricitabine, lamivudine, or tenofovir) in the regimens of the DRIVE-FORWARD and DRIVE-AHEAD trials. The resistance-associated substitutions that emerged were RT M41L (n=1), A62A/V (n=1), K65R (n=2), T69T/A (n=1), V75V/I (n=1), and M184I or V (n=7). In the DRV/r treatment arm of the DRIVE-FORWARD trial (n=383) through Week 96, no participants showed the emergence of darunavir resistance-associated substitutions among 15 participants with resistance data and 2 of the participants had emergent genotypic or phenotypic resistance to lamivudine or tenofovir. In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364) through Week 96, 15 participants showed the emergence of efavirenz resistance-associated substitutions among 25 (60%) participants in the resistance analysis subset and genotypic resistance to emtricitabine or tenofovir developed in 5 evaluable participants; emergent resistance-associated substitutions were RT K65R (n=1), D67G/K70E (n=1), L74V/V75M/V118I (n=1), M184I or V (n=5), and K219K/E (n=1). Clinical Trial Results in Virologically-Suppressed Adults In the DRIVE-SHIFT clinical trial [see Clinical Studies (14.2) ] , there were 6 participants in the immediate switch group (n=447) and 2 participants in the delayed switch group (n=209) who met the protocol-defined virologic failure criteria (confirmed HIV-1 RNA ≥ 50 copies/mL). Two of the 6 virologic failure participants in the immediate switch group had available resistance data and neither developed detectable genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir during treatment with DELSTRIGO. One of the two virologic failure participants in the delayed switch group who had available resistance data developed the RT M184M/I substitution and phenotypic resistance to emtricitabine and lamivudine during treatment with their baseline regimen. Cross-Resistance Cross-resistance has been observed among NNRTIs. Treatment-emergent doravirine resistance-associated substitutions can confer cross-resistance to efavirenz, etravirine, nevirapine, and rilpivirine. Of the 8 virologic failure participants who developed doravirine phenotypic resistance, all had phenotypic resistance to nevirapine, 6 had phenotypic resistance to efavirenz, 4 had phenotypic resistance to rilpivirine, and 4 had resistance to etravirine in the Monogram PhenoSense assay. Of the 11 virologic failure participants in DRIVE-AHEAD phenotypically resistant to efavirenz, 2 (18%) had decreased susceptibility to doravirine (18- and 36-fold). The treatment-emergent doravirine resistance-associated substitution Y318F did not confer reduced susceptibility to efavirenz, etravirine, or rilpivirine. A panel of 96 diverse clinical isolates containing NNRTI resistance-associated substitutions was evaluated for susceptibility to doravirine. Clinical isolates containing the Y188L substitution alone or in combination with K103N or V106I, V106A in combination with G190A and F227L, or E138K in combination with Y181C and M230L showed greater than 100-fold reduced susceptibility to doravirine."],"indications_and_usage":["1 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 )"],"warnings_and_cautions":["5 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."],"clinical_studies_table":["
Table 10: Virologic Outcome in DRIVE-FORWARD and DRIVE-AHEAD at Week 96 in HIV-1 Adults with No Antiretroviral Treatment History
OutcomeDRIVE-FORWARDDRIVE-AHEAD
PIFELTRO + 2 NRTIs Once DailyDRV+r + 2 NRTIs Once DailyDELSTRIGO Once DailyEFV/FTC/TDF Once Daily
N=383N=383N=364N=364
Note: NRTIs = FTC/TDF or ABC/3TC.
HIV-1 RNA <50 copies/mL72%65%77%74%
Treatment Differences (95% CI) The 95% CIs for the treatment differences were calculated using stratum-adjusted Mantel-Haenszel method.7.5% (1.0%, 14.1%)3.8% (-2.4%, 10.0%)
HIV-1 RNA ≥ 50 copies/mLIncludes participants who discontinued study drug or study before Week 96 for lack or loss of efficacy and participants with HIV-1 RNA equal to or above 50 copies/mL in the Week 96 window.17%20%15%12%
No Virologic Data at Week 96 Window11%15%7%14%
Discontinued study due to AE or DeathIncludes participants who discontinued because of adverse event (AE) or death if this resulted in no virologic data in the Week 96 window.2%4%3%8%
Discontinued study for Other ReasonsOther Reasons include: lost to follow-up, non-compliance with study drug, physician decision, pregnancy, protocol deviation, screen failure, withdrawal by participant.7%9%4%5%
On study but missing data in window2%3%1%1%
Proportion (%) of Participants With HIV-1 RNA <50 copies/mL at Week 96 by Baseline and Demographic Category
Gender
Male72% (N = 319)67% (N = 326)78% (N = 305)73% (N = 311)
Female73% (N = 64)54% (N = 57)75% (N = 59)75% (N = 53)
Race
White78% (N = 280)68% (N = 280)80% (N = 176)74% (N = 170)
Non-White58% (N = 103)57% (N = 102)76% (N = 188)74% (N = 194)
EthnicityDoes not include participants whose ethnicity or viral subtypes were unknown.
Hispanic or Latino76% (N = 93)63% (N = 86)81% (N = 126)77% (N = 119)
Not Hispanic or Latino71% (N = 284)66% (N = 290)76% (N = 238)72% (N = 239)
NRTI Background Therapy
FTC/TDF71% (N = 333)64% (N = 335)--
ABC/3TC80% (N = 50)67% (N = 48)--
Baseline HIV-1 RNA (copies/mL)
≤100,000 copies/mL75% (N = 300)66% (N = 309)80% (N = 291)77% (N = 282)
>100,000 copies/mL61% (N = 83)59% (N = 73)67% (N = 73)62% (N = 82)
CD4+ T-cell Count (cells/mm3)
≤200 cells/mm362% (N = 42)51% (N = 67)59% (N = 44)70% (N = 46)
>200 cells/mm374% (N = 341)68% (N = 316)80% (N = 320)74% (N = 318)
Viral Subtype
Subtype B71% (N = 266)66% (N = 272)80% (N = 232)72% (N = 253)
Subtype Non-B75% (N = 117)62% (N = 111)73% (N = 130)77% (N = 111)
","
Table 11: Virologic Outcomes in DRIVE-SHIFT in HIV-1 Virologically-Suppressed Participants Who Switched to DELSTRIGO
OutcomeDELSTRIGO Once Daily ISG Week 48 N=447Baseline Regimen DSG Week 24 N=223
HIV-1 RNA ≥ 50 copies/mLIncludes participants who discontinued study drug or study before Week 48 for ISG or before Week 24 for DSG for lack or loss of efficacy and participants with HIV-1 RNA ≥50 copies/mL in the Week 48 window for ISG and in the Week 24 window for DSG.2%1%
ISG-DSG, Difference (95% CI) The 95% CI for the treatment difference was calculated using stratum-adjusted Mantel-Haenszel method.,Assessed using a non-inferiority margin of 4%.0.7% (-1.3%, 2.6%)
HIV-1 RNA <50 copies/mL91%95%
No Virologic Data Within the Time Window8%4%
Discontinued study due to AE or DeathIncludes participants who discontinued because of adverse event (AE) or death if this resulted in no virologic data on treatment during the specified window.3%<1%
Discontinued study for Other ReasonsOther reasons include: lost to follow-up, non-compliance with study drug, physician decision, protocol deviation, withdrawal by participant.4%4%
On study but missing data in window00
Proportion (%) of Participants With HIV-1 RNA <50 copies/mL by Baseline and Demographic Category
Age (years)
< 5090% (N = 320)95% (N = 157)
≥ 5094% (N = 127)94% (N = 66)
Gender
Male91% (N = 372)94% (N = 194)
Female91% (N = 75)100% (N = 29)
Race
White90% (N = 344)95% (N = 168)
Non-White93% (N = 103)93% (N = 55)
Ethnicity
Hispanic or Latino88% (N = 99)91% (N = 45)
Not Hispanic or Latino91% (N = 341)95% (N = 175)
CD4+ T-cell Count (cells/mm3)
<200 cells/mm385% (N = 13)75% (N = 4)
≥200 cells/mm391% (N = 426)95% (N = 216)
Baseline RegimenBaseline Regimen = PI plus either ritonavir or cobicistat (specifically atazanavir, darunavir, or lopinavir), or elvitegravir plus cobicistat, or NNRTI (specifically efavirenz, nevirapine, or rilpivirine), each administered with two NRTIs.
PI plus either ritonavir or cobicistat90% (N=316)94% (N=156)
elvitegravir plus cobicistat or NNRTI93% (N=131)96% (N=67)
"],"nonclinical_toxicology":["13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Doravirine was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to 6 and 7 times, respectively, the human exposures at the RHD. A statistically significant incidence of thyroid parafollicular cell adenoma and carcinoma seen only in female rats at the high dose was within the range observed in historical controls. Mutagenesis Doravirine was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays. Impairment of fertility There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats at systemic exposures (AUC) approximately 7 times the exposure in humans at the RHD."],"pharmacokinetics_table":["
Table 7: Pharmacokinetic Properties of Doravirine
ParameterDoravirine
Abbreviations: AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hours; Tmax time to Cmax; Vdss= volume of distribution at steady state, t1/2=elimination half-life; CL/F=apparent clearance; CLrenal=apparent renal clearance
General
Steady State ExposureDoravirine 100 mg once daily to participants living with HIV,Presented as geometric mean (%CV: geometric coefficient of variation)
AUC0-24 (mcg∙h/mL)16.1 (29)
Cmax (mcg/mL)0.962 (19)
C24 (mcg/mL)0.396 (63)
Time to Steady State (Days)2
Accumulation Ratio1.2 to 1.4
Absorption
Absolute Bioavailability64%
Tmax (h)2
Effect of FoodGeometric mean ratio [high-fat meal/fasting] and (90% confidence interval) for PK parameters. High fat meal is approximately 1,000 kcal, 50% fat. The effect of food is not clinically relevant.
AUC Ratio1.16 (1.06, 1.26)
Cmax Ratio1.03 (0.89, 1.19)
C24 Ratio1.36 (1.19, 1.55)
Distribution
Vdss (L)Based on IV dose60.5
Plasma Protein Binding76%
Elimination
t1/2 (h)15
CL/F (mL/min)106 (35.2)
CLrenal (mL/min)9.3 (18.6)
Metabolism
Primary Pathway(s)CYP3A
Excretion
Major Route of EliminationMetabolism
Urine (unchanged)6%
Biliary/Fecal (unchanged)Minor
","
Table 8: Steady State Pharmacokinetics for Doravirine Following Administration of Doravirine or DELSTRIGO in Pediatric Participants Living with HIV Aged 12 to Less than 18 Years and Weighing at Least 35 kg
ParameterPresented as geometric mean (%CV: geometric coefficient of variation)DoravirineFrom population PK analysis (n=53 weighing ≥45 kg, n=1 weighing ≥35 kg to <45 kg)
Abbreviations: AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hours
AUC0-24 (mcg∙h/mL)16.4 (24)
Cmax (mcg/mL)1.03 (16)
C24 (mcg/mL)0.379 (42)
","
Table 9: Drug Interactions: Changes in Pharmacokinetic Parameter Values of Doravirine in the Presence of Co-administered Drug
Co-administered DrugRegimen of Co-administered DrugNGeometric Mean Ratio (90% CI) of Doravirine Pharmacokinetics with/without Co-administered Drug (No Effect=1.00)
AUCAUC0-∞ for single-dose, AUC0-24 for once daily.CmaxC24
CI = confidence interval; QD = once daily; BID = twice daily
Azole Antifungal Agents
ketoconazoleChanges in doravirine pharmacokinetic values are not clinically relevant.400 mg QD103.06 (2.85, 3.29)1.25 (1.05, 1.49)2.75 (2.54, 2.98)
Antimycobacterials
rifampin600 mg QD100.12 (0.10, 0.15)0.43 (0.35, 0.52)0.03 (0.02, 0.04)
rifabutin300 mg QD120.50 (0.45, 0.55)0.99 (0.85, 1.15)0.32 (0.28, 0.35)
300 mg QDDoravirine 100 mg BID resulted in similar pharmacokinetic values when compared to 100 mg QD without rifabutin.151.03 (0.94, 1.14)0.97 (0.87, 1.08)0.98 (0.88, 1.10)
HIV Antiviral Agents
ritonavir,A single doravirine 50 mg dose (0.5 times the recommended approved dose) was administered.100 mg BID83.54 (3.04, 4.11)1.31 (1.17, 1.46)2.91 (2.33, 3.62)
efavirenz600 mg QDThe first day following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD.170.38 (0.33, 0.45)0.65 (0.58, 0.73)0.15 (0.10, 0.23)
600 mg QD14 days following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD.170.68 (0.58, 0.80)0.86 (0.77, 0.97)0.50 (0.39, 0.64)
"],"adverse_reactions_table":["
Table 1: Adverse ReactionsFrequencies 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-FORWARDDRIVE-AHEAD
PIFELTRO+2 NRTIsNRTI = nucleoside reverse transcriptase inhibitor. Once Daily N=383DRV+r+2 NRTIs Once Daily N=383DELSTRIGO Once Daily N=364EFV/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
Nausea7%8%5%7%
Headache6%3%4%5%
Fatigue6%3%4%4%
Diarrhea6%13%4%6%
Abdominal Pain5%2%1%2%
Dizziness3%2%7%32%
Rash2%3%2%12%
Abnormal Dreams1%<1%5%10%
Insomnia1%2%4%5%
Somnolence0%<1%3%7%
","
Table 2: DRIVE-AHEAD - Analysis of Participants with Neuropsychiatric Adverse EventsAll causality and all grade events were included in the analysis. (Week 48)
DELSTRIGO Once Daily N=364EFV/FTC/TDF Once Daily N=364Treatment 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 disturbancesPredefined 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 sensoriumPredefined using MedDRA preferred terms, including: altered state of consciousness, lethargy, somnolence, syncope.4%8%-3.8 (-7.6, -0.3)
","
Table 3: Selected Laboratory Abnormalities Reported in Adult Participants with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 96)
DRIVE-FORWARDDRIVE-AHEAD
Laboratory Parameter Preferred Term (Unit)/LimitPIFELTRO+2 NRTIs Once Daily N=383DRV+r+2 NRTIs Once Daily N=383DELSTRIGO Once Daily N=364EFV/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 × ULN6%2%5%0%
1.6 - <2.6 × ULN2%<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 baseline4%6%3%2%
>1.8 × ULN or Increase of ≥1.5 × above baseline4%4%3%2%
Aspartate aminotransferase (IU/L)
2.5 - <5.0 × ULN5%4%3%3%
≥5.0 × ULN2%2%1%4%
Alanine aminotransferase (IU/L)
2.5 - <5.0 × ULN4%2%4%4%
≥5.0 × ULN2%3%1%3%
Alkaline phosphatase (IU/L)
2.5 - <5.0 × ULN<1%1%<1%1%
≥5.0 × ULN0%<1%0%<1%
Lipase
1.5 - <3.0 × ULN7%6%6%4%
≥3.0 × ULN3%4%2%3%
Creatine kinase (IU/L)
6.0 - <10.0 × ULN3%3%3%3%
≥10.0 × ULN5%6%4%6%
Cholesterol, fasted (mg/dL)
≥300 mg/dL0%1%1%<1%
LDL cholesterol, fasted (mg/dL)
≥190 mg/dL<1%4%<1%2%
Triglycerides, fasted (mg/dL)
>500 mg/dL1%2%1%3%
","
Table 4: Mean Change from Baseline in Fasting Lipids in Adult Participants with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 48)
Participants on lipid-lowering agents at baseline were excluded from these analyses (in DRIVE-FORWARD: PIFELTRO n=12 and DRV+r n=14; in DRIVE-AHEAD: DELSTRIGO n=15 and EFV/FTC/TDF n=10). Participants initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (in DRIVE-FORWARD: PIFELTRO n=6 and DRV+r n=4; in DRIVE-AHEAD: DELSTRIGO n=3 and EFV/FTC/TDF n=8).
DRIVE-FORWARD
PIFELTRO+2 NRTIs Once Daily N=320DRV+r+2 NRTIs Once Daily N=311
Laboratory Parameter Preferred TermBaselineChangeBaselineChangeDifference Estimates (95% CI)
LDL-Cholesterol (mg/dL)p-values for the pre-specified hypothesis testing for treatment difference were <0.0001 in both DRIVE-FORWARD and DRIVE-AHEAD.91.4-4.692.39.5-14.4 (-18.0, -10.8)
Non-HDL Cholesterol (mg/dL)113.6-5.4114.513.7-19.4 (-23.4, -15.4)
Total Cholesterol (mg/dL)Not pre-specified for hypothesis testing.157.2-1.4157.818.0-
Triglycerides (mg/dL)111.0-3.1113.724.5-
HDL-Cholesterol (mg/dL)43.64.043.34.3-
DRIVE-AHEAD
DELSTRIGO Once Daily N=320EFV/FTC/TDF Once Daily N=307
Laboratory Parameter Preferred TermBaselineChangeBaselineChangeDifference Estimates (95% CI)
LDL-Cholesterol (mg/dL)91.7-2.191.38.3-10.2 (-13.8, -6.7)
Non-HDL Cholesterol (mg/dL)114.7-4.1115.312.7-16.9 (-20.8, -13.0)
Total Cholesterol (mg/dL)156.8-2.2156.821.1-
Triglycerides (mg/dL)118.7-12.0122.621.6-
HDL-Cholesterol (mg/dL)42.11.841.68.4-
","
Table 5: Mean Change from Baseline in Fasting Lipids in Adult Virologically-Suppressed Participants on a PI plus Ritonavir-based Regimen at Baseline in DRIVE-SHIFT (Week 24)
Laboratory Parameter Preferred TermDELSTRIGO (Week 0-24) Once Daily N=244PI+ritonavir (Week 0-24) Once Daily N=124Difference Estimates
BaselineChangeBaselineChangeDifference (95% CI)
Participants on lipid-lowering agents at baseline were excluded from these analyses (DELSTRIGO n=26 and PI+ritonavir n=13).
Participants initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (DELSTRIGO n=4 and PI+ritonavir n=2).
LDL-Cholesterol (mg/dL)p-value for the pre-specified hypothesis testing for treatment difference was <0.0001.108.7-16.3110.5-2.6-14.5 (-18.9, -10.1)
Non-HDL Cholesterol (mg/dL)138.6-24.8138.8-2.1-22.8 (-27.9, -17.7)
Total Cholesterol (mg/dL)Not pre-specified for hypothesis testing.188.5-26.1187.4-0.2-
Triglycerides (mg/dL)153.1-44.4151.4-0.4-
HDL-Cholesterol (mg/dL)50.0-1.348.51.9-
"],"drug_interactions_table":["
Table 6: Drug Interactions with PIFELTROThis table is not all inclusive.
Concomitant Drug Class: Drug NameEffect on ConcentrationClinical Comment
↑ = increase, ↓ = decrease All other drug-drug interactions shown are anticipated based on the known metabolic and elimination pathways.
Androgen Receptors
enzalutamide↓ doravirineCo-administration is contraindicated with enzalutamide. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO.
Anticonvulsants
carbamazepine oxcarbazepine phenobarbital phenytoin↓ doravirineCo-administration is contraindicated with these anticonvulsants. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO.
Antimycobacterials
rifampinThe interaction between PIFELTRO and the concomitant drug was evaluated in a clinical study. rifapentine↓ doravirineCo-administration is contraindicated with rifampin or rifapentine. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO.
rifabutin↓ doravirineIncrease PIFELTRO dosage to one tablet twice daily when co-administered with rifabutin [see Dosage and Administration (2.2)].
Cytotoxic Agents
mitotane↓ doravirineCo-administration is contraindicated with mitotane. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO.
HIV Antiviral Agents
efavirenz etravirine nevirapine↓ doravirineUse with efavirenz, etravirine, or nevirapine is not recommended.
Herbal Products
St. John's wort↓ doravirineCo-administration is contraindicated with St. John's wort. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO.
"],"information_for_patients":["17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Severe Skin Reactions Inform patients that severe skin reactions including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) have been reported with PIFELTRO. Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking PIFELTRO and seek medical attention if a painful rash with mucosal involvement develops [see Warnings and Precautions (5.1) ] . Drug Interactions Inform patients that PIFELTRO may interact with certain other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort [see Contraindications (4) , Warnings and Precautions (5.2) , and Drug Interactions (7.1) ] . For patients concomitantly receiving rifabutin, take one tablet of PIFELTRO twice daily (approximately 12 hours apart) [see Dosage and Administration (2.2) ] . Immune Reconstitution Syndrome Inform patients that in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions (5.3) ]. Dosing Instructions Advise patients to take PIFELTRO every day at a regularly scheduled time with or without food. Inform patients that it is important not to miss or skip doses as it can result in development of resistance. If a patient forgets to take PIFELTRO, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take 2 doses at one time and to take the next dose at the regularly scheduled time. Pregnancy Registry Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in pregnant individuals exposed to PIFELTRO [see Use in Specific Populations (8.1) ]. Lactation Inform individuals with HIV-1 infection that the potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1– positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2) ] ."],"spl_unclassified_section":["Manufactured for: Merck Sharp & Dohme LLC Rahway, NJ 07065, USA For patent information: www.msd.com/research/patent The trademarks depicted herein are owned by their respective companies. Copyright © 2018-2025 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. uspi-mk1439-t-2510r008","Manufactured for: Merck Sharp & Dohme LLC Rahway, NJ 07065, USA For patent information: www.msd.com/research/patent The trademarks depicted herein are owned by their respective companies. Copyright © 2018-2024 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. usppi-mk1439-t-2411r005 For more information, go to www.PIFELTRO.com or call 1-877-888-4231. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2024"],"dosage_and_administration":["2 DOSAGE AND ADMINISTRATION Recommended dosage: One tablet taken orally once daily with or without food in adults and pediatric patients weighing at least 35 kg. ( 2.1 ) Dosage adjustment with rifabutin: One tablet taken twice daily (approximately 12 hours apart). ( 2.2 ) 2.1 Recommended Dosage The recommended dosage regimen of PIFELTRO in adults and pediatric patients weighing at least 35 kg is one 100 mg tablet taken orally once daily with or without food [see Clinical Pharmacology (12.3) ] . 2.2 Dosage Adjustment with Rifabutin If PIFELTRO is co-administered with rifabutin, increase PIFELTRO dosage to one tablet twice daily (approximately 12 hours apart) for the duration of rifabutin co-administration [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]."],"spl_product_data_elements":["PIFELTRO doravirine doravirine doravirine silicon dioxide croscarmellose sodium hypromellose acetate succinate 06081224 (3 MM2/S) microcrystalline cellulose magnesium stearate carnauba wax hypromellose, unspecified lactose monohydrate titanium dioxide triacetin logo;700"],"dosage_forms_and_strengths":["3 DOSAGE FORMS AND STRENGTHS PIFELTRO film-coated tablets are white, oval-shaped tablets, debossed with the corporate logo and 700 on one side and plain on the other side. Each tablet contains 100 mg doravirine. Tablets: 100 mg doravirine. ( 3 )"],"recent_major_changes_table":["
Warnings and Precautions, Severe Skin Reactions (5.1)11/2024
"],"spl_patient_package_insert":["Patient Information PIFELTRO ® (pih-FEL-tro) (doravirine) tablets What is PIFELTRO? PIFELTRO is a prescription medicine that is used together with other HIV-1 medicines to treat Human Immunodeficiency Virus-1 (HIV-1) infection in adults and children who weigh at least 77 pounds (35 kg): who have not received HIV-1 medicines in the past, or to replace their current HIV-1 medicines for people whose healthcare provider determines that they meet certain requirements. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). It is not known if PIFELTRO is safe and effective in children who weigh less than 77 pounds (35 kg). Who should not take PIFELTRO? Do not take PIFELTRO if you take any of the following medicines: carbamazepine oxcarbazepine phenobarbital phenytoin enzalutamide rifampin rifapentine mitotane St. John's wort Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above. If you have taken any of the medicines in the past 4 weeks, talk to your healthcare provider or pharmacist before starting treatment with PIFELTRO. What should I tell my healthcare provider before treatment with PIFELTRO? Before treatment with PIFELTRO, tell your healthcare provider about all of your medical conditions, including if you: are pregnant or plan to become pregnant. It is not known if PIFELTRO can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with PIFELTRO. Pregnancy Registry: There is a pregnancy registry for people who take PIFELTRO during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed. PIFELTRO may pass to your baby in your breast milk. Talk with your healthcare provider about the following risks to your baby from breastfeeding during treatment with PIFELTRO: the HIV-1 virus may pass to your baby if your baby does not have HIV-1 infection. the HIV-1 virus may become harder to treat if your baby has HIV-1 infection. your baby may get side effects from PIFELTRO. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with PIFELTRO . Keep a list of your medicines to show your healthcare provider and pharmacist. Tell your healthcare provider if you have taken rifabutin in the past 4 weeks. You can ask your healthcare provider or pharmacist for a list of medicines that interact with PIFELTRO. Do not start taking a new medicine without telling your healthcare provider . Your healthcare provider can tell you if it is safe to take PIFELTRO with other medicines. How do I take PIFELTRO? Take PIFELTRO every day exactly as your healthcare provider tells you to take it. Take PIFELTRO 1 time each day, at about the same time every day. If you take the medicine rifabutin during treatment with PIFELTRO, take PIFELTRO 2 times each day, about 12 hours apart, as prescribed by your healthcare provider. You may not have enough doravirine in your blood if you take rifabutin during treatment with PIFELTRO. Take PIFELTRO with or without food. Do not change your dose or stop taking PIFELTRO without talking to your healthcare provider. Stay under a healthcare provider's care when taking PIFELTRO. It is important that you do not miss or skip doses of PIFELTRO. If you miss a dose of PIFELTRO, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses of PIFELTRO at the same time. If you have any questions, call your healthcare provider or pharmacist. When your PIFELTRO supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to PIFELTRO and become harder to treat. What are the possible side effects of PIFELTRO? PIFELTRO can cause serious side effects, including: Severe skin reactions have happened in people treated with PIFELTRO. Call your healthcare provider right away if you develop a rash during treatment with PIFELTRO. Stop taking PIFELTRO and get medical help right away if you develop a painful rash with any of the following symptoms: fever, blisters or sores in the mouth, blisters or peeling of the skin, or redness or swelling of the eyes (conjunctivitis). Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine. The most common side effects of PIFELTRO include: nausea dizziness headache tiredness diarrhea stomach (abdominal) pain abnormal dreams These are not all of the possible side effects of PIFELTRO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store PIFELTRO? Store PIFELTRO tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep PIFELTRO in the original bottle. Do not take the tablets out of the bottle to store in another container, such as a pill box. Keep the bottle tightly closed to protect PIFELTRO from moisture. The PIFELTRO bottle contains a desiccant to help keep your medicine dry (protect it from moisture). Keep the desiccant in the bottle. Do not eat the desiccant. Keep PIFELTRO and all medicines out of the reach of children. General information about the safe and effective use of PIFELTRO. Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use PIFELTRO for a condition for which it was not prescribed. Do not give PIFELTRO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PIFELTRO that is written for healthcare professionals. What are the ingredients in PIFELTRO? Active ingredient: doravirine. Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablet film coating contains hypromellose, lactose monohydrate, titanium dioxide and triacetin. The coated tablets are polished with carnauba wax."],"clinical_pharmacology_table":["
Table 7: Pharmacokinetic Properties of Doravirine
ParameterDoravirine
Abbreviations: AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hours; Tmax time to Cmax; Vdss= volume of distribution at steady state, t1/2=elimination half-life; CL/F=apparent clearance; CLrenal=apparent renal clearance
General
Steady State ExposureDoravirine 100 mg once daily to participants living with HIV,Presented as geometric mean (%CV: geometric coefficient of variation)
AUC0-24 (mcg∙h/mL)16.1 (29)
Cmax (mcg/mL)0.962 (19)
C24 (mcg/mL)0.396 (63)
Time to Steady State (Days)2
Accumulation Ratio1.2 to 1.4
Absorption
Absolute Bioavailability64%
Tmax (h)2
Effect of FoodGeometric mean ratio [high-fat meal/fasting] and (90% confidence interval) for PK parameters. High fat meal is approximately 1,000 kcal, 50% fat. The effect of food is not clinically relevant.
AUC Ratio1.16 (1.06, 1.26)
Cmax Ratio1.03 (0.89, 1.19)
C24 Ratio1.36 (1.19, 1.55)
Distribution
Vdss (L)Based on IV dose60.5
Plasma Protein Binding76%
Elimination
t1/2 (h)15
CL/F (mL/min)106 (35.2)
CLrenal (mL/min)9.3 (18.6)
Metabolism
Primary Pathway(s)CYP3A
Excretion
Major Route of EliminationMetabolism
Urine (unchanged)6%
Biliary/Fecal (unchanged)Minor
","
Table 8: Steady State Pharmacokinetics for Doravirine Following Administration of Doravirine or DELSTRIGO in Pediatric Participants Living with HIV Aged 12 to Less than 18 Years and Weighing at Least 35 kg
ParameterPresented as geometric mean (%CV: geometric coefficient of variation)DoravirineFrom population PK analysis (n=53 weighing ≥45 kg, n=1 weighing ≥35 kg to <45 kg)
Abbreviations: AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hours
AUC0-24 (mcg∙h/mL)16.4 (24)
Cmax (mcg/mL)1.03 (16)
C24 (mcg/mL)0.379 (42)
","
Table 9: Drug Interactions: Changes in Pharmacokinetic Parameter Values of Doravirine in the Presence of Co-administered Drug
Co-administered DrugRegimen of Co-administered DrugNGeometric Mean Ratio (90% CI) of Doravirine Pharmacokinetics with/without Co-administered Drug (No Effect=1.00)
AUCAUC0-∞ for single-dose, AUC0-24 for once daily.CmaxC24
CI = confidence interval; QD = once daily; BID = twice daily
Azole Antifungal Agents
ketoconazoleChanges in doravirine pharmacokinetic values are not clinically relevant.400 mg QD103.06 (2.85, 3.29)1.25 (1.05, 1.49)2.75 (2.54, 2.98)
Antimycobacterials
rifampin600 mg QD100.12 (0.10, 0.15)0.43 (0.35, 0.52)0.03 (0.02, 0.04)
rifabutin300 mg QD120.50 (0.45, 0.55)0.99 (0.85, 1.15)0.32 (0.28, 0.35)
300 mg QDDoravirine 100 mg BID resulted in similar pharmacokinetic values when compared to 100 mg QD without rifabutin.151.03 (0.94, 1.14)0.97 (0.87, 1.08)0.98 (0.88, 1.10)
HIV Antiviral Agents
ritonavir,A single doravirine 50 mg dose (0.5 times the recommended approved dose) was administered.100 mg BID83.54 (3.04, 4.11)1.31 (1.17, 1.46)2.91 (2.33, 3.62)
efavirenz600 mg QDThe first day following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD.170.38 (0.33, 0.45)0.65 (0.58, 0.73)0.15 (0.10, 0.23)
600 mg QD14 days following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD.170.68 (0.58, 0.80)0.86 (0.77, 0.97)0.50 (0.39, 0.64)
"],"use_in_specific_populations":["8 USE IN SPECIFIC POPULATIONS Pediatrics: Not recommended for patients weighing less than 35 kg. ( 8.4 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary No adequate human data are available to establish whether or not PIFELTRO poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when doravirine was administered at exposures ≥8 times the exposure in humans at the recommended human dose (RHD) of PIFELTRO ( see Data ). The background rate of major birth defects is 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates individuals and infants from the limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation. Data Animal Data Doravirine was administered orally to pregnant rabbits (up to 300 mg/kg/day on gestation days (GD) 7 to 20) and rats (up to 450 mg/kg/day on GD 6 to 20 and separately from GD 6 to lactation/postpartum day 20). No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed at exposures (AUC) approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the RHD. Doravirine was transferred to the fetus through the placenta in embryo-fetal studies, with fetal plasma concentrations of up to 40% (rabbits) and 52% (rats) that of maternal concentrations observed on GD 20. 8.2 Lactation Risk Summary It is unknown whether doravirine is present in human milk, affects human milk production, or has effects on the breastfed infant. Doravirine is present in the milk of lactating rats ( see Data ). Potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1-negative infants), (2) developing viral resistance (in HIV-1-positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults. Data Doravirine was excreted into the milk of lactating rats following oral administration (450 mg/kg/day) from GD 6 to lactation day 14, with milk concentrations approximately 1.5 times that of maternal plasma concentrations observed 2 hours post dose on lactation day 14. 8.4 Pediatric Use The safety and efficacy of PIFELTRO for the treatment of HIV-1 infection have been established in pediatric patients weighing at least 35 kg [see Indications and Usage (1) and Dosage and Administration (2.1) ]. Use of PIFELTRO in this group is supported by evidence from adequate and well-controlled trials in adults and an open-label trial in virologically-suppressed or treatment-naïve pediatric participants 12 to less than 18 years of age. The safety, efficacy, and exposure of doravirine in these pediatric participants were similar to that in adults [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.3) ]. Safety and efficacy of PIFELTRO in pediatric patients weighing less than 35 kg have not been established. 8.5 Geriatric Use Clinical trials of PIFELTRO did not include sufficient numbers of participants aged 65 years and over to determine whether they respond differently from younger participants. In general, caution should be exercised in the administration of PIFELTRO in elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) ] . 8.6 Renal Impairment No dosage adjustment of PIFELTRO is required in patients with mild, moderate, or severe renal impairment. PIFELTRO has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients [see Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment No dosage adjustment of PIFELTRO is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. PIFELTRO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3) ] ."],"spl_patient_package_insert_table":["
Patient Information PIFELTRO® (pih-FEL-tro) (doravirine) tablets
What is PIFELTRO?
PIFELTRO is a prescription medicine that is used together with other HIV-1 medicines to treat Human Immunodeficiency Virus-1 (HIV-1) infection in adults and children who weigh at least 77 pounds (35 kg):who have not received HIV-1 medicines in the past, orto replace their current HIV-1 medicines for people whose healthcare provider determines that they meet certain requirements.HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). It is not known if PIFELTRO is safe and effective in children who weigh less than 77 pounds (35 kg). Who should not take PIFELTRO?
Do not take PIFELTRO if you take any of the following medicines:
carbamazepineoxcarbazepinephenobarbitalphenytoinenzalutamiderifampinrifapentinemitotaneSt. John's wort
Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above. If you have taken any of the medicines in the past 4 weeks, talk to your healthcare provider or pharmacist before starting treatment with PIFELTRO. What should I tell my healthcare provider before treatment with PIFELTRO?
Before treatment with PIFELTRO, tell your healthcare provider about all of your medical conditions, including if you:are pregnant or plan to become pregnant. It is not known if PIFELTRO can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with PIFELTRO. Pregnancy Registry: There is a pregnancy registry for people who take PIFELTRO during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.are breastfeeding or plan to breastfeed. PIFELTRO may pass to your baby in your breast milk. Talk with your healthcare provider about the following risks to your baby from breastfeeding during treatment with PIFELTRO:the HIV-1 virus may pass to your baby if your baby does not have HIV-1 infection.the HIV-1 virus may become harder to treat if your baby has HIV-1 infection.your baby may get side effects from PIFELTRO.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Some medicines interact with PIFELTRO. Keep a list of your medicines to show your healthcare provider and pharmacist.Tell your healthcare provider if you have taken rifabutin in the past 4 weeks.You can ask your healthcare provider or pharmacist for a list of medicines that interact with PIFELTRO.Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take PIFELTRO with other medicines.How do I take PIFELTRO?
Take PIFELTRO every day exactly as your healthcare provider tells you to take it.Take PIFELTRO 1 time each day, at about the same time every day.If you take the medicine rifabutin during treatment with PIFELTRO, take PIFELTRO 2 times each day, about 12 hours apart, as prescribed by your healthcare provider. You may not have enough doravirine in your blood if you take rifabutin during treatment with PIFELTRO.Take PIFELTRO with or without food.Do not change your dose or stop taking PIFELTRO without talking to your healthcare provider. Stay under a healthcare provider's care when taking PIFELTRO.It is important that you do not miss or skip doses of PIFELTRO.If you miss a dose of PIFELTRO, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses of PIFELTRO at the same time.If you have any questions, call your healthcare provider or pharmacist.When your PIFELTRO supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to PIFELTRO and become harder to treat.What are the possible side effects of PIFELTRO?
PIFELTRO can cause serious side effects, including:Severe skin reactions have happened in people treated with PIFELTRO. Call your healthcare provider right away if you develop a rash during treatment with PIFELTRO. Stop taking PIFELTRO and get medical help right away if you develop a painful rash with any of the following symptoms: fever, blisters or sores in the mouth, blisters or peeling of the skin, or redness or swelling of the eyes (conjunctivitis).Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine.The most common side effects of PIFELTRO include:
nauseadizzinessheadachetirednessdiarrheastomach (abdominal) painabnormal dreams
These are not all of the possible side effects of PIFELTRO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store PIFELTRO?
Store PIFELTRO tablets at room temperature between 68°F to 77°F (20°C to 25°C).Keep PIFELTRO in the original bottle.Do not take the tablets out of the bottle to store in another container, such as a pill box.Keep the bottle tightly closed to protect PIFELTRO from moisture.The PIFELTRO bottle contains a desiccant to help keep your medicine dry (protect it from moisture). Keep the desiccant in the bottle. Do not eat the desiccant.Keep PIFELTRO and all medicines out of the reach of children. General information about the safe and effective use of PIFELTRO.
Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use PIFELTRO for a condition for which it was not prescribed. Do not give PIFELTRO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PIFELTRO that is written for healthcare professionals. What are the ingredients in PIFELTRO?
Active ingredient: doravirine. Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablet film coating contains hypromellose, lactose monohydrate, titanium dioxide and triacetin. The coated tablets are polished with carnauba wax.
"],"package_label_principal_display_panel":["PRINCIPAL DISPLAY PANEL - 100 mg Bottle Label NDC 0006-3069-01 Pifeltro ® (doravirine) tablets 100 mg Each tablet contains 100 mg doravirine. ALERT: Find out about medicines that should NOT be taken with Pifeltro ® . Rx only 30 Tablets PRINCIPAL DISPLAY PANEL - 100 mg Bottle Label"],"carcinogenesis_and_mutagenesis_and_impairment_of_fertility":["13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Doravirine was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to 6 and 7 times, respectively, the human exposures at the RHD. A statistically significant incidence of thyroid parafollicular cell adenoma and carcinoma seen only in female rats at the high dose was within the range observed in historical controls. Mutagenesis Doravirine was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays. Impairment of fertility There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats at systemic exposures (AUC) approximately 7 times the exposure in humans at the RHD."]},"tags":[{"label":"Human Immunodeficiency Virus 1 Non-Nucleoside Analog Reverse Transcriptase Inhibitor","category":"class"},{"label":"Small Molecule","category":"modality"},{"label":"J05AG06","category":"atc"},{"label":"Oral","category":"route"},{"label":"Tablet","category":"form"},{"label":"Active","category":"status"},{"label":"Human immunodeficiency virus infection","category":"indication"},{"label":"Msd Merck Co","category":"company"},{"label":"Approved 2010s","category":"decade"}],"phase":"marketed","safety":{"boxedWarnings":[],"safetySignals":[{"llr":136.355,"date":"","count":30,"signal":"Pathogen resistance","source":"DrugCentral FAERS","actionTaken":"Reported 30 times (LLR=136)"},{"llr":122.742,"date":"","count":25,"signal":"Virologic failure","source":"DrugCentral FAERS","actionTaken":"Reported 25 times (LLR=123)"},{"llr":88.421,"date":"","count":15,"signal":"Blood HIV RNA increased","source":"DrugCentral FAERS","actionTaken":"Reported 15 times (LLR=88)"},{"llr":84.415,"date":"","count":26,"signal":"Treatment noncompliance","source":"DrugCentral FAERS","actionTaken":"Reported 26 times (LLR=84)"},{"llr":71.541,"date":"","count":22,"signal":"Drug resistance","source":"DrugCentral FAERS","actionTaken":"Reported 22 times (LLR=72)"},{"llr":65.843,"date":"","count":14,"signal":"Viral mutation identified","source":"DrugCentral FAERS","actionTaken":"Reported 14 times (LLR=66)"},{"llr":49.188,"date":"","count":6,"signal":"Viral load abnormal","source":"DrugCentral FAERS","actionTaken":"Reported 6 times (LLR=49)"}],"commonSideEffects":[{"effect":"Dizziness","drugRate":"32%","severity":"common","_validated":true},{"effect":"Fatigue","drugRate":"7%","severity":"common","_validated":true},{"effect":"Nausea","drugRate":"7%","severity":"common","_validated":true},{"effect":"Diarrhea","drugRate":"6%","severity":"common","_validated":true},{"effect":"Abdominal Pain","drugRate":"6%","severity":"common","_validated":true},{"effect":"Headache","drugRate":"5%","severity":"common","_validated":true},{"effect":"Rash","drugRate":"5%","severity":"common","_validated":true},{"effect":"Abnormal Dreams","drugRate":"5%","severity":"common","_validated":true},{"effect":"Insomnia","drugRate":"reported","severity":"unknown"},{"effect":"Somnolence","drugRate":"reported","severity":"unknown"},{"effect":"Sleep disorders and disturbances","drugRate":"reported","severity":"unknown"},{"effect":"Altered sensorium","drugRate":"reported","severity":"unknown"},{"effect":"Depression and suicide/self-injury","drugRate":"reported","severity":"unknown"},{"effect":"Neuropsychiatric adverse events","drugRate":"reported","severity":"unknown"},{"effect":"Doravirine","drugRate":"reported","severity":"unknown"},{"effect":"Asthenia","drugRate":"reported","severity":"unknown"},{"effect":"Malaise","drugRate":"reported","severity":"unknown"},{"effect":"Abdominal discomfort","drugRate":"reported","severity":"unknown"},{"effect":"Epigastric discomfort","drugRate":"reported","severity":"unknown"}],"specialPopulations":{"Lactation":"The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking potential transmission of HIV-1 infection. It is unknown whether doravirine is present in human milk, affects human milk production, or has effects on the breastfed infant.","Pregnancy":"There is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. No adequate human data are available to establish whether or not PIFELTRO poses risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when doravirine was administered at exposures >=8 times the exposure in humans at the recommended human dose (RHD) of PIFELTRO.","Geriatric use":"Clinical trials of PIFELTRO did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of PIFELTRO in elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.","Paediatric use":"The safety and efficacy of PIFELTRO for the treatment of HIV-1 infection have been established in pediatric patients weighing at least 35 kg. Use of PIFELTRO in this group is supported by evidence from adequate and well-controlled trials in adults and an open-label trial in virologically-suppressed or treatment-naive pediatric subjects 12 to less than 18 years of age."}},"trials":[],"aliases":[],"company":"Merck & Co.","patents":[{"applNo":"N210806","source":"FDA Orange Book","status":"Active","expires":"Aug 30, 2032","useCode":"U-2630","territory":"US","drugProduct":true,"patentNumber":"8486975","drugSubstance":true}],"pricing":[],"_sources":{"trials":{"url":"https://clinicaltrials.gov/search?intr=DORAVIRINE","method":"api_direct","source":"ClinicalTrials.gov","rawText":"","confidence":1,"sourceType":"ctgov","retrievedAt":"2026-04-20T06:32:31.252660+00:00"},"patents":{"url":"","method":"deterministic","source":"FDA Orange Book","rawText":"","confidence":1,"sourceType":"fda_orange_book","retrievedAt":"2026-04-20T06:32:24.648435+00:00"},"regulatory.ca":{"url":"","method":"api_direct","source":"Health Canada DPD","rawText":"","confidence":1,"sourceType":"health_canada_dpd","retrievedAt":"2026-04-20T06:32:38.086679+00:00"},"regulatory.eu":{"url":"","method":"api_direct","source":"European Medicines Agency","rawText":"","confidence":1,"sourceType":"ema_api","retrievedAt":"2026-04-20T06:32:31.279616+00:00"},"publicationCount":{"url":"https://pubmed.ncbi.nlm.nih.gov/?term=DORAVIRINE","method":"api_direct","source":"PubMed/NCBI","rawText":"","confidence":1,"sourceType":"pubmed","retrievedAt":"2026-04-20T06:32:38.881842+00:00"},"mechanism.drugClass":{"url":"https://api.fda.gov/drug/label.json","method":"deterministic","source":"FDA Label (EPC)","rawText":"","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-20T06:32:22.417340+00:00"},"administration.route":{"url":"","method":"deterministic","source":"FDA Label","rawText":"","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-20T06:32:22.417378+00:00"},"safety.boxedWarnings":{"url":"","method":"deterministic","source":"FDA Label (no boxed warning)","rawText":"","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-20T06:32:22.417385+00:00"},"mechanism.target_chembl":{"url":"","method":"api_direct","source":"ChEMBL mechanism: Human immunodeficiency virus type 1 reverse transcriptase negative allosteric modulator","rawText":"","confidence":1,"sourceType":"chembl","retrievedAt":"2026-04-20T06:32:39.519181+00:00"},"crossReferences.chemblId":{"url":"https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL2364608/","method":"api_direct","source":"ChEMBL (EMBL-EBI)","rawText":"","confidence":1,"sourceType":"chembl","retrievedAt":"2026-04-20T06:32:39.370474+00:00"},"regulatory.fda_application":{"url":"","method":"deterministic","source":"FDA Label","rawText":"NDA210806","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-20T06:32:22.417390+00:00"}},"allNames":"pifeltro","offLabel":[],"synonyms":["doravirine","pifeltro","MK-1439"],"timeline":[{"date":"2018-01-01","type":"neutral","source":"FDA Orange Book","milestone":"Rights transferred from MSD MERCK CO to Msd Merck Co"},{"date":"2018-08-30","type":"positive","source":"DrugCentral","milestone":"FDA approval (Msd Merck Co)"},{"date":"2018-11-22","type":"positive","source":"DrugCentral","milestone":"EMA approval (Merck Sharp & Dohme B.V.)"},{"date":"2020-01-14","type":"positive","source":"DrugCentral","milestone":"PMDA approval (Msd K.K.)"},{"date":"2032-08-30","type":"negative","source":"FDA Orange Book","milestone":"Substance patent 8486975 expires"}],"approvals":[{"date":"2018-08-30","orphan":false,"company":"MSD MERCK CO","regulator":"FDA"},{"date":"2018-11-22","orphan":false,"company":"MERCK SHARP & DOHME B.V.","regulator":"EMA"},{"date":"2020-01-14","orphan":true,"company":"MSD K.K.","regulator":"PMDA"}],"brandName":"Pifeltro","ecosystem":[{"indication":"Human immunodeficiency virus infection","otherDrugs":[{"name":"abacavir","slug":"abacavir","company":"Viiv Hlthcare"},{"name":"amprenavir","slug":"amprenavir","company":"Glaxosmithkline"},{"name":"atazanavir","slug":"atazanavir","company":"Bristol Myers Squibb"},{"name":"bictegravir","slug":"bictegravir","company":"Gilead Sciences Inc"}],"globalPrevalence":null}],"mechanism":{"novelty":"Follow-on","moaClass":"Non-Nucleoside Reverse Transcriptase Inhibitors","modality":"Small Molecule","drugClass":"Human Immunodeficiency Virus 1 Non-Nucleoside Analog Reverse Transcriptase Inhibitor [EPC]","explanation":"Doravirine is an antiretroviral drug [see Microbiology (12.4)].","oneSentence":"Pifeltro works by blocking the reverse transcriptase enzyme, which is essential for the replication of the HIV virus.","technicalDetail":"Pifeltro (Doravirine) is a non-nucleoside analog reverse transcriptase inhibitor that binds to the reverse transcriptase enzyme, specifically to the non-nucleoside binding site, and inhibits its activity, thereby blocking the replication of the HIV virus."},"commercial":{"launchDate":"2018","_launchSource":"DrugCentral (FDA 2018-08-30, MSD MERCK CO)"},"references":[{"id":1,"url":"https://drugcentral.org/drugcard/5295","fields":["approvals","synonyms","ATC","PK","indications","contraindications","DDIs","targets","patents","FAERS"],"source":"DrugCentral"},{"id":2,"url":"https://clinicaltrials.gov/search?intr=DORAVIRINE","fields":["trials"],"source":"ClinicalTrials.gov"},{"id":3,"url":"https://pubmed.ncbi.nlm.nih.gov/?term=DORAVIRINE","fields":["publications"],"source":"PubMed/NCBI"},{"id":4,"url":"https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-data-files","fields":["patents","exclusivity","genericManufacturers"],"source":"FDA Orange Book"}],"_emaChecked":true,"_enrichedAt":"2026-03-30T10:49:37.494410","_validation":{"fieldsValidated":0,"lastValidatedAt":"2026-04-20T06:32:46.094467+00:00","fieldsConflicting":0,"overallConfidence":0.95},"biosimilars":[],"competitors":[{"drugName":"nevirapine","drugSlug":"nevirapine","fdaApproval":"1996-06-21","patentExpiry":"Mar 12, 2029","patentStatus":"Patent protected","relationship":"same-class"},{"drugName":"delavirdine","drugSlug":"delavirdine","fdaApproval":"1997-04-04","patentStatus":"Unknown","relationship":"same-class"},{"drugName":"efavirenz","drugSlug":"efavirenz","fdaApproval":"1998-09-17","genericCount":8,"patentStatus":"Off-patent — generic available","relationship":"same-class"},{"drugName":"etravirine","drugSlug":"etravirine","fdaApproval":"2008-01-18","genericCount":3,"patentStatus":"Off-patent — generic available","relationship":"same-class"},{"drugName":"rilpivirine","drugSlug":"rilpivirine","fdaApproval":"2011-05-20","patentExpiry":"Oct 23, 2037","patentStatus":"Patent protected","relationship":"same-class"}],"genericName":"doravirine","indications":{"approved":[{"name":"Human immunodeficiency virus infection","source":"DrugCentral","snomedId":86406008,"regulator":"FDA","eligibility":{"with no prior antiretroviral treatment history":"","to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine":{"age":"adults and pediatric patients weighing at least 35 kg","resistance":"no known substitutions associated with resistance to doravirine","viral load":"HIV-1 RNA less than 50 copies per mL","prior treatment":"no prior antiretroviral treatment history","treatment failure":"no history of treatment failure"}}}],"offLabel":[],"pipeline":[]},"currentOwner":"Msd Merck Co","drugCategory":"active","labelChanges":[],"relatedDrugs":[{"drugId":"nevirapine","brandName":"nevirapine","genericName":"nevirapine","approvalYear":"1996","relationship":"same-class"},{"drugId":"delavirdine","brandName":"delavirdine","genericName":"delavirdine","approvalYear":"1997","relationship":"same-class"},{"drugId":"efavirenz","brandName":"efavirenz","genericName":"efavirenz","approvalYear":"1998","relationship":"same-class"},{"drugId":"etravirine","brandName":"etravirine","genericName":"etravirine","approvalYear":"2008","relationship":"same-class"},{"drugId":"rilpivirine","brandName":"rilpivirine","genericName":"rilpivirine","approvalYear":"2011","relationship":"same-class"}],"trialDetails":[{"nctId":"NCT04223791","phase":"PHASE3","title":"Switch to Doravirine/Islatravir (DOR/ISL) in Human Immunodeficiency Virus 1 (HIV-1) Participants Treated With Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF) (MK-8591A-018)","status":"COMPLETED","sponsor":"Merck Sharp & Dohme LLC","startDate":"2020-02-18","conditions":["HIV Infection"],"enrollment":643,"completionDate":"2025-02-27"},{"nctId":"NCT04375800","phase":"PHASE2","title":"Doravirine (DOR) in Human Immunodeficiency Virus (HIV)-Infected Children Aged 4 Weeks to <12 Years and <45 kg (MK-1439-066)","status":"RECRUITING","sponsor":"Merck Sharp & Dohme LLC","startDate":"2021-02-03","conditions":["Human Immunodeficiency Virus (HIV) Infection"],"enrollment":84,"completionDate":"2034-04-11"},{"nctId":"NCT07086079","phase":"PHASE1","title":"A Study of Doravirine/Islatravir in Healthy Lactating Females (MK-8591A-061)","status":"COMPLETED","sponsor":"Merck Sharp & Dohme LLC","startDate":"2025-09-26","conditions":["Healthy"],"enrollment":12,"completionDate":"2026-02-04"},{"nctId":"NCT05630638","phase":"PHASE4","title":"Doravirine Dose Optimisation in Pregnancy","status":"RECRUITING","sponsor":"University of Liverpool","startDate":"2023-10-10","conditions":["HIV"],"enrollment":76,"completionDate":"2028-07"},{"nctId":"NCT04223778","phase":"PHASE3","title":"Safety and Efficacy of a Switch to Doravirine/Islatravir in Participants With HIV-1 (MK-8591A-017)","status":"COMPLETED","sponsor":"Merck Sharp & Dohme LLC","startDate":"2020-02-18","conditions":["HIV Infection"],"enrollment":672,"completionDate":"2024-08-26"},{"nctId":"NCT04820933","phase":"EARLY_PHASE1","title":"Doravirine Versus Integrase Inhibitors on Backbone of Emtricitabine and Tenofovir Alafenamide in HIV","status":"COMPLETED","sponsor":"University of Texas Southwestern Medical Center","startDate":"2024-03-01","conditions":["HIV I Infection","Cardiovascular Risk Factor","Lipid Metabolism Disorders"],"enrollment":26,"completionDate":"2025-12-01"},{"nctId":"NCT04233879","phase":"PHASE3","title":"Study of Doravirine/Islatravir (DOR/ISL 100 mg/0.75 mg) to Evaluate the Antiretroviral Activity, Safety, and Tolerability in Treatment-Naïve Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Infection (MK-8591A-020)","status":"COMPLETED","sponsor":"Merck Sharp & Dohme LLC","startDate":"2020-02-28","conditions":["HIV-1 Infection"],"enrollment":599,"completionDate":"2025-01-29"},{"nctId":"NCT07357584","phase":"PHASE4","title":"Efficacy and Safety of Doravirine in the Rapid Initiation","status":"NOT_YET_RECRUITING","sponsor":"Fundación Huésped","startDate":"2026-07-13","conditions":["HIV-1-infection"],"enrollment":100,"completionDate":"2028-01-13"},{"nctId":"NCT06203132","phase":"PHASE3","title":"DORAvirine Versus DOlutegravir Based Antiretroviral Regimens in Treatment-naïve People Living With HIV-1 Infection","status":"RECRUITING","sponsor":"ANRS, Emerging Infectious Diseases","startDate":"2025-01-27","conditions":["HIV-1-infection"],"enrollment":610,"completionDate":"2027-11"},{"nctId":"NCT05421806","phase":"","title":"A Cohort Study of Use of Doravirine (DOR) Based Regimens in Clinical Practice 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Weekly Islatravir/Lenacapavir Regimen With Standard of Care in Virologically Suppressed People With HIV-1","status":"ACTIVE_NOT_RECRUITING","sponsor":"Gilead Sciences","startDate":"2024-10-08","conditions":["HIV-1-Infection"],"enrollment":600,"completionDate":"2030-08"},{"nctId":"NCT04518228","phase":"","title":"Pharmacokinetic Properties of Antiretroviral and Anti-Tuberculosis Drugs During Pregnancy and Postpartum","status":"COMPLETED","sponsor":"National Institute of Allergy and Infectious Diseases (NIAID)","startDate":"2021-09-01","conditions":["HIV Infections","Tuberculosis"],"enrollment":205,"completionDate":"2025-07-10"},{"nctId":"NCT05705349","phase":"PHASE3","title":"DOR/ISL in HIV-1 Antiretroviral Treatment-naïve Participants (MK-8591A-053)","status":"ACTIVE_NOT_RECRUITING","sponsor":"Merck Sharp & Dohme LLC","startDate":"2023-03-08","conditions":["HIV-1 Infection"],"enrollment":537,"completionDate":"2029-08-05"},{"nctId":"NCT05502341","phase":"PHASE2,PHASE3","title":"Study to Compare Bictegravir/Lenacapavir Versus Current Therapy in People With HIV-1 Who Are Successfully Treated With a Complicated Regimen","status":"ACTIVE_NOT_RECRUITING","sponsor":"Gilead Sciences","startDate":"2022-08-16","conditions":["HIV-1-infection"],"enrollment":689,"completionDate":"2028-07"},{"nctId":"NCT04233372","phase":"PHASE4","title":"Evaluation of (Doravirine / Lamivudine / Tenofovir Disoproxil Fumarate) (Delstrigo®) as a New Strategy for Non-occupational Post Exposure Prophylaxis, a Prospective Open Label Study","status":"COMPLETED","sponsor":"Hospital Clinic of Barcelona","startDate":"2020-08-27","conditions":["Hiv"],"enrollment":399,"completionDate":"2022-07-28"},{"nctId":"NCT07075146","phase":"PHASE3","title":"DOR/TDF/3TC COmpared With BIC/FTC/TAF in ART-Naïve People Living With HIV and Overweight or Obesity","status":"RECRUITING","sponsor":"José Antonio Mata Marín","startDate":"2025-05-05","conditions":["HIV - Human Immunodeficiency Virus","Obesity","Overweight and/or Obesity"],"enrollment":306,"completionDate":"2028-08-01"},{"nctId":"NCT06034938","phase":"PHASE2","title":"DOR/TDF/3TC Switch With M184V/I in People With Controlled HIV (Drive Off-Road)","status":"RECRUITING","sponsor":"University Hospital, Caen","startDate":"2024-02-08","conditions":["Hiv"],"enrollment":32,"completionDate":"2026-05-01"},{"nctId":"NCT04665375","phase":"PHASE4","title":"Can INSTI-associated Weight Gain be Halted or Reversed With a Switch to Doravirine/Lamivudine/Tenofovir DF?","status":"TERMINATED","sponsor":"University Health Network, Toronto","startDate":"2021-04-26","conditions":["Hiv","Weight Gain"],"enrollment":4,"completionDate":"2024-03-31"},{"nctId":"NCT04636437","phase":"PHASE4","title":"Doravirine for Obese Persons on Integrase Inhibitors and Tenofovir Alafenamide","status":"COMPLETED","sponsor":"Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections","startDate":"2021-07-27","conditions":["HIV 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