SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationPIFELTRO(TM) (pih-FEL-tro) (doravirine) tabletsWhat is PIFELTROPIFELTRO is 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. Johns wortAsk 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 weeks, talk to your healthcare provider or pharmacist before starting treatment with PIFELTRO. What should 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 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. Do not breastfeed if you take PIFELTRO.You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.It is not known if PIFELTRO can pass into your breast milk.Talk with your healthcare provider about the best way to feed your baby. 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 list of your medicines to show your healthcare provider and pharmacist.Tell your healthcare provider if you have taken rifabutin in the past weeks.You can ask your healthcare provider or pharmacist for list of medicines that interact with PIFELTRO.Do not start taking 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 take PIFELTRO Take PIFELTRO every day exactly as your healthcare provider tells you to take it.Take PIFELTRO time each day, at about the same time every day.If you take the medicine rifabutin during treatment with PIFELTRO, take PIFELTRO 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 healthcare providers care when taking PIFELTRO.It is important that you do not miss or skip doses of PIFELTRO.If you miss 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 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 short time. The virus may develop resistance to PIFELTRO and become harder to treat.What are the possible side effects of PIFELTROPIFELTRO can cause serious side effects, including: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 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 dreamsThese are not all 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 store PIFELTRO Store PIFELTRO tablets at room temperature between 68F to 77F (20C to 25C).Keep PIFELTRO in the original bottle.Do not take the tablets out of the bottle to store in another container, such as pill box.Keep the bottle tightly closed to protect PIFELTRO from moisture.The PIFELTRO bottle contains 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 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.. 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.. carbamazepine. oxcarbazepine. phenobarbital. phenytoin. enzalutamide. rifampin. rifapentine. mitotane. St. Johns wort. 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 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. Do not breastfeed if you take PIFELTRO.You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.It is not known if PIFELTRO can pass into your breast milk.Talk with your healthcare provider about the best way to feed your baby. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. It is not known if PIFELTRO can pass into your breast milk.. Talk with your healthcare provider about the best way to feed your baby.. Some medicines interact with PIFELTRO. Keep list of your medicines to show your healthcare provider and pharmacist.. Tell your healthcare provider if you have taken rifabutin in the past weeks.. You can ask your healthcare provider or pharmacist for list of medicines that interact with PIFELTRO.. Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take PIFELTRO with other medicines.. Take PIFELTRO every day exactly as your healthcare provider tells you to take it.. Take PIFELTRO time each day, at about the same time every day.. If you take the medicine rifabutin during treatment with PIFELTRO, take PIFELTRO 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 healthcare providers care when taking PIFELTRO.. It is important that you do not miss or skip doses of PIFELTRO.. If you miss 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 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 short time. The virus may develop resistance to PIFELTRO and become harder to treat.. 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 long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine.. nausea. dizziness. headache. tiredness. diarrhea. stomach (abdominal) pain. abnormal dreams. Store PIFELTRO tablets at room temperature between 68F to 77F (20C to 25C).. Keep PIFELTRO in the original bottle.. Do not take the tablets out of the bottle to store in another container, such as pill box.. Keep the bottle tightly closed to protect PIFELTRO from moisture.. The PIFELTRO bottle contains desiccant to help keep your medicine dry (protect it from moisture). Keep the desiccant in the bottle. Do not eat the desiccant.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of the labeling:Immune Reconstitution Syndrome [see Warnings and Precautions (5.2)] Immune Reconstitution Syndrome [see Warnings and Precautions (5.2)] 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 .. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 HistoryThe 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 subjects 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 subjects 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 subjects in any treatment group in DRIVE-FORWARD and DRIVE-AHEAD are presented in Table 1.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 or higher (moderate or severe) occurred in >= 2% of subjects treated with doravirine. of Subjects in Any Treatment Group in Adults with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 96)DRIVE-FORWARDDRIVE-AHEADPIFELTRO+2 NRTIsNRTI nucleoside reverse transcriptase inhibitor. Once DailyN=383DRV+r+2 NRTIs Once DailyN=383DELSTRIGOOnce DailyN=364EFV/FTC/TDFOnce DailyN=364NRTIs FTC/TDF or ABC/3TC.Fatigue: includes fatigue, asthenia, malaiseAbdominal Pain: includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, epigastric discomfortRash: includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustularNausea7%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%The majority (77%) of adverse reactions associated with doravirine occurred at severity Grade (mild).. Neuropsychiatric Adverse EventsFor DRIVE-AHEAD, the analysis of subjects with neuropsychiatric adverse events by Week 48 is presented in Table 2. The proportion of subjects 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 subjects compared to EFV/FTC/TDF-treated subjects 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 Subjects with Neuropsychiatric Adverse EventsAll causality and all grade events were included in the analysis. (Week 48)DELSTRIGOOnce DailyN=364EFV/FTC/TDFOnce DailyN=364Treatment DifferenceDELSTRIGO EFV/FTC/TDFEstimate (95% CI)The 95% CIs were calculated using Miettinen and Nurminens 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)Neuropsychiatric adverse events in the pre-defined category of depression and suicide/self-injury were reported in 4% and 7% of subjects, in the DELSTRIGO and EFV/FTC/TDF groups, respectively.In DRIVE-AHEAD through 48 weeks of treatment, the majority of subjects 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 subjects reported these events in the first 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 subjects in the DELSTRIGO and EFV/FTC/TDF groups, respectively. The proportion of subjects who reported neuropsychiatric adverse events through Week 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 AbnormalitiesThe percentages of subjects with selected laboratory abnormalities (that represent 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 Subjects with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 96)DRIVE-FORWARDDRIVE-AHEADLaboratory Parameter Preferred Term (Unit)/LimitPIFELTRO+2 NRTIsOnce DailyN=383DRV+r+2 NRTIsOnce DailyN=383DELSTRIGOOnce DailyN=364EFV/FTC/TDFOnce DailyN=364Blood ChemistryEach subject is only counted once per parameter at the highest toxicity grade. Only subjects with baseline value and at least one on-treatment value for given laboratory parameter are included.ULN Upper limit of normal range.Note: NRTIs FTC/TDF or ABC/3TC.Total bilirubin1.1 < 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%Lipase1.5 <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%. Change in Lipids from BaselineFor 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 Subjects with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 48)Subjects 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). Subjects initiating 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-FORWARDPIFELTRO+2 NRTIsOnce DailyN=320DRV+r+2 NRTIsOnce DailyN=311Laboratory 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-AHEADDELSTRIGO Once DailyN=320EFV/FTC/TDF Once DailyN=307Laboratory 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-. Adverse Reactions in Virologically-Suppressed AdultsThe safety of DELSTRIGO in virologically-suppressed adults was based on Week 48 data from 670 subjects in the DRIVE-SHIFT trial (Protocol 024), randomized, international, multicenter, open-label trial in which virologically-suppressed subjects were switched from baseline regimen consisting of two NRTIs in combination with protease inhibitor (PI) plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or non-nucleoside reverse transcriptase inhibitor (NNRTI) to DELSTRIGO. Overall, the safety profile in virologically-suppressed adult subjects was similar to that in subjects with no antiretroviral treatment history.. Laboratory Abnormalities. Serum ALT and AST Elevations: In the DRIVE-SHIFT trial, 22% and 16% of subjects 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 subjects had ALT or AST elevations greater than x 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 subjects 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 BaselineChanges from baseline at Week 24 in LDL-cholesterol, non-HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol in subjects on 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 Subjects on PI plus Ritonavir-based Regimen at Baseline in DRIVE-SHIFT (Week 24)Laboratory Parameter Preferred TermDELSTRIGO(Week 0-24)Once DailyN=244PI+ritonavir(Week 0-24)Once DailyN=124Difference EstimatesBaselineChangeBaselineChangeDifference (95% CI)Subjects on lipid-lowering agents at baseline were excluded from these analyses (DELSTRIGO n=26 and PI+ritonavir n=13).Subjects initiating 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-Adverse Reactions in Pediatric PatientsThe safety of doravirine as component of DELSTRIGO was evaluated in 45 HIV-1-infected virologically-suppressed or treatment-naive pediatric patients 12 to less than 18 years of age through Week 24 in an open-label trial (IMPAACT 2014 (Protocol 027)) [see Clinical Studies (14.3)]. The safety profile in pediatric subjects was similar to that in adults. There were no serious or Grade or adverse reactions. No subjects discontinued due to an adverse event.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Doravirine is an antiretroviral drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics. In Phase trial evaluating doravirine over dose range of 0.25 to times the recommended dose of PIFELTRO, (in combination with FTC/TDF) in HIV-1-infected subjects with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine.. Cardiac ElectrophysiologyAt doravirine dose of 1200 mg, which provides approximately 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 subjects and HIV-1-infected subjects. Doravirine pharmacokinetics are provided in Table 7.Table 7: Pharmacokinetic Properties of DoravirineParameterDoravirineAbbreviations: 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 clearanceGeneral Steady State Exposure Doravirine 100 mg once daily to HIV-1-infected subjects ,Presented as geometric mean (%CV: geometric coefficient of variation) AUC0-24 (mcgh/mL)16.1 (29)Cmax (mcg/mL)0.962 (19)C24 (mcg/mL)0.396 (63) Time to Steady State (Days) Accumulation Ratio 1.2 to 1.4AbsorptionAbsolute 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)DistributionVdss (L)Based on IV dose 60.5Plasma Protein Binding76%Eliminationt1/2 (h)15CL/F (mL/min) 106 (35.2)CLrenal (mL/min) 9.3 (18.6) Metabolism Primary Pathway(s)CYP3A Excretion Major Route of EliminationMetabolismUrine (unchanged)6%Biliary/Fecal (unchanged)Minor. Specific PopulationsIn 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 ImpairmentIn study comparing subjects with severe renal impairment to subjects without renal impairment, the single dose exposure of doravirine was 43% higher in subjects with severe renal impairment. In population pharmacokinetic analysis, renal function did not have 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 ImpairmentNo clinically significant difference in the pharmacokinetics of doravirine was observed in subjects with moderate hepatic impairment (Child-Pugh score B) compared to subjects without hepatic impairment. Doravirine has not been studied in subjects 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 patients 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 patients weighing >= 35 kg and 45 kg who receive doravirine 100 mg or DELSTRIGO, the population pharmacokinetic model-predicted mean C24 of doravirine was comparable to that achieved in adults, whereas mean AUC0-24 and Cmax of doravirine were 25% and 36% higher than adult values, respectively. However, the predicted AUC0-24 and Cmax increases are not considered clinically significant.Table 8: Steady State Pharmacokinetics for Doravirine Following Administration of Doravirine or DELSTRIGO in HIV-1-Infected Pediatric Patients Aged 12 to Less than 18 Years and Weighing at Least 35 kgParameterPresented 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 hoursAUC0-24 (mcgh/mL)16.4 (24)Cmax (mcg/mL)1.03 (16)C24 (mcg/mL)0.379 (42). Drug Interaction StudiesDoravirine 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 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 (Cmax, AUC, and C24) of doravirine are summarized in Table 9. 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 DrugCo-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. Cmax C24 CI confidence interval; QD once daily; BID twice dailyAzole Antifungal AgentsketoconazoleChanges 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)Antimycobacterialsrifampin600 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 Agentsritonavir 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)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 ActionDoravirine is 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% (IC50) of doravirine for RNA-dependent DNA polymerization of recombinant wild-type HIV-1 RT in biochemical assay was 12.2+-2.0 nM (n=3). Doravirine does not inhibit the human cellular DNA polymerases , and mitochondrial DNA polymerase .. Antiviral Activity in Cell CultureDoravirine exhibited an EC50 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 median EC50 value for HIV-1 subtype primary isolates (n=118) of 4.1 nM (range: 1.0 nM-16.0 nM). Doravirine demonstrated antiviral activity against broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC50 values ranging from 1.2 nM to 10.0 nM.. Antiviral Activity in Combination with other HIV Antiviral AgentsThe 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 CultureDoravirine-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, and F227C conferred greater decreases in susceptibility to doravirine than Y318F alone, which conferred 10-fold reduction in susceptibility to doravirine.. In Clinical Trials. Clinical Trial Results in Adults with No Antiretroviral Treatment HistoryIn the doravirine treatment arms of the DRIVE-FORWARD and DRIVE-AHEAD trials (n=747) through Week 96, 13 subjects showed the emergence of doravirine resistance-associated substitutions in their HIV among 36 (36%) subjects in the resistance analysis subset (subjects 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%) subjects with emergent doravirine resistance-associated substitutions showed doravirine phenotypic resistance and most of them had at least 100-fold reduction in doravirine susceptibility (range >95- to >211-fold reduction in doravirine susceptibility). The other 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 subjects in the resistance analysis subset, 10 subjects (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 (n=7).In the DRV/r treatment arm of the DRIVE-FORWARD trial (n=383) through Week 96, no subjects showed the emergence of darunavir resistance-associated substitutions among 15 subjects with resistance data and of the subjects 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 subjects showed the emergence of efavirenz resistance-associated substitutions among 25 (60%) subjects in the resistance analysis subset and genotypic resistance to emtricitabine or tenofovir developed in evaluable subjects; emergent resistance-associated substitutions were RT K65R (n=1), D67G/K70E (n=1), L74V/V75M/V118I (n=1), M184I or (n=5), and K219K/E (n=1).. Clinical Trial Results in Virologically-Suppressed AdultsIn the DRIVE-SHIFT clinical trial [see Clinical Studies (14.2)], there were subjects in the immediate switch group (n=447) and subjects 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 virologic failure subjects 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 subjects 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-ResistanceCross-resistance has been observed among NNRTIs. Treatment-emergent doravirine resistance-associated substitutions can confer cross-resistance to efavirenz, etravirine, nevirapine, and rilpivirine. Of the virologic failure subjects who developed doravirine phenotypic resistance, all had phenotypic resistance to nevirapine, had phenotypic resistance to efavirenz, had phenotypic resistance to rilpivirine, and had resistance to etravirine in the Monogram PhenoSense assay. Of the 11 virologic failure subjects in DRIVE-AHEAD phenotypically resistant to efavirenz, (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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Clinical 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 trials (DRIVE-FORWARD, NCT02275780 and DRIVE-AHEAD, NCT02403674) in HIV-1-infected subjects with no antiretroviral treatment history (n=1494).In DRIVE-FORWARD, 766 subjects were randomized and received at least 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 subjects was 33 years, 16% were female, 27% were non-white, 4% had hepatitis and/or virus co-infection, 10% had history of AIDS, 20% had HIV-1 RNA greater than 100,000 copies/mL, 86% had CD4+ T-cell count greater than 200 cells/mm3, 13% received ABC/3TC, and 87% received FTC/TDF; these characteristics were similar between treatment groups.In DRIVE-AHEAD, 728 subjects were randomized and received at least 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 subjects was 31 years, 15% were female, 52% were non-white, 3% had hepatitis or co-infection, 14% had 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/mm3; 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/mm3, 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/mm3, respectively.Table 10: Virologic Outcome in DRIVE-FORWARD and DRIVE-AHEAD at Week 96 in HIV-1 Adults with No Antiretroviral Treatment HistoryOutcomeDRIVE-FORWARDDRIVE-AHEADPIFELTRO 2 NRTIsOnce DailyDRV+r 2 NRTIsOnce DailyDELSTRIGOOnce DailyEFV/FTC/TDF Once DailyN=383N=383N=364N=364Note: NRTIs FTC/3TC 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 subjects who discontinued study drug or study before Week 96 for lack or loss of efficacy and subjects 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 subjects 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 subject. 7%9%4%5% On study but missing data in window2%3%1%1%Proportion (%) of Subjects With HIV-1 RNA <50 copies/mL at Week 96 by Baseline and Demographic CategoryGender 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 subjects 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/mm3 62% (N 42)51% (N 67)59% (N 44)70% (N 46) >200 cells/mm3 74% (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). 14.2Clinical Trial Results in Virologically-Suppressed Adults. The efficacy of switching from baseline regimen consisting of two NRTIs in combination with PI plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI to DELSTRIGO was evaluated in randomized, open-label trial (DRIVE-SHIFT, NCT02397096), in virologically-suppressed HIV-1-infected adults. Subjects must have been virologically-suppressed (HIV-1 RNA 50 copies/mL) on their baseline regimen for at least months prior to trial entry, with no history of virologic failure. Subjects 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 subjects was 43 years, 16% were female, and 24% were Non-White, 21% were of Hispanic or Latino ethnicity, 3% had hepatitis and/or virus co-infection, 17% had history of AIDS, 96% had CD4+ T-cell count greater than or equal to 200 cells/mm3, 70% were on regimen containing PI plus ritonavir, 24% were on regimen containing an NNRTI, 6% were on regimen containing elvitegravir plus cobicistat, and 1% were on regimen containing 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 Subjects Who Switched to DELSTRIGOOutcomeDELSTRIGOOnce Daily ISGWeek 48N=447Baseline RegimenDSGWeek 24N=223HIV-1 RNA >= 50 copies/mLIncludes subjects who discontinued study drug or study before Week 48 for ISG or before Week 24 for DSG for lack or loss of efficacy and subjects 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 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 subjects 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 subject. 4%4% On study but missing data in window00Proportion (%) of Subjects With HIV-1 RNA <50 copies/mL by Baseline and Demographic CategoryAge (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/mm3 85% (N 13)75% (N 4) >=200 cells/mm3 91% (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). 14.3 Clinical Trial Results in Pediatric Patients. The efficacy of DELSTRIGO (DOR/3TC/TDF) was evaluated in cohort of an open-label, single-arm 2-cohort trial in HIV-1-infected pediatric patients 12 to less than 18 years of age (IMPAACT 2014 (Protocol 027), NCT03332095). In cohort 1, virologically-suppressed subjects (n=9) received single 100 mg dose of PIFELTRO followed by intensive PK sampling. In cohort 2, virologically-suppressed subjects (n=43) were switched to DELSTRIGO and treatment-naive subjects (n=2) were started on DELSTRIGO. In cohort 2, at baseline the median age of subjects 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 mm3 (range 84 to 1397). After switching to DELSTRIGO, 95% (41/43) of virologically-suppressed subjects remained suppressed (HIV-1 RNA <50 copies/mL) at Week 24. One of the two treatment-naive subjects achieved HIV-1 RNA <50 copies/mL at Week 24. The other treatment-naive subject met the protocol-defined virologic failure criteria (defined as 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. (8.2)Pediatrics: Not recommended for patients weighing less than 35 kg. (8.4). Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. (8.2). Pediatrics: Not recommended for patients weighing less than 35 kg. (8.4). 8.1 Pregnancy. Pregnancy Exposure RegistryThere 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.. Risk SummaryNo 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 (see Data ).The background rate of major birth defects is 2.7% in 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 DataDoravirine was administered orally to pregnant rabbits (up to 300 mg/kg/day on gestation days (GD) to 20) and rats (up to 450 mg/kg/day on GD to 20 and separately from GD 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 times (rats) and 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 gestation day 20.. 8.2 Lactation. Risk SummaryThe 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. Doravirine is present in the milk of lactating rats (see Data ). Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in breastfed infant, instruct mothers not to breastfeed if they are receiving PIFELTRO.. DataDoravirine was excreted into the milk of lactating rats following oral administration (450 mg/kg/day) from gestation day to lactation day 14, with milk concentrations approximately 1.5 times that of maternal plasma concentrations observed 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-naive pediatric subjects 12 to less than 18 years of age. The safety, efficacy, and exposure of doravirine in these pediatric subjects 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 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 [see Clinical Pharmacology (12.3)].. 8.6Renal 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)].. 8.7Hepatic 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)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Consult the full prescribing information prior to and during treatment for important potential drug-drug interactions. (4, 5.1, 7). 7.1Effect of Other Drugs on PIFELTRO. Co-administration of PIFELTRO with CYP3A inducer decreases doravirine plasma concentrations, which may reduce PIFELTRO efficacy [see Contraindications (4), Warnings and Precautions (5.1), 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 shows significant drug interactions with PIFELTRO.Table 6: Drug Interactions with PIFELTROThis table is not all inclusive. Concomitant Drug Class:Drug NameEffect on ConcentrationClinical Comment increase, decreaseAll other drug-drug interactions shown are anticipated based on the known metabolic and elimination pathways.Androgen Receptorsenzalutamide doravirineCo-administration is contraindicated with enzalutamide.At least 4-week cessation period is recommended prior to initiation of PIFELTRO.Anticonvulsantscarbamazepineoxcarbazepinephenobarbitalphenytoin doravirineCo-administration is contraindicated with these anticonvulsants.At least 4-week cessation period is recommended prior to initiation of PIFELTRO.AntimycobacterialsrifampinThe interaction between PIFELTRO and the concomitant drug was evaluated in clinical study. rifapentine doravirineCo-administration is contraindicated with rifampin or rifapentine. At least 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 Agentsmitotane doravirineCo-administration is contraindicated with mitotane.At least 4-week cessation period is recommended prior to initiation of PIFELTRO.HIV Antiviral Agentsefavirenz etravirinenevirapine doravirineUse with efavirenz, etravirine, or nevirapine is not recommended.Herbal ProductsSt. Johns wort doravirineCo-administration is contraindicated with St. Johns wort.At least 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)]. 7.2Effect 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)].

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionDoravirine is 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% (IC50) of doravirine for RNA-dependent DNA polymerization of recombinant wild-type HIV-1 RT in biochemical assay was 12.2+-2.0 nM (n=3). Doravirine does not inhibit the human cellular DNA polymerases , and mitochondrial DNA polymerase .. Antiviral Activity in Cell CultureDoravirine exhibited an EC50 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 median EC50 value for HIV-1 subtype primary isolates (n=118) of 4.1 nM (range: 1.0 nM-16.0 nM). Doravirine demonstrated antiviral activity against broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC50 values ranging from 1.2 nM to 10.0 nM.. Antiviral Activity in Combination with other HIV Antiviral AgentsThe 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 CultureDoravirine-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, and F227C conferred greater decreases in susceptibility to doravirine than Y318F alone, which conferred 10-fold reduction in susceptibility to doravirine.. In Clinical Trials. Clinical Trial Results in Adults with No Antiretroviral Treatment HistoryIn the doravirine treatment arms of the DRIVE-FORWARD and DRIVE-AHEAD trials (n=747) through Week 96, 13 subjects showed the emergence of doravirine resistance-associated substitutions in their HIV among 36 (36%) subjects in the resistance analysis subset (subjects 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%) subjects with emergent doravirine resistance-associated substitutions showed doravirine phenotypic resistance and most of them had at least 100-fold reduction in doravirine susceptibility (range >95- to >211-fold reduction in doravirine susceptibility). The other 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 subjects in the resistance analysis subset, 10 subjects (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 (n=7).In the DRV/r treatment arm of the DRIVE-FORWARD trial (n=383) through Week 96, no subjects showed the emergence of darunavir resistance-associated substitutions among 15 subjects with resistance data and of the subjects 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 subjects showed the emergence of efavirenz resistance-associated substitutions among 25 (60%) subjects in the resistance analysis subset and genotypic resistance to emtricitabine or tenofovir developed in evaluable subjects; emergent resistance-associated substitutions were RT K65R (n=1), D67G/K70E (n=1), L74V/V75M/V118I (n=1), M184I or (n=5), and K219K/E (n=1).. Clinical Trial Results in Virologically-Suppressed AdultsIn the DRIVE-SHIFT clinical trial [see Clinical Studies (14.2)], there were subjects in the immediate switch group (n=447) and subjects 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 virologic failure subjects 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 subjects 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-ResistanceCross-resistance has been observed among NNRTIs. Treatment-emergent doravirine resistance-associated substitutions can confer cross-resistance to efavirenz, etravirine, nevirapine, and rilpivirine. Of the virologic failure subjects who developed doravirine phenotypic resistance, all had phenotypic resistance to nevirapine, had phenotypic resistance to efavirenz, had phenotypic resistance to rilpivirine, and had resistance to etravirine in the Monogram PhenoSense assay. Of the 11 virologic failure subjects in DRIVE-AHEAD phenotypically resistant to efavirenz, (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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects. Doravirine pharmacokinetics are provided in Table 7.Table 7: Pharmacokinetic Properties of DoravirineParameterDoravirineAbbreviations: 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 clearanceGeneral Steady State Exposure Doravirine 100 mg once daily to HIV-1-infected subjects ,Presented as geometric mean (%CV: geometric coefficient of variation) AUC0-24 (mcgh/mL)16.1 (29)Cmax (mcg/mL)0.962 (19)C24 (mcg/mL)0.396 (63) Time to Steady State (Days) Accumulation Ratio 1.2 to 1.4AbsorptionAbsolute 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)DistributionVdss (L)Based on IV dose 60.5Plasma Protein Binding76%Eliminationt1/2 (h)15CL/F (mL/min) 106 (35.2)CLrenal (mL/min) 9.3 (18.6) Metabolism Primary Pathway(s)CYP3A Excretion Major Route of EliminationMetabolismUrine (unchanged)6%Biliary/Fecal (unchanged)Minor. Specific PopulationsIn 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 ImpairmentIn study comparing subjects with severe renal impairment to subjects without renal impairment, the single dose exposure of doravirine was 43% higher in subjects with severe renal impairment. In population pharmacokinetic analysis, renal function did not have 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 ImpairmentNo clinically significant difference in the pharmacokinetics of doravirine was observed in subjects with moderate hepatic impairment (Child-Pugh score B) compared to subjects without hepatic impairment. Doravirine has not been studied in subjects 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 patients 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 patients weighing >= 35 kg and 45 kg who receive doravirine 100 mg or DELSTRIGO, the population pharmacokinetic model-predicted mean C24 of doravirine was comparable to that achieved in adults, whereas mean AUC0-24 and Cmax of doravirine were 25% and 36% higher than adult values, respectively. However, the predicted AUC0-24 and Cmax increases are not considered clinically significant.Table 8: Steady State Pharmacokinetics for Doravirine Following Administration of Doravirine or DELSTRIGO in HIV-1-Infected Pediatric Patients Aged 12 to Less than 18 Years and Weighing at Least 35 kgParameterPresented 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 hoursAUC0-24 (mcgh/mL)16.4 (24)Cmax (mcg/mL)1.03 (16)C24 (mcg/mL)0.379 (42). Drug Interaction StudiesDoravirine 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 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 (Cmax, AUC, and C24) of doravirine are summarized in Table 9. 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 DrugCo-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. Cmax C24 CI confidence interval; QD once daily; BID twice dailyAzole Antifungal AgentsketoconazoleChanges 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)Antimycobacterialsrifampin600 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 Agentsritonavir 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)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.