Table 6: Drug Interactions with PIFELTROThis table is not all inclusive.
Concomitant Drug Class:Drug Name	Effect on Concentration	Clinical Comment
↑ = increase, ↓ = decreaseAll 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
carbamazepineoxcarbazepinephenobarbitalphenytoin	↓ doravirine	Co-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	↓ 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 etravirinenevirapine	↓ 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.

PIFELTRO (doravirine 100 mg) Dailymed

Generic: doravirine

IMPRINT: LOGO 700 SHAPE: oval
COLOR: white

All Imprints

doravirine 100 mg oral tablet [pifeltro] - logo 700 oval white

Go PRO for all pill images

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)

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)

2.1Recommended 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)].

2.2Dosage 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)].

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)

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 (5.1), 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)

5 Warnings And Precautions

Monitor for Immune Reconstitution Syndrome. (5.2)

5.1Risk 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.

5.2Immune 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.

6 Adverse Reactions

The following adverse reactions are discussed in other sections of the labeling:

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 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 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 2 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-FORWARD DRIVE-AHEAD

PIFELTRO+2 NRTIsNRTI = nucleoside reverse transcriptase inhibitor. Once DailyN=383 DRV+r+2 NRTIs Once DailyN=383 DELSTRIGOOnce DailyN=364 EFV/FTC/TDFOnce DailyN=364

NRTIs = 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 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 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=364 EFV/FTC/TDFOnce DailyN=364 Treatment DifferenceDELSTRIGO - EFV/FTC/TDFEstimate (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)

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 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 subjects in the DELSTRIGO and EFV/FTC/TDF groups, respectively. The proportion of subjects 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 subjects 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 Subjects 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 NRTIsOnce DailyN=383 DRV+r+2 NRTIsOnce DailyN=383 DELSTRIGOOnce DailyN=364 EFV/FTC/TDFOnce DailyN=364

Blood Chemistry

Each subject is only counted once per parameter at the highest toxicity grade. Only subjects 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

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 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 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 NRTIsOnce DailyN=320 DRV+r+2 NRTIsOnce DailyN=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 DailyN=320 EFV/FTC/TDF Once DailyN=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 subjects in the DRIVE-SHIFT trial (Protocol 024), a randomized, international, multicenter, open-label trial in which virologically-suppressed subjects 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 subjects was similar to that in subjects with no antiretroviral treatment history.

Laboratory Abnormalities

Change in Lipids from Baseline

Changes from baseline at Week 24 in LDL-cholesterol, non-HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol in subjects 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 Subjects on a PI plus Ritonavir-based Regimen at Baseline in DRIVE-SHIFT (Week 24)

Laboratory Parameter Preferred Term DELSTRIGO(Week 0-24)Once DailyN=244 PI+ritonavir(Week 0-24)Once DailyN=124 Difference Estimates

Baseline Change Baseline Change Difference (95% CI)

Subjects on lipid-lowering agents at baseline were excluded from these analyses (DELSTRIGO n=26 and PI+ritonavir n=13).

Subjects 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 Patients

The safety of doravirine as a component of DELSTRIGO was evaluated in 45 HIV-1-infected virologically-suppressed or treatment-naïve 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 3 or 4 adverse reactions. No subjects discontinued due to an adverse event.

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 a 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 6 shows significant drug interactions with PIFELTRO.

Table 6: Drug Interactions with PIFELTROThis table is not all inclusive.

Concomitant Drug Class:Drug Name Effect on Concentration Clinical Comment

↑ = increase, ↓ = decreaseAll 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

carbamazepineoxcarbazepinephenobarbitalphenytoin ↓ doravirine Co-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 ↓ 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 etravirinenevirapine ↓ 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)].

7.2Effect 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)].

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)

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

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. Doravirine is present in the milk of lactating rats (seeData ). 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 a breastfed infant, instruct mothers not to breastfeed if they are receiving PIFELTRO.

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 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)].

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-1H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy]benzonitrile.

It has a molecular formula of C₁₇H₁₁ClF₃N₅O₃ and a molecular weight of 425.75.

It has the following structural formula:

Doravirine is practically insoluble in water.

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 HIV-1-infected subjects 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 subjects and HIV-1-infected subjects. 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; C₂₄=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 HIV-1-infected subjects ^, 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)

C₂₄ (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 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 Ratio 1.16 (1.06, 1.26)

C_max Ratio 1.03 (0.89, 1.19)

C₂₄ 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 subjects with severe renal impairment to 8 subjects without renal impairment, the single dose exposure of doravirine was 43% higher in subjects 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 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 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 HIV-1-Infected Pediatric Patients 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; C_max=maximum concentration; C₂₄=concentration at 24 hours

AUC_0-24 (mcg∙h/mL) 16.4 (24)

C_max (mcg/mL) 1.03 (16)

C₂₄ (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 C₂₄) 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)

AUCAUC_0- _∞ for single-dose, AUC_0-24 for once daily. C_max C₂₄

CI = confidence interval; QD = once daily; BID = twice daily

Azole Antifungal Agents

ketoconazoleChanges 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 QDDoravirine 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 QDThe 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 QD14 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% (IC₅₀) 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 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 a median EC₅₀ 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 EC₅₀ 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

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 subjects 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 subjects 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.

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.

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 3 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 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 subjects 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/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 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 subjects 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/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 History

Outcome DRIVE-FORWARD DRIVE-AHEAD

PIFELTRO + 2 NRTIsOnce Daily DRV+r + 2 NRTIsOnce Daily DELSTRIGOOnce Daily EFV/FTC/TDF Once Daily

N=383 N=383 N=364 N=364

Note: NRTIs = FTC/3TC 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 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 Window 11% 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 window 2% 3% 1% 1%

Proportion (%) of Subjects 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)

EthnicityDoes not include subjects 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/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 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)

14.2Clinical 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 HIV-1-infected adults. Subjects 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. 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 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/mm³, 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 Subjects Who Switched to DELSTRIGO

Outcome DELSTRIGOOnce Daily ISGWeek 48N=447 Baseline RegimenDSGWeek 24N=223

HIV-1 RNA ≥ 50 copies/mL Includes 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 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 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 window 0 0

Proportion (%) of Subjects 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/mm³)

  <200 cells/mm³ 85% (N = 13) 75% (N = 4)

  ≥200 cells/mm³ 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 Patients

The efficacy of DELSTRIGO (DOR/3TC/TDF) was evaluated in cohort 2 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 a 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-naïve 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-naïve subjects achieved HIV-1 RNA <50 copies/mL at Week 24. The other treatment-naïve subject 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.

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.

STORAGE AND HANDLING SECTION

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].

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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 (5.1), 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 (5.2)].

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

Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].

Manufactured for: Merck Sharp & Dohme LLCRahway, NJ 07065, USA

For patent information: www.msd.com/research/patent

The trademarks depicted herein are owned by their respective companies.

Copyright © 2018-2023 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates.All rights reserved.

uspi-mk1439-t-2311r006

Spl Patient Package Insert Section

Patient InformationPIFELTRO^® (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 uled 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. 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 a ul 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 ul 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:

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 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 uled 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.

Manufactured for: Merck Sharp & Dohme LLCRahway, NJ 07065, USA

For patent information: www.msd.com/research/patent

The trademarks depicted herein are owned by their respective companies.

Copyright © 2018-2023 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates.All rights reserved.

usppi-mk1439-t-2311r004

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: 11/2023

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 thatshould NOT be taken with Pifeltro^®.

Rx only

30 Tablets

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 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-FORWARD	DRIVE-AHEAD
NRTIs = 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 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%

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=364	EFV/FTC/TDFOnce DailyN=364	Treatment DifferenceDELSTRIGO - EFV/FTC/TDFEstimate (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 Subjects with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 96)
	DRIVE-FORWARD	DRIVE-AHEAD
Each subject is only counted once per parameter at the highest toxicity grade. Only subjects 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
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%

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 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 NRTIsOnce DailyN=320	DRV+r+2 NRTIsOnce DailyN=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 DailyN=320	EFV/FTC/TDF Once DailyN=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	-

Table 5: Mean Change from Baseline in Fasting Lipids in Adult Virologically-Suppressed Subjects on a PI plus Ritonavir-based Regimen at Baseline in DRIVE-SHIFT (Week 24)
Laboratory Parameter Preferred Term	DELSTRIGO(Week 0-24)Once DailyN=244	PI+ritonavir(Week 0-24)Once DailyN=124	Difference Estimates
Subjects on lipid-lowering agents at baseline were excluded from these analyses (DELSTRIGO n=26 and PI+ritonavir n=13).
Subjects 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	-

Table 7: Pharmacokinetic Properties of Doravirine
Parameter	Doravirine
Abbreviations: AUC=area under the time concentration curve; C_max=maximum concentration; C₂₄=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 HIV-1-infected subjects ^, 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)
C₂₄ (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 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 Ratio	1.16 (1.06, 1.26)
C_max Ratio	1.03 (0.89, 1.19)
C₂₄ 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

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 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; C_max=maximum concentration; C₂₄=concentration at 24 hours
AUC_0-24 (mcg∙h/mL)	16.4 (24)
C_max (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 Drug	Regimen of Co-administered Drug	N	Geometric Mean Ratio (90% CI) of Doravirine Pharmacokinetics with/without Co-administered Drug (No Effect=1.00)
CI = confidence interval; QD = once daily; BID = twice daily
Azole Antifungal Agents
ketoconazoleChanges 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 QDDoravirine 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 QDThe 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 QD14 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)

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
Note: NRTIs = FTC/3TC 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 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 Window	11%	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 window	2%	3%	1%	1%
Proportion (%) of Subjects 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)
EthnicityDoes not include subjects 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/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 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)

Table 11: Virologic Outcomes in DRIVE-SHIFT in HIV-1 Virologically-Suppressed Subjects Who Switched to DELSTRIGO
Outcome	DELSTRIGOOnce Daily ISGWeek 48N=447	Baseline RegimenDSGWeek 24N=223
HIV-1 RNA ≥ 50 copies/mL Includes 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 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 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 window	0	0
Proportion (%) of Subjects 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/mm³)
<200 cells/mm³	85% (N = 13)	75% (N = 4)
≥200 cells/mm³	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)

Patient InformationPIFELTRO^® (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 uled 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. 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 a ul 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 ul 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: 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 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 uled 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.

DISCLAIMER:

"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."

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"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."

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	DRIVE-FORWARD		DRIVE-AHEAD
	PIFELTRO+2 NRTIsNRTI = nucleoside reverse transcriptase inhibitor. Once DailyN=383	DRV+r+2 NRTIs Once DailyN=383	DELSTRIGOOnce DailyN=364	EFV/FTC/TDFOnce DailyN=364
NRTIs = 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 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%

	DRIVE-FORWARD		DRIVE-AHEAD
Laboratory Parameter Preferred Term (Unit)/Limit	PIFELTRO+2 NRTIsOnce DailyN=383	DRV+r+2 NRTIsOnce DailyN=383	DELSTRIGOOnce DailyN=364	EFV/FTC/TDFOnce DailyN=364
Blood Chemistry
Each subject is only counted once per parameter at the highest toxicity grade. Only subjects 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
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%

Laboratory Parameter Preferred Term	DELSTRIGO(Week 0-24)Once DailyN=244		PI+ritonavir(Week 0-24)Once DailyN=124		Difference Estimates
	Baseline	Change	Baseline	Change	Difference (95% CI)
Subjects on lipid-lowering agents at baseline were excluded from these analyses (DELSTRIGO n=26 and PI+ritonavir n=13).
Subjects 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	-

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)
Co-administered Drug	Regimen of Co-administered Drug	N	AUCAUC_0- _∞ for single-dose, AUC_0-24 for once daily.	C_max	C₂₄
CI = confidence interval; QD = once daily; BID = twice daily
Azole Antifungal Agents
ketoconazoleChanges 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)
rifabutin	300 mg QDDoravirine 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 QDThe 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)
efavirenz	600 mg QD14 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)

Outcome	DRIVE-FORWARD		DRIVE-AHEAD
	PIFELTRO + 2 NRTIsOnce Daily	DRV+r + 2 NRTIsOnce Daily	DELSTRIGOOnce Daily	EFV/FTC/TDF Once Daily
	N=383	N=383	N=364	N=364
Note: NRTIs = FTC/3TC 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 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 Window	11%	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 window	2%	3%	1%	1%
Proportion (%) of Subjects 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)
EthnicityDoes not include subjects 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/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 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)

PIFELTRO (doravirine 100 mg) Dailymed

Drug Classes

Version History

Generic: doravirine

All Imprints

FDA Adverse Reactions

1 Indications And Usage

2 Dosage And Administration

2.1Recommended Dosage

2.2Dosage Adjustment with Rifabutin

3 Dosage Forms And Strengths

4 Contraindications

5 Warnings And Precautions

5.1Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

5.2Immune Reconstitution Syndrome

6 Adverse Reactions

6.1Clinical Trials Experience

7 Drug Interactions

7.1Effect of Other Drugs on PIFELTRO

7.2Effect of PIFELTRO on Other Drugs

8 Use In Specific Populations

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6Renal Impairment

8.7Hepatic Impairment

11 Description

12 Clinical Pharmacology

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 Clinical Studies

14.1Clinical Trial Results in Adults with No Antiretroviral Treatment History

14.2Clinical Trial Results in Virologically-Suppressed Adults

14.3 Clinical Trial Results in Pediatric Patients

16 How Supplied/storage And Handling

STORAGE AND HANDLING SECTION

17 Patient Counseling Information

Spl Patient Package Insert Section

Principal Display Panel - 100 Mg Bottle Label