PIFELTRO

PIFELTRO- doravirine tablet, film coated
Merck Sharp & Dohme Corp.

1 INDICATIONS AND USAGE

PIFELTRO is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adult patients:

  • 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)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage regimen of PIFELTRO in adults is one 100 mg tablet taken orally once daily with or without food [see Clinical Pharmacology (12.3)].

2.2 Dosage Adjustment with Rifabutin

If PIFELTRO is co-administered with rifabutin, increase PIFELTRO dosage to one tablet twice daily (approximately 12 hours apart) for the duration of rifabutin co-administration [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

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.

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)

5 WARNINGS AND PRECAUTIONS

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

The concomitant use of PIFELTRO and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of PIFELTRO and possible development of resistance [see Dosage and Administration (2.2), Contraindications (4) and Drug Interactions (7.1)].

See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during PIFELTRO therapy, review concomitant medications during PIFELTRO therapy, and monitor for adverse reactions.

5.2 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

6 ADVERSE REACTIONS

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

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions in Adults with No Antiretroviral Treatment History

The safety assessment of PIFELTRO used in combination with other antiretroviral agents is based on Week 96 data from two Phase 3, randomized, international, multicenter, double-blind, active-controlled trials (DRIVE-FORWARD (Protocol 018) and DRIVE-AHEAD (Protocol 021)).

In DRIVE-FORWARD, 766 adult 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 Reactions * (All Grades) Reported in ≥5% 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 NRTIs 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
*
Frequencies of adverse reactions are based on all adverse events attributed to trial drugs by the investigator.
No adverse reactions of Grade 2 or higher (moderate or severe) occurred in ≥ 2% of subjects treated with doravirine.
NRTI = nucleoside reverse transcriptase inhibitor.
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 Events * (Week 48)
DELSTRIGOOnce DailyN=364 EFV/FTC/TDFOnce DailyN=364 Treatment DifferenceDELSTRIGO — EFV/FTC/TDFEstimate (95% CI)
*
All causality and all grade events were included in the analysis.
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).
Predefined using MedDRA preferred terms, including: abnormal dreams, hyposomnia, initial insomnia, insomnia, nightmare, sleep disorder, somnambulism.
§
Predefined using MedDRA preferred terms, including: altered state of consciousness, lethargy, somnolence, syncope.
Sleep disorders and disturbances 12% 26% -13.5 (-19.1, -7.9)
Dizziness 9% 37% -28.3 (-34.0, -22.5)
Altered sensorium § 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).
*
p-values for the pre-specified hypothesis testing for treatment difference were <0.0001 in both DRIVE-FORWARD and DRIVE-AHEAD.
Not pre-specified for hypothesis testing.
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)* 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) 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

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 5 × ULN through 48 weeks on DELSTRIGO. The ALT and AST elevations were generally asymptomatic and not associated with bilirubin elevations. In comparison, 4% and 4% of 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 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).
*
P-value for the pre-specified hypothesis testing for treatment difference was <0.0001.
Not pre-specified for hypothesis testing.
LDL-Cholesterol (mg/dL)* 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) 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 -

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