PIFELTRO® doravirine 100 mg tablets
DELSTRIGO® doravirine 100 mg/ lamivudine 300 mg/
tenofovir disoproxil fumarate 300 mg tablets
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Resistance profile of PIFELTRO® (doravirine)

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DRIVE-SHIFT: In a 48-week study of virologically suppressed adults, which evaluated doravirine-based FDCa (n=656):

Zero cases of doravirine resistance in two subjects in the Immediate Switch Group (ISG)1

Graphic Showing Virologic Outcomes After Switch to DOR/3TC/TDF in Patients Who Entered 48-Week DRIVE-SHIFT Study

aDoravirine-based FDC (fixed-dose combination) = doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg tablets.
bProtocol-defined virologic failure is defined as two consecutive measurements of HIV-1 RNA ≥50 copies/mL at least one week apart.1
cTwo of the 6 virologic failure subjects in the ISG had available resistance data and neither developed detectable genotypic or phenotypic resistance to doraviririne, lamivudine, or tenofovir during treatment with a doravirine-based FDC.
dOne of the 2 virologic failure subjects in the DSG who had available resistance data developed the RT M184M/I substitution and phenotypic resistance to emtricitabine and lamivudine during treatment with their baseline regimen.
eThis subject developed the RT M184M/I substitution and phenotypic resistance to FTC and 3TC during treatment with their baseline regimen.

View DRIVE-SHIFT study design

DRIVE-SHIFT: 144-week extension phase evaluating doravirine-based FDC vs baseline regimen. After the 144-week extension phase (week 48 to week 144), there were

Zero Cases of Resistance to Doravirine in the Four Participants with Samples Available2,6

Graphic Showing Virologic Outcomes After Switch to DOR/3TC/TDF in Patients Who Entered 144-Week Extension Phase in the DRIVE-SHIFT Study

fProtocol-defined virologic failure is defined as two consecutive measurements of HIV-1 RNA ≥50 copies/mL at least one week apart.2
gParticipants who were tested for resistance in the extension to Week 144: 4 participants had resistance data after 144 weeks in the extension phase. None of these 4 participants had resistance to DOR, 3TC, or TDF. 2 participants were in the ISG—they did not have PDVF but discontinued early.6
hParticipants who were tested for resistance in the extension to week 144: 4 participants had resistance data after 144 weeks in the extension phase. None of these 4 participants had resistance to DOR, 3TC, or TDF. Two participants were in the DSG and had PDVF.6

Limitation: No formal statistics testing was planned for this updated analysis, and, therefore, no statistical conclusions can be drawn.

View DRIVE-SHIFT study design

DRIVE-FORWARD and DRIVE-AHEAD: Two studies of treatment-naïve adults, which evaluated PIFELTRO + 2 NRTIs and a doravirine-based FDC, respectively (n=747).

Low rate of resistance across clinical trials

Of the 36 subjects in the resistance analysis subset, 10 subjects (28%) developed genotypic and/or phenotypic resistance to the other drugs (abacavir, emtricitabine, lamivudine, or tenofovir) in the regimens of the DRIVE-FORWARD and DRIVE-AHEAD trials.

In the DRV/r treatment arm of DRIVE-FORWARD (n=383) through week 96, no subjects showed the emergence of darunavir resistance-associated substitutions among 15 subjects with resistance data and 2 of the subjects had emergent genotypic or phenotypic resistance to lamivudine or tenofovir.

In the EFV/FTC/TDF treatment arm of DRIVE-AHEAD (n=364) through week 96, 15 subjects showed the emergence of efavirenz resistance-associated substitutions among 25 (60%) subjects in the resistance analysis subset and genotypic resistance to emtricitabine or tenofovir developed in 5 evaluable subjects; emergent resistance-associated substitutions were RT K65R (n=1), D67G/K70E (n=1), L74V/V75M/V118I (n=1), M184I or V (n=5), and K219K/E (n=1).

DRIVE-FORWARD and DRIVE-AHEAD Week-96 Graphic Showing Breakdown of Subjects in the Doravirine Treatment Arms That Showed Doravirine Resistance-Associated Substitutions

iThere were 36 subjects in the resistance analysis subset (HIV-1 RNA >400 copies per mL at virologic failure or early study discontinuation and having post-baseline resistance samples) from the doravirine treatment arms of 2 clinical trials evaluating a doravirine-based FDC (N=747) through week 96.
jMost subjects had at least a 100-fold reduction in doravirine susceptibility.
kSubjects had only amino acid mixtures of NNRTI resistance substitutions.

View DRIVE-FORWARD study design

View DRIVE-AHEAD study design

Study designs

DRIVE-SHIFT study design

A randomized, multicenter, active-controlled, non-inferior, open-label phase 3 trial of adult participants with virologically suppressed HIV-1 for ≥6 months on 2 NRTIs with a PI plus either ritonavir or cobicistat, elvitegravir plus cobicistat, or an NNRTI, with no history of virologic failure. Participants were either immediately switched to a doravirine-based FDC (100 mg DOR/300 mg 3TC/300 mg TDF) on day 1 of the 48-week trial (Immediate Switch Group (ISG) [n=447]) or continued their baseline regimen and switched after 24 weeks (Delayed Switch Group (DSG) [n=223]) to a doravirine-based FDC.1,2

Extension Study: Participants who completed the 48-week visit were eligible to continue receiving open-label doravirine-based FDC for an additional 96 weeks, up to week 144.1,2

Primary efficacy end point: Percentage of participants with HIV-1 RNA ≥50 copies/mL in the ISG at week 48 vs the DSG at week 24: 2% for the doravirine-based FDC vs 1% for the baseline regimen. Difference (95% CI): 0.7 (-1.3, 2.6).1

Additional efficacy end point: Percentage of participants with HIV-1 RNA <50 copies/mL in the ISG at week 48 vs the DSG at week 24: 91% for the doravirine-based FDC vs 95% for a baseline regimen.1

Safety end point: For participants whose baseline regimen included a PI plus ritonavir: Mean change from baseline to week 24 in fasting LDL-C and non-HDL-C.1

DRIVE-FORWARD study design

A randomized, multicenter, double-blind, active-controlled, non-inferior, phase 3 trial comparing PIFELTRO 100 mg once daily (n=383) vs darunavir 800 mg + ritonavir 100 mg once daily (n=383), each in combination with 2 NRTIs, FTC/TDF or ABC/3TC selected by the investigator, in treatment-naïve adult participants with HIV-1 RNA ≥1000 copies/mL.4,7

Primary efficacy end point: Percentage of participants with HIV-1 RNA <50 copies/mL at week 48 for PIFELTRO + 2 NRTIs vs DRV/r + 2 NRTIs: 84% vs 80%. Difference (95% CI): 3.9 (-1.6, 9.4).4

Secondary efficacy end point: Percentage of participants with HIV-1 RNA <50 copies/mL at week 96 for PIFELTRO + 2 NRTIs vs DRV/r + 2 NRTIs: 72% vs 65%. Difference (95% CI): 7.5 (1.0, 14.1).7

Safety end point: Mean change from baseline to week 48 in fasting LDL-C and non-HDL-C.4

DRIVE-AHEAD study design

A randomized, multicenter, double-blind, active-controlled, non-inferior, phase 3 trial comparing a doravirine-based FDC (100 mg DOR/300 mg 3TC/300 mg TDF) once daily (n=364) vs 600 mg EFV/200 mg FTC/300 mg TDF once daily (n=364) in treatment-naïve adult participants with HIV-1 RNA ≥1000 copies/mL.3,5

Primary efficacy end point: Percentage of participants with HIV-1 RNA <50 copies/mL at week 48 for a doravirine-based FDC vs EFV/FTC/TDF: 84% vs 81%. Difference (95% CI): 3.5 (-2.0, 9.0).3

Secondary safety end point: Percentage of participants with HIV-1 RNA <50 copies/mL at week 96 for a doravirine-based FDC vs EFV/FTC/TDF: 77% vs 74%. Difference (95% CI): 3.8 (-2.4, 10.0).5

Primary safety end point: Percentage of participants with three pre-specified neuropsychiatric events (dizziness, sleep disorders/disturbances, and altered sensorium) at week 48.3,a,b

  • Dizziness: 9% for doravirine-based FDC vs 37% for EFV/FTC/TDF. Difference (95% CI): -28.3 (-34.0, -22.5); P<0.001
  • Sleep disorders and disturbancesc: 12% for doravirine-based FDC vs 26% for EFV/FTC/TDF. Difference (95% CI): -13.5 (-19.1, -7.9); P<0.001
  • Altered sensoriumd: 4% for doravirine-based FDC vs 8% for EFV/FTC/TDF. Difference (95% CI): -3.8 (-7.6, -0.3); P=0.033

Safety end point: Mean change from baseline to week 48 in fasting LDL-C and non-HDL-C.3

an=364 for each treatment group.

bThe 95% CIs were calculated using Miettinen and Nurminen’s method.

cPredefined using MedDRA preferred terms, including: abnormal dreams, hyposomnia, initial insomnia, insomnia, nightmare, sleep disorder, and somnambulism.

dPredefined using MedDRA preferred terms, including: altered state of consciousness, lethargy, somnolence, and syncope.

Acronyms

3TC, lamivudine; ABC, abacavir; DOR, doravirine; DRV/r, darunavir/ritonavir; EFV, efavirenz; FDC, fixed-dose combination; FTC, emtricitabine; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; MedDRA, Medical Dictionary for Regulatory Activities; NNRTI, non-nucleoside reverse transcriptase inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; PI, protease inhibitor; RNA, ribonucleic acid; TDF, tenofovir disoproxil fumarate.

References

  1. Johnson M, Kumar P, Molina JM, et al; for the DRIVE-SHIFT Study Group. Switching to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) maintains HIV-1 virologic suppression through 48 weeks: results of the DRIVE-SHIFT trial. J Acquir Immune Defic Syndr. 2019;81(4):463-472. doi:10.1097/QAI.0000000000002056.
  2. Kumar P, Johnson M, Molina JM, et al; for the DRIVE-SHIFT Study Group. Switching to DOR/3TC/TDF maintains HIV-1 virologic suppression through week 144 in the DRIVE-SHIFT Trial. J Acquir Immune Defic Syndr. 2021;87(2):801- 805. doi:10.1097/QAI.0000000000002642.
  3. Orkin C, Squires KE, Molina JM, et al; for the DRIVE-AHEAD Study Group. Doravirine/lamivudine/tenofovir disoproxil fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results of the DRIVE-AHEAD trial. Clin Infect Dis. 2019;68(4):535-544. doi: 10.1093/cid/ciy540.
  4. Molina JM, Squires K, Sax PE, et al; for the DRIVE-FORWARD Study Group. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018;5(5):e211-e220. Epub 2018 Mar 25. doi: 10.1016/S2352-3018(18)30021-3.
  5. Orkin C, Squires KE, Molina JM, et al. Doravirine/lamivudine/tenofovir disoproxil fumarate (TDF) versus efavirenz/emtricitabine/TDF in treatment-naive adults with human immunodeficiency virus type 1 infection: week 96 results of the randomized, double-blind, phase 3 DRIVE-AHEAD noninferiority trial. Clin Infect Dis. 2021;73(1):33-42. doi: 10.1093/cid/ciaa822.
  6. Data available on request from Merck Professional Services-DAP, WP1, PO Box 4, West Point, PA 19486-0004. Please specify information package US-DOV-01329.
  7. Molina JM, Squires K, Sax PE, et al; for the DRIVE-FORWARD Trial Group. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double-blind, non-inferiority, phase 3 trial. Lancet HIV. 2020;7(1):e16-e26. Epub 2019 Nov 15. doi: 10.1016/S2352-3018(19)30336-4.

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Indications

PIFELTRO® (doravirine) is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine.

DELSTRIGO® (doravirine/lamivudine/tenofovir disoproxil fumarate) is indicated as a complete regimen for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO.

 
Selected Safety Information

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B (HBV)

All patients with HIV-1 should be tested for the presence of HBV before initiating ARV therapy. Severe acute exacerbations of HBV have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing lamivudine or tenofovir disoproxil fumarate (TDF), which are components of DELSTRIGO. Patients coinfected with HIV-1 and HBV who discontinue DELSTRIGO should be monitored with both clinical and laboratory follow-up for at least several months after stopping DELSTRIGO. If appropriate, initiation of anti-HBV therapy may be warranted.

Contraindications

PIFELTRO and DELSTRIGO are contraindicated when coadministered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers (including the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin; the androgen receptor inhibitor enzalutamide; the antimycobacterials rifampin and rifapentine; the cytotoxic agent mitotane; and the herbal product St. John’s wort (Hypericum perforatum)), as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO and PIFELTRO.

DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine.

Warnings and Precautions

Renal Impairment: New or Worsening of Renal Impairment
Renal impairment, including cases of acute renal failure and Fanconi syndrome, have been reported with the use of TDF. DELSTRIGO should be avoided with concurrent or recent use of a nephrotoxic agent (eg, high-dose or multiple NSAIDs). Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in patients with risk factors for renal dysfunction who appeared stable on TDF.

Prior to or when initiating DELSTRIGO, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue DELSTRIGO in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Discontinue DELSTRIGO if estimated creatinine clearance declines below 50 mL/min.

Bone Loss and Mineralization Defects
In clinical trials in HIV-1 infected adults, TDF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher. Cases of osteomalacia associated with proximal renal tubulopathy have been reported with the use of TDF.

Immune Reconstitution Syndrome
Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.

Drug Interactions
Because DELSTRIGO is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.

Coadministration of PIFELTRO with efavirenz, etravirine, or nevirapine is not recommended.

If DELSTRIGO is coadministered with rifabutin, take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO.

If PIFELTRO is coadministered with rifabutin, increase PIFELTRO dosage to one tablet twice daily (approximately 12 hours apart).

Consult the full Prescribing Information prior to and during treatment for more information on potential drug-drug interactions.

Dosage and Administration/Special Populations

Renal Impairment
Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF cannot be adjusted, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min.

Adverse Reactions
The most common adverse reactions with DELSTRIGO (incidence ≥5%, all intensities) were dizziness (7%), nausea (5%), and abnormal dreams (5%). The most common adverse reactions with PIFELTRO (incidence ≥5%, all intensities) were nausea (7%), dizziness (7%), headache (6%), fatigue (6%), diarrhea (6%), abdominal pain (5%), and abnormal dreams (5%).

By week 96 in DRIVE-FORWARD, 2% of adult subjects in the PIFELTRO group and 3% in the DRV+r group had adverse events leading to discontinuation of study medication.

By week 96 in DRIVE-AHEAD, 3% of adult subjects in the DELSTRIGO group and 7% in the efavirenz (EFV)/emtricitabine (FTC)/TDF group had adverse events leading to discontinuation of study medication.

In DRIVE-FORWARD, mean changes from baseline at week 48 in LDL-cholesterol (LDL-C) and non HDL-cholesterol (non-HDL-C) were pre-specified. LDL-C: -4.6 mg/dL in the PIFELTRO group vs 9.5 mg/dL in the DRV+r group. Non-HDL-C: -5.4 mg/dL in the PIFELTRO group vs 13.7 mg/dL in the DRV+r group. The clinical benefits of these findings have not been demonstrated.

In DRIVE-AHEAD, mean changes from baseline at week 48 in LDL-C and non-HDL-C were pre-specified. LDL-C: -2.1 mg/dL in the DELSTRIGO group vs 8.3 mg/dL in the EFV/FTC/TDF group. Non-HDL-C: -4.1 mg/dL in the DELSTRIGO group vs 12.7 mg/dL in the EFV/FTC/TDF group. The clinical benefits of these findings have not been demonstrated.

In DRIVE-SHIFT, mean changes from baseline at week 24 in LDL-C and non-HDL-C were pre-specified. LDL-C: -16.3 mg/dL in the DELSTRIGO group vs -2.6 mg/dL in the PI + ritonavir group. Non-HDL-C: -24.8 mg/dL in the DELSTRIGO group vs -2.1 mg/dL in the PI + ritonavir group. The clinical benefits of these findings have not been demonstrated.

In DRIVE-AHEAD, neuropsychiatric adverse events were reported in the three pre-specified categories of sleep disorders and disturbances, dizziness, and altered sensorium. Twelve percent of adult subjects in the DELSTRIGO group and 26% in the EFV/FTC/TDF group reported neuropsychiatric adverse events of sleep disorders and disturbances; 9% in the DELSTRIGO group and 37% in the EFV/FTC/TDF group reported dizziness; and 4% in the DELSTRIGO group and 8% in the EFV/FTC/TDF group reported altered sensorium.

The safety of DELSTRIGO in virologically-suppressed adults was based on week 48 data from subjects in the DRIVE-SHIFT trial. Overall, the safety profile in virologically-suppressed adult subjects was similar to that in subjects with no ARV treatment history.

Pregnancy/Breastfeeding

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO or DELSTRIGO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Mothers infected with HIV-1 should be instructed not to breastfeed if they are receiving PIFELTRO or DELSTRIGO due to the potential for HIV-1 transmission.

Before prescribing PIFELTRO® (doravirine), please read the accompanying Prescribing Information. The Patient Information also is available.

Before prescribing DELSTRIGO® (doravirine/lamivudine/tenofovir disoproxil fumarate), please read the accompanying Prescribing information, including the Boxed Warning about posttreatment acute exacerbation of Hepatitis B. The Patient information also is available.

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Indications

PIFELTRO® (doravirine) is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine.

 

DELSTRIGO® (doravirine/lamivudine/tenofovir disoproxil fumarate) is indicated as a complete regimen for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO.

Selected Safety Information

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B (HBV)

All patients with HIV-1 should be tested for the presence of HBV before initiating ARV therapy. Severe acute exacerbations of HBV have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing lamivudine or tenofovir disoproxil fumarate (TDF), which are components of DELSTRIGO. Patients coinfected with HIV-1 and HBV who discontinue DELSTRIGO should be monitored with both clinical and laboratory follow-up for at least several months after stopping DELSTRIGO. If appropriate, initiation of anti-HBV therapy may be warranted.

Contraindications

 

PIFELTRO and DELSTRIGO are contraindicated when coadministered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers (including the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin; the androgen receptor inhibitor enzalutamide; the antimycobacterials rifampin and rifapentine; the cytotoxic agent mitotane; and the herbal product St. John’s wort (Hypericum perforatum)), as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO and PIFELTRO.

 

DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine.

 

Warnings and Precautions

 

Renal Impairment: New or Worsening of Renal Impairment
Renal impairment, including cases of acute renal failure and Fanconi syndrome, have been reported with the use of TDF. DELSTRIGO should be avoided with concurrent or recent use of a nephrotoxic agent (eg, high-dose or multiple NSAIDs). Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in patients with risk factors for renal dysfunction who appeared stable on TDF.

 

Prior to or when initiating DELSTRIGO, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue DELSTRIGO in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Discontinue DELSTRIGO if estimated creatinine clearance declines below 50 mL/min.

 

Bone Loss and Mineralization Defects
In clinical trials in HIV-1 infected adults, TDF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher. Cases of osteomalacia associated with proximal renal tubulopathy have been reported with the use of TDF.

 

Immune Reconstitution Syndrome
Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.

 

Drug Interactions
Because DELSTRIGO is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.

 

Coadministration of PIFELTRO with efavirenz, etravirine, or nevirapine is not recommended.

 

If DELSTRIGO is coadministered with rifabutin, take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO.

 

If PIFELTRO is coadministered with rifabutin, increase PIFELTRO dosage to one tablet twice daily (approximately 12 hours apart).

 

Consult the full Prescribing Information prior to and during treatment for more information on potential drug-drug interactions.

 

Dosage and Administration/Special Populations

 

Renal Impairment
Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF cannot be adjusted, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min.

 

Adverse Reactions
The most common adverse reactions with DELSTRIGO (incidence ≥5%, all intensities) were dizziness (7%), nausea (5%), and abnormal dreams (5%). The most common adverse reactions with PIFELTRO (incidence ≥5%, all intensities) were nausea (7%), dizziness (7%), headache (6%), fatigue (6%), diarrhea (6%), abdominal pain (5%), and abnormal dreams (5%).

 

By week 96 in DRIVE-FORWARD, 2% of adult subjects in the PIFELTRO group and 3% in the DRV+r group had adverse events leading to discontinuation of study medication.

 

By week 96 in DRIVE-AHEAD, 3% of adult subjects in the DELSTRIGO group and 7% in the efavirenz (EFV)/emtricitabine (FTC)/TDF group had adverse events leading to discontinuation of study medication.

 

In DRIVE-FORWARD, mean changes from baseline at week 48 in LDL-cholesterol (LDL-C) and non HDL-cholesterol (non-HDL-C) were pre-specified. LDL-C: -4.6 mg/dL in the PIFELTRO group vs 9.5 mg/dL in the DRV+r group. Non-HDL-C: -5.4 mg/dL in the PIFELTRO group vs 13.7 mg/dL in the DRV+r group. The clinical benefits of these findings have not been demonstrated.

 

In DRIVE-AHEAD, mean changes from baseline at week 48 in LDL-C and non-HDL-C were pre-specified. LDL-C: -2.1 mg/dL in the DELSTRIGO group vs 8.3 mg/dL in the EFV/FTC/TDF group. Non-HDL-C: -4.1 mg/dL in the DELSTRIGO group vs 12.7 mg/dL in the EFV/FTC/TDF group. The clinical benefits of these findings have not been demonstrated.

 

In DRIVE-SHIFT, mean changes from baseline at week 24 in LDL-C and non-HDL-C were pre-specified. LDL-C: -16.3 mg/dL in the DELSTRIGO group vs -2.6 mg/dL in the PI + ritonavir group. Non-HDL-C: -24.8 mg/dL in the DELSTRIGO group vs -2.1 mg/dL in the PI + ritonavir group. The clinical benefits of these findings have not been demonstrated.

 

In DRIVE-AHEAD, neuropsychiatric adverse events were reported in the three pre-specified categories of sleep disorders and disturbances, dizziness, and altered sensorium. Twelve percent of adult subjects in the DELSTRIGO group and 26% in the EFV/FTC/TDF group reported neuropsychiatric adverse events of sleep disorders and disturbances; 9% in the DELSTRIGO group and 37% in the EFV/FTC/TDF group reported dizziness; and 4% in the DELSTRIGO group and 8% in the EFV/FTC/TDF group reported altered sensorium.

 

The safety of DELSTRIGO in virologically-suppressed adults was based on week 48 data from subjects in the DRIVE-SHIFT trial. Overall, the safety profile in virologically-suppressed adult subjects was similar to that in subjects with no ARV treatment history.

 

Pregnancy/Breastfeeding

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO or DELSTRIGO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

 

Mothers infected with HIV-1 should be instructed not to breastfeed if they are receiving PIFELTRO or DELSTRIGO due to the potential for HIV-1 transmission.

 

Before prescribing PIFELTRO® (doravirine), please read the accompanying Prescribing Information. The Patient Information also is available.

 

Before prescribing DELSTRIGO® (doravirine/lamivudine/tenofovir disoproxil fumarate), please read the accompanying Prescribing Information, including the Boxed Warning about posttreatment acute exacerbation of Hepatitis B. The Patient Information also is available.

Indications

PIFELTRO® (doravirine) is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine.

 

DELSTRIGO® (doravirine/lamivudine/tenofovir disoproxil fumarate) is indicated as a complete regimen for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO.

PIFELTRO® (doravirine) is indicated in combination with other antiretroviral

PIFELTRO® (doravirine) is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable

Selected Safety Information

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B (HBV)

All patients with HIV-1 should be tested for the presence of HBV before initiating ARV therapy. Severe acute exacerbations of HBV have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing lamivudine or tenofovir disoproxil fumarate (TDF), which are components of DELSTRIGO. Patients coinfected with HIV-1 and HBV who discontinue DELSTRIGO should be monitored with both clinical and laboratory follow-up for at least several months after stopping DELSTRIGO. If appropriate, initiation of anti-HBV therapy may be warranted.

Contraindications

 

PIFELTRO and DELSTRIGO are contraindicated when coadministered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers (including the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin; the androgen receptor inhibitor enzalutamide; the antimycobacterials rifampin and rifapentine; the cytotoxic agent mitotane; and the herbal product St. John’s wort (Hypericum perforatum)), as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO and PIFELTRO.

 

DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine.

 

Warnings and Precautions

 

Renal Impairment: New or Worsening of Renal Impairment
Renal impairment, including cases of acute renal failure and Fanconi syndrome, have been reported with the use of TDF. DELSTRIGO should be avoided with concurrent or recent use of a nephrotoxic agent (eg, high-dose or multiple NSAIDs). Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in patients with risk factors for renal dysfunction who appeared stable on TDF.

 

Prior to or when initiating DELSTRIGO, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue DELSTRIGO in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Discontinue DELSTRIGO if estimated creatinine clearance declines below 50 mL/min.

 

Bone Loss and Mineralization Defects
In clinical trials in HIV-1 infected adults, TDF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher. Cases of osteomalacia associated with proximal renal tubulopathy have been reported with the use of TDF.

 

Immune Reconstitution Syndrome
Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.

 

Drug Interactions
Because DELSTRIGO is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.

 

Coadministration of PIFELTRO with efavirenz, etravirine, or nevirapine is not recommended.

 

If DELSTRIGO is coadministered with rifabutin, take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO.

 

If PIFELTRO is coadministered with rifabutin, increase PIFELTRO dosage to one tablet twice daily (approximately 12 hours apart).

 

Consult the full Prescribing Information prior to and during treatment for more information on potential drug-drug interactions.

 

Dosage and Administration/Special Populations

 

Renal Impairment
Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF cannot be adjusted, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min.

 

Adverse Reactions
The most common adverse reactions with DELSTRIGO (incidence ≥5%, all intensities) were dizziness (7%), nausea (5%), and abnormal dreams (5%). The most common adverse reactions with PIFELTRO (incidence ≥5%, all intensities) were nausea (7%), dizziness (7%), headache (6%), fatigue (6%), diarrhea (6%), abdominal pain (5%), and abnormal dreams (5%).

 

By week 96 in DRIVE-FORWARD, 2% of adult subjects in the PIFELTRO group and 3% in the DRV+r group had adverse events leading to discontinuation of study medication.

 

By week 96 in DRIVE-AHEAD, 3% of adult subjects in the DELSTRIGO group and 7% in the efavirenz (EFV)/emtricitabine (FTC)/TDF group had adverse events leading to discontinuation of study medication.

 

In DRIVE-FORWARD, mean changes from baseline at week 48 in LDL-cholesterol (LDL-C) and non HDL-cholesterol (non-HDL-C) were pre-specified. LDL-C: -4.6 mg/dL in the PIFELTRO group vs 9.5 mg/dL in the DRV+r group. Non-HDL-C: -5.4 mg/dL in the PIFELTRO group vs 13.7 mg/dL in the DRV+r group. The clinical benefits of these findings have not been demonstrated.

 

In DRIVE-AHEAD, mean changes from baseline at week 48 in LDL-C and non-HDL-C were pre-specified. LDL-C: -2.1 mg/dL in the DELSTRIGO group vs 8.3 mg/dL in the EFV/FTC/TDF group. Non-HDL-C: -4.1 mg/dL in the DELSTRIGO group vs 12.7 mg/dL in the EFV/FTC/TDF group. The clinical benefits of these findings have not been demonstrated.

 

In DRIVE-SHIFT, mean changes from baseline at week 24 in LDL-C and non-HDL-C were pre-specified. LDL-C: -16.3 mg/dL in the DELSTRIGO group vs -2.6 mg/dL in the PI + ritonavir group. Non-HDL-C: -24.8 mg/dL in the DELSTRIGO group vs -2.1 mg/dL in the PI + ritonavir group. The clinical benefits of these findings have not been demonstrated.

 

In DRIVE-AHEAD, neuropsychiatric adverse events were reported in the three pre-specified categories of sleep disorders and disturbances, dizziness, and altered sensorium. Twelve percent of adult subjects in the DELSTRIGO group and 26% in the EFV/FTC/TDF group reported neuropsychiatric adverse events of sleep disorders and disturbances; 9% in the DELSTRIGO group and 37% in the EFV/FTC/TDF group reported dizziness; and 4% in the DELSTRIGO group and 8% in the EFV/FTC/TDF group reported altered sensorium.

 

The safety of DELSTRIGO in virologically-suppressed adults was based on week 48 data from subjects in the DRIVE-SHIFT trial. Overall, the safety profile in virologically-suppressed adult subjects was similar to that in subjects with no ARV treatment history.

 

Pregnancy/Breastfeeding

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO or DELSTRIGO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

 

Mothers infected with HIV-1 should be instructed not to breastfeed if they are receiving PIFELTRO or DELSTRIGO due to the potential for HIV-1 transmission.

 

Before prescribing PIFELTRO® (doravirine), please read the accompanying Prescribing Information. The Patient Information also is available.

 

Before prescribing DELSTRIGO® (doravirine/lamivudine/tenofovir disoproxil fumarate), please read the accompanying Prescribing Information, including the Boxed Warning about posttreatment acute exacerbation of Hepatitis B. The Patient Information also is available.

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B (HBV)

All patients with HIV-1 should be tested for the presence of HBV before initiating ARV therapy. Severe acute

All patients with HIV-1 should be tested for the presence of HBV before initiating ARV therapy. Severe acute exacerbations of HBV have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing lamivudine or tenofovir disoproxil fumarate (TDF), which are components of DELSTRIGO. Patients coinfected with HIV-1 and HBV who discontinue DELSTRIGO should be monitored with both clinical and laboratory follow-up