PIFELTRO™ (doravirine 100 mg) tablets and DELSTRIGO™ (doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg) tablets

 

Lipid profile of PIFELTRO

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In adults with HIV-1, doravirine demonstrated a:

Superior lipid profile across clinical trials

Mean change from baseline in pre-specified LDL-C and non-HDL-C end points

DRIVE-SHIFT: Significant difference shown in virologically suppressed patients with a doravirine-based FDCa vs a PI plus ritonavir at week 24.b

DRIVE-SHIFT: Significant difference shown in virologically suppressed patients with a doravirine-based FDC^a versus a PI plus ritonavir at week 24.^b Mean change from baseline (mg/dL) for a doravirine-based FDC, Immediate Switch Group (ISG) (n=244) versus a PI + ritonavir, Delayed Switch Group (DSG) (n=124). LDL-C: -16.3 for a doravirine-based FDC (ISG) versus -2.6 for a PI + ritonavir (DSG). Difference (95% CI): -14.5 (-18.9, -10.1); P less than 0.0001. Non-HDL-C: -24.8 for doravirine-based FDC (ISG) versus -2.1 for a PI + ritonavir (DSG). Difference (95% CI): -22.8 (-27.9, -17.7); P less than 0.0001. Total cholesterol: -26.1 for doravirine-based FDC (ISG) versus -0.2 for a PI + ritonavir (DSG). Triglycerides: -44.4 for doravirine-based FDC (ISG) versus -0.4 for a PI + ritonavir (DSG). HDL-C: -1.3 for doravirine-based FDC (ISG) versus 1.9 for a PI + ritonavir (DSG). -30.0-10.00.010.0-20.0-40.0-50.0HDL-C1.9-1.3Total Cholesterol-0.2-26.1Triglycerides-44.4-0.4LDL-C-2.6-16.3Difference (95% CI):-14.5 (-18.9, -10.1)P<0.0001 Non-HDL-C-24.8-2.1Difference (95% CI):-22.8 (-27.9, -17.7)P<0.0001 Doravirine-based FDC Immediate Switch Group (n=244)PI + ritonavirDelayed Switch Group (n=124)

The clinical benefit of these findings has not been demonstrated.

View DRIVE-SHIFT study design

DRIVE-FORWARD: Significant difference in treatment-naïve patients with PIFELTRO + 2 NRTIs vs DRV/r + 2 NRTIs at week 48.b

DRIVE-FORWARD: Significant difference in treatment-naïve patients with PIFELTRO + 2 NRTIs versus DRV/r + 2 NRTIs at week 48.^b Change from baseline (mg/dL) for PIFELTRO + 2 NRTIs (n=320) versus DRV/r + 2 NRTIs (n=311). LDL-C: -4.6 for PIFELTRO + 2 NRTIs versus 9.5 for DRV/r + 2 NRTIs. Difference (95% CI): -14.4 (-18.0, -10.8); P less than 0.0001. Non-HDL-C: -5.4 for PIFELTRO + 2 NRTIs versus 13.7 for DRV/r + 2 NRTIs. Difference (95% CI): -19.4 (-23.4, -15.4); P less than 0.0001. Total cholestrerol: -1.4 for PIFELTRO + 2 NRTIs versus 18.0 for DRV/r + 2 NRTIs. Triglycerides: -3.1 for PIFELTRO + 2 NRTIs versus 24.5 for DRV/r + 2 NRTIs. HDL-C: 4.0 for PIFELTRO + 2 NRTIs versus 4.3 for DRV/r + 2 NRTIs. -5.00.010.020.025.015.05.0-10.0LDL-C-4.69.5Difference (95% CI): -14.4 (-18.0, -10.8)P<0.0001Total Cholesterol-1.418.0HDL-C4.04.3Triglycerides24.5-3.1Non-HDL-C-5.413.7Difference (95% CI): -19.4 (-23.4, -15.4)P<0.0001PIFELTRO + 2 NRTIs (n=320)DRV/r + 2 NRTIs (n=311)

The clinical benefit of these findings has not been demonstrated.

In DRIVE-FORWARD, changes from baseline at week 96 were similar to those seen at week 48.

  • aDoravirine-based FDC (DELSTRIGO) = doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg tablets.
  • bPatients on lipid-lowering agents at baseline were excluded from these analyses.
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Study design

DRIVE-SHIFT study design

A randomized, international, multicenter, open-label study of adults with virologically suppressed HIV-1 for ≥6 months on 2 NRTIs with a PI plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI, with no history of virologic failure. Patients either immediately switched to a doravirine-based FDC on Day 1 of the study for 48 weeks (ISG [n=447]) or continued on their baseline regimen and switched after 24 weeks to a doravirine-based FDC (DSG [n=223]).

  • Primary efficacy outcome: Proportion of patients with HIV-1 ≥50 copies/mL: 2% for a doravirine-based FDC (ISG at week 48) vs 1% (DSG at week 24). Difference (95% CI): (-1.3, 2.6)
  • Secondary safety end point: Mean change from baseline in fasting LDL-C and non-HDL-C1

DRIVE-FORWARD study design

A randomized, multicenter, double-blind, active-controlled, non-inferior, phase 3 study comparing PIFELTRO 100 mg once daily (n=383) vs DRV 800 mg + ritonavir 100 mg once daily (n=383), each in combination with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator, in treatment-naïve adult patients with HIV-1 RNA ≥1000 copies/mL.2

  • Primary efficacy end point: Proportion of patients who had plasma HIV-1 RNA <50 copies/mL at week 482

Definitions

  • 3TC, lamivudine, ABC, abacavir; DRV+r; darunavir+ritonavir; FDC, fixed-dose combination; FTC, emtricitabine; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein-cholesterol, NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; 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. 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. doi:10.1016/S2352-3018(18)30021-3. Epub 2018 March 25.

Indications

PIFELTRO 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 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 co-administered 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, co-administration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.

Co-administration of PIFELTRO with efavirenz, etravirine, or nevirapine is not recommended.

If DELSTRIGO is co-administered 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 co-administered 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 EFV/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 prespecified. 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 48 in LDL-C and non-HDL-C were prespecified. 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 PIFELTROTM (doravirine), please read the accompanying Prescribing Information. The Patient Information also is available. Before prescribing DELSTRIGOTM (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.

US-DOR-0064210/20