DELSTRIGO (Page 2 of 10)

5.5 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 DELSTRIGO is based on Week 96 data from two Phase 3, randomized, international, multicenter, double-blind, active-controlled trials. A total of 747 subjects received doravirine either as the single entity in combination with other antiretroviral drugs as background regimens (n=383) or as the fixed-dose DELSTRIGO (n=364), and a total of 747 subjects were randomized to control arms.

In DRIVE-AHEAD (Protocol 021), 728 adult subjects received either DELSTRIGO (n=364) or 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-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-AHEAD (Week 96)
DELSTRIGOOnce DailyN=364 EFV/FTC/TDFOnce DailyN=364
*
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 DELSTRIGO.
Rash: includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic.
Dizziness 7% 32%
Nausea 5% 7%
Abnormal Dreams 5% 10%
Headache 4% 5%
Insomnia 4% 5%
Diarrhea 4% 6%
Somnolence 3% 7%
Rash 2% 12%

The majority (66%) of adverse reactions associated with DELSTRIGO 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 Difference(DELSTRIGO — EFV/FTC/TDF)Estimate (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 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-AHEAD (Week 96)
Laboratory Parameter Preferred Term (Unit)/Limit 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.
Total bilirubin
1.1 — <1.6 × ULN 5% 0%
1.6 — <2.6 × ULN 2% 0%
≥2.6 × ULN 1% <1%
Creatinine (mg/dL)
>1.3 — 1.8 × ULN or Increase of >0.3 mg/dL above baseline 3% 2%
>1.8 × ULN or Increase of ≥1.5 × above baseline 3% 2%
Aspartate aminotransferase (IU/L)
2.5 — <5.0 × ULN 3% 3%
≥5.0 × ULN 1% 4%
Alanine aminotransferase (IU/L)
2.5 — <5.0 × ULN 4% 4%
≥5.0 × ULN 1% 3%
Alkaline phosphatase (IU/L)
2.5 — <5.0 × ULN <1% 1%
≥5.0 × ULN 0% <1%
Lipase
1.5 — <3.0 × ULN 6% 4%
≥3.0 × ULN 2% 3%
Creatine kinase (IU/L)
6.0 — <10.0 × ULN 3% 3%
≥10.0 × ULN 4% 6%
Cholesterol, fasted (mg/dL)
≥300 mg/dL 1% <1%
LDL cholesterol, fasted (mg/dL)
≥190 mg/dL <1% 2%
Triglycerides, fasted (mg/dL)
>500 mg/dL 1% 3%

Change in Lipids from Baseline

For 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 findings 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 of DELSTRIGO 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-AHEAD (Week 48)
Laboratory Parameter Preferred Term DELSTRIGOOnce DailyN=320 EFV/FTC/TDFOnce DailyN=307 Difference Estimates(DELSTRIGO — EFV/FTC/TDF)
Baseline Change Baseline Change Difference (95% CI)
Subjects on lipid-lowering agents at baseline were excluded from these analyses (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 (DELSTRIGO n=3 and EFV/FTC/TDF n=8).
*
P-value for the pre-specified hypothesis testing for treatment difference was <0.0001.
Not pre-specified for hypothesis testing.
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 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a protease inhibitor (PI) plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an 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 of greater than 1.25 × ULN, respectively, through 48 weeks on DELSTRIGO. For these ALT and AST elevations, no apparent time 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

Adverse Reactions in Pediatric Patients

The safety 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.

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