DELSTRIGO SIDE EFFECTS
- Generic Name: doravirine, lamivudine, and tenofovir disoproxil fumarate tablets
- Brand Name: Delstrigo
SIDE EFFECTS
The following adverse reactions are discussed in other sections of the labeling:
- Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV.
- New Onset or Worsening Renal Impairment.
- Bone Loss and Mineralization Defects.
- Immune Reconstitution Syndrome.
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)
| DELSTRIGO Once Daily N=364 |
EFV/FTC/TDF Once Daily N=364 |
|
| 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% |
| *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. |
||
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)
| DELSTRIGO Once Daily N=364 |
EFV/FTC/TDF Once Daily N=364 |
Treatment Difference (DELSTRIGO -EFV/FTC/TDF) Estimate (95% CI)† | |
| 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) |
| *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. |
|||
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 | DELSTRIGO Once Daily N=364 |
EFV/FTC/TDF Once Daily N=364 |
| Blood Chemistry | ||
| Total bilirubin | ||
| 1.1 – <1.6 x ULN | 5% | 0% |
| 1.6 – <2.6 x ULN | 2% | 0% |
| ≥2.6 x ULN | 1% | <1% |
| Creatinine (mg/dL) | ||
| >1.3 – 1.8 x ULN or Increase of >0.3 mg/dL above baseline | 3% | 2% |
| >1.8 x ULN or Increase of ≥1.5 x above baseline | 3% | 2% |
| Aspartate aminotransferase (IU/L) | ||
| 2.5 – <5.0 x ULN | 3% | 3% |
| ≥5.0 x ULN | 1% | 4% |
| Alanine aminotransferase (IU/L) | ||
| 2.5 – <5.0 x ULN | 4% | 4% |
| ≥5.0 x ULN | 1% | 3% |
| Alkaline phosphatase (IU/L) | ||
| 2.5 – <5.0 x ULN | <1% | 1% |
| ≥5.0 x ULN | 0% | <1% |
| Lipase | ||
| 1.5 – <3.0 x ULN | 6% | 4% |
| ≥3.0 x ULN | 2% | 3% |
| Creatine kinase (IU/L) | ||
| 6.0 – <10.0 x ULN | 3% | 3% |
| ≥10.0 x 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% |
| 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. |
||
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 Week48.
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 | DELSTRIGO Once Daily N=320 |
EFV/FTC/TDF Once Daily N=307 |
Difference Estimates (DELSTRIGO -EFV/FTC/TDF) | ||
| Baseline | Change | Baseline | Change | Difference (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 | – |
| 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. |
|||||
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 DRIVESHIFT 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 x 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 x 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 x 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 HDLcholesterol 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 Daily N=244 |
PI + ritonavir (Week 0-24) Once Daily N=124 |
Difference Estimates | ||
| Baseline | Change | Baseline | Change | Difference (95% CI) | |
| 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 | – |
| 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. |
|||||
Postmarketing Experience
The following adverse reactions have been identified during postmarketing experience in patients receiving lamivudine- or TDF-containing regimens. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Lamivudine
Body as a Whole: redistribution/accumulation of body fat
Endocrine and Metabolic: hyperglycemia
General: Weakness
Hemic and Lymphatic: anemia (including pure red cell aplasia and severe anemias progressing on therapy)
Hepatic and Pancreatic: lactic acidosis and hepatic steatosis, posttreatment exacerbations of hepatitis B
Hypersensitivity: anaphylaxis, urticaria
Musculoskeletal: muscle weakness, CPK elevation, rhabdomyolysis
Skin: alopecia, pruritus
TDF
Immune System Disorders: allergic reaction, including angioedema
Metabolism and Nutrition Disorders: lactic acidosis, hypokalemia, hypophosphatemia
Respiratory, Thoracic, and Mediastinal Disorders: dyspnea
Gastrointestinal Disorders: pancreatitis, increased amylase, abdominal pain
Hepatobiliary Disorders: hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)
Skin and Subcutaneous Tissue Disorders: rash
Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy
Renal and Urinary Disorders: acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria
General Disorders and Administration Site Conditions: asthenia
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.
SRC: NLM .