JULUCA SIDE EFFECTS
- Generic Name: dolutegravir and rilpivirine tablets, for oral use
- Brand Name: Juluca
- Drug Class: HIV, NNRTIs, HIV, Integrase Inhibitors
SIDE EFFECTS
The following adverse reactions are described below and in other sections of the labeling:
- Skin and hypersensitivity reactions
- Hepatotoxicity
- Depressive disorders
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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety assessment of JULUCA in HIV-1–infected, virologically suppressed subjects switching from their current antiretroviral regimen to dolutegravir plus rilpivirine is based on the pooled primary Week 48 analyses of data from 2 identical, international, multicenter, open-label trials, SWORD-1 and SWORD-2.
A total of 1,024 adult HIV-1–infected subjects who were on a stable suppressive antiretroviral regimen (containing 2 nucleoside reverse transcriptase inhibitors [NRTIs] plus either an integrase strand transfer inhibitor [INSTI], a non-nucleoside reverse transcriptase inhibitor [NNRTI], or a protease inhibitor [PI]) for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine, were randomized and received treatment. Subjects were randomized 1:1 to continue their current antiretroviral regimen or be switched to dolutegravir plus rilpivirine administered once daily. In the pooled analyses, the proportion of subjects who discontinued treatment due to an adverse event was 4% in subjects receiving dolutegravir plus rilpivirine once daily and less than 1% in subjects who remained on their current antiretroviral regimen. The most common adverse events leading to discontinuation were psychiatric disorders: 2% of subjects receiving dolutegravir plus rilpivirine and less than 1% on the current antiretroviral regimen.
The most common adverse reactions (ARs) (all grades) reported in at least 2% of subjects in the Week 48 pooled analyses from SWORD-1 and SWORD-2 are provided in Table 2.
Table 1. Adverse Reactions (Grades 1 to 4) Reported in at Least 2% of Virologically Suppressed Subjects with HIV-1 Infection in SWORD-1 and SWORD-2 Trials (Week 48 Pooled Analyses)
| Adverse Reaction | Dolutegravir plus Rilpivirine (n = 513) |
Current Antiretroviral Regimen (n = 511) |
| Diarrhea | 2% | <1% |
| Headache | 2% | 0 |
Less Common Adverse Reactions
The following ARs occurred in less than 2% of subjects receiving dolutegravir plus rilpivirine or are from studies described in the prescribing information of the individual components, TIVICAY (dolutegravir) and EDURANT (rilpivirine). Some events have been included because of their seriousness and assessment of potential causal relationship.
General Disorders: Fatigue.
Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, nausea, upper abdominal pain, vomiting.
Hepatobiliary Disorders: Cholecystitis, cholelithiasis, hepatitis.
Immune System Disorders: Immune reconstitution syndrome.
Metabolism and Nutrition Disorders: Decreased appetite.
Musculoskeletal Disorders: Myositis.
Nervous System Disorders: Dizziness, somnolence.
Psychiatric Disorders: Depressive disorders including depressed mood; depression; suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Other reported psychiatric adverse reactions include anxiety, insomnia, sleep disorders, and abnormal dreams.
Renal and Urinary Disorders: Glomerulonephritis membranous, glomerulonephritis mesangioproliferative, nephrolithiasis, renal impairment.
Skin and Subcutaneous Tissue Disorders: Pruritus, rash.
Laboratory Abnormalities
Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects are presented in Table 3.
Table 2. Selected Laboratory Abnormalities (Grades 2 and 3 to 4; Week 48 Pooled Analyses) in SWORD-1 and SWORD-2 Trials
| Laboratory Parameter Preferred Term | Dolutegravir plus Rilpivirine (n = 513) |
Current Antiretroviral Regimen (n = 511) |
| ALT | ||
| Grade 2 (>2.5-5.0 x ULN) | 2% | <1% |
| Grade 3 to 4 (>5.0 x ULN) | <1% | <1% |
| AST | ||
| Grade 2 (>2.5-5.0 x ULN) | <1% | 2% |
| Grade 3 to 4 (>5.0 x ULN) | <1% | <1% |
| Total Bilirubin | ||
| Grade 2 (1.6-2.5 x ULN) | 2% | 4% |
| Grade 3 to 4 (>2.5 x ULN) | 0 | 3% |
| Creatine kinase | ||
| Grade 2 (6.0-9.9 x ULN) | <1% | <1% |
| Grade 3 to 4 (≥10.0 x ULN) | 1% | 2% |
| Hyperglycemia | ||
| Grade 2 (126-250 mg/dL) | 4% | 5% |
| Grade 3 to 4 (>250 mg/dL) | <1% | <1% |
| Lipase | ||
| Grade 2 (>1.5-3.0 x ULN) | 5% | 5% |
| Grade 3 to 4 (>3.0 x ULN) | 2% | 2% |
| ULN = Upper limit of normal. | ||
Changes in Serum Creatinine
Dolutegravir and rilpivirine have been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Increases in serum creatinine occurred within the first 4 weeks of treatment with dolutegravir plus rilpivirine and remained stable through 48 weeks. A mean change from baseline of 0.093 mg per dL (range: -0.30 to 0.58 mg per dL) was observed after 48 weeks of treatment with dolutegravir plus rilpivirine. These changes are not considered to be clinically relevant.
Serum Lipids
At 48 weeks, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and total cholesterol to HDL ratio were similar between the treatment arms.
Bone Mineral Density Effects
Mean bone mineral density (BMD) increased from baseline to Week 48 in subjects who switched from an antiretroviral treatment (ART) regimen containing tenofovir disoproxil fumarate (TDF) to dolutegravir plus rilpivirine (1.34% total hip and 1.46% lumbar spine) compared with those who continued on treatment with a TDF-containing antiretroviral regimen (0.05% total hip and 0.15% lumbar spine) in a dual-energy X-ray absorptiometry (DXA) substudy. BMD declines of 5% or greater at the lumbar spine were experienced by 2% of subjects receiving JULUCA and 5% of subjects who continued their TDF-containing regimen. The long-term clinical significance of these BMD changes is not known.
Fractures (excluding fingers and toes) were reported in 3 (0.6%) subjects who switched to dolutegravir plus rilpivirine and 9 (1.8%) subjects who continued their current antiretroviral regimen through 48 weeks.
Adrenal Function
In the pooled Phase 3 trials results analysis of rilpivirine, at Week 96, there was an overall mean change from baseline in basal cortisol of -0.69 (-1.12, 0.27) micrograms/dL in the rilpivirine group and of -0.02 (-0.48, 0.44) micrograms/dL in the efavirenz group. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the rilpivirine group is not known. Refer to the EDURANT (rilpivirine) Prescribing Information for additional information.
Postmarketing Experience
The following adverse reactions have been identified during postmarketing experience in patients receiving a dolutegravir-or rilpivirine-containing regimen. Because these 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.
Hepatobiliary Disorders
Acute liver failure, hepatotoxicity.
Investigations
Weight increased.
Musculoskeletal Disorders
Arthralgia, myalgia.
Renal And Genitourinary Disorders
Nephrotic syndrome.
Skin And Subcutaneous Tissue Disorders
Severe skin and hypersensitivity reactions, including DRESS.
SRC: NLM .