RUKOBIA SIDE EFFECTS

Generic Name: fostemsavir extended-release tablets
Brand Name: Rukobia
Drug Class: HIV, Attachment Inhibitors

Last updated on MDtodate: 10/10/2022

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Immune reconstitution syndrome
QTc prolongation
Elevations in hepatic transaminases in patients with hepatitis B or C virus co-infection

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.

A total of 620 subjects with HIV-1 infection received at least one dose of RUKOBIA as part of a controlled clinical trial.

The primary safety assessment of RUKOBIA is based on 96 weeks of data from a Phase 3 partially randomized, international, multicenter, double-blind, placebo-controlled trial (BRIGHTE) conducted in 371 heavily treatment-experienced adult subjects. In the randomized cohort, 203 subjects received at least one dose of blinded RUKOBIA 600 mg twice daily and 69 subjects received placebo in addition to their current failing regimen for 8 days of functional monotherapy. Beyond Day 8, all randomized subjects except one received open-label RUKOBIA 600 mg twice daily plus an optimized background therapy (OBT). In the nonrandomized cohort, 99 subjects received open-label RUKOBIA 600 mg twice daily plus OBT from Day 1 onward.

A total of 370 subjects (271 randomized and 99 nonrandomized) received at least 1 dose of RUKOBIA 600 mg twice daily in the BRIGHTE trial. Overall, most (81%) of the adverse reactions reported with RUKOBIA were mild or moderate in severity. The proportion of subjects who discontinued treatment with RUKOBIA due to an adverse event was 7% at Week 96 (randomized: 5% and nonrandomized: 12%). The most common adverse events leading to discontinuation were related to infections (3% of subjects receiving RUKOBIA). Serious drug reactions occurred in 3% of subjects and included 3 cases of severe immune reconstitution inflammatory syndrome.

Data from the randomized cohort form the basis of the safety assessment of RUKOBIA because the presence of significant comorbid illness in the nonrandomized cohort (associated with advanced HIV infection) may confound the assessment of causality. Adverse reactions (all grades) reported in ≥2% of subjects in the randomized cohort in the Week 96 analysis are listed in Table 1.

Table 1. Adverse Reactions^a (Grades 1 to 4) Reported in ≥2% of Subjects Receiving RUKOBIA plus OBT in the BRIGHTE Trial, Randomized Cohort (Week 96 Analysis)

Adverse Reaction	RUKOBIA plus OBT (n = 271)^b
Nausea	10%
Diarrhea	4%
Headache	4%
Abdominal pain^c	3%
Dyspepsia	3%
Fatigue^d	3%
Rash^e	3%
Sleep disturbance^f	3%
Immune Reconstitution Inflammatory Syndrome	2%
Somnolence	2%
Vomiting	2%
^a Frequencies of adverse reactions are based on all treatment-emergent adverse events attributed to study drug by the investigator. ^b Of the 272 subjects enrolled in the randomized cohort, 1 subject who received placebo withdrew from the trial prior to receiving RUKOBIA in the open-label phase of the trial. ^c Includes pooled terms: abdominal discomfort, abdominal pain, and abdominal pain upper. ^d Includes pooled terms: fatigue and asthenia. ^e Includes pooled terms: rash, rash generalized, rash maculo-papular, rash pruritic, and dermatitis allergic. ^f Includes pooled terms: insomnia, sleep deficit, sleep disorder, abnormal dreams.

Adverse reactions in the nonrandomized cohort were similar to those observed in the randomized cohort. The most common adverse reactions reported in nonrandomized subjects were fatigue (7%), nausea (6%), and diarrhea (6%).

Less Common Adverse Reactions

The following adverse reactions occurred in <2% of subjects receiving RUKOBIA in the randomized cohort of the BRIGHTE trial. These events have been included based on the assessment of potential causal relationship and were also reported in the nonrandomized cohort.

Cardiac Disorders: Electrocardiogram QT prolonged. All reports were asymptomatic.

Musculoskeletal Disorders: Myalgia.

Nervous System Disorders: Dizziness, dysgeusia, neuropathy peripheral (includes pooled terms:neuropathy peripheral and peripheral sensory neuropathy).

Skin and Subcutaneous Tissue Disorders: Pruritus.

Laboratory Abnormalities

Selected laboratory abnormalities (Grades 3 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in ≥2% of subjects in the randomized cohort of the BRIGHTE trial are presented in Table 2.

Table 2. Selected Laboratory Abnormalities (Grades 3 to 4) Reported in ≥ 2% of Subjects in the Randomized Cohort Receiving RUKOBIA plus OBT in the BRIGHTE Trial (Week 96 Analysis)

Laboratory Parameter Preferred Term	RUKOBIA plus OBT (n = 271^a)
ALT (>5.0 x ULN)	5%
AST (>5.0 x ULN)	4%
Direct bilirubin (>ULN)^b	7%
Bilirubin ( ≥2.6 x ULN)	3%
Cholesterol (≥300 mg/dL)^b	5%
Creatinine (>1.8 x ULN or 1.5 x baseline)	19%
Creatine kinase (≥10 x ULN)	2%
Hemoglobin (<9.0 g/dL)	6%
Hyperglycemia (>250 mg/dL)	4%
Lipase (>3.0 x ULN)	5%
LDL cholesterol (≥190 mg/dL)	4%
Neutrophils (≤599 cells/mm³ )	4%
Triglycerides (>500 mg/dL)	5%
Urate (>12 mg/dL)	3%
ULN = Upper limit of normal. ^a Percentages were calculated based on the number of subjects with post-baseline toxicity grades for each laboratory parameter (n = 221 for cholesterol and triglycerides, n = 216 for LDL cholesterol, and n = 268 for all other parameters). ^b Grade 3 only (no Grade 4 values reported).

The incidence of selected laboratory abnormalities (Grades 3 to 4) in the nonrandomized cohort were overall consistent with those of the randomized cohort, with the exception of direct bilirubin (14% versus 7%), bilirubin (6% versus 3%), lipase (10% versus 5%), triglycerides (10% versus 5%), neutrophils (7% versus 4%), and leukocytes (6% versus 1%), respectively.

Changes in Serum Creatinine

Clinically relevant increases in serum creatinine have primarily occurred in patients with identifiable risk factors for reduced renal function, including preexisting medical history of renal disease and/or concomitant medications known to cause increases in creatinine. A causal association between RUKOBIA and elevation in serum creatinine has not been established.

Changes in Direct Bilirubin

Increases in direct (conjugated) bilirubin have been observed following treatment with RUKOBIA (Table 2). Cases of clinical significance were uncommon and were confounded by the presence of intercurrent serious comorbid events (e.g., sepsis, cholangiocarcinoma, or other complications of viral hepatitis co-infection). In the remaining cases, elevations in direct bilirubin (without clinical jaundice) were typically transient, occurred without increases in liver transaminases, and resolved on continued RUKOBIA.

Changes in ALT and AST in Subjects with Hepatitis B and/or Hepatitis C Virus Co-infection

A total of 29 subjects with Hepatitis B and/or Hepatitis C co-infection were enrolled in the BRIGHTE trial (randomized and nonrandomized cohorts combined). Grade 3 and 4 elevations in ALT and AST occurred in 14% of these subjects compared with 3% (ALT) and 2% (AST) of subjects without viral hepatitis co-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn.

SRC: NLM .

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