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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapies. ( 5.1 ) • QTc prolongation: Use RUKOBIA with caution in patients with a history of QTc prolongation or with relevant pre-existing cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. ( 5.2 ) • Elevations in hepatic transaminases in patients with hepatitis B (HBV) or C (HCV) virus co-infection: Elevations in hepatic transaminases were observed in a greater proportion of subjects with HBV and/or HCV co-infection compared with those with HIV mono-infection. ( 5.3 ) 5.1 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RUKOBIA [see Adverse Reactions ( 6.1 )] . During the initial phase of combination antiretroviral treatment, patients whose immune systems respond 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. 5.2 QTc Prolongation with Higher than Recommended Dosages RUKOBIA at 2,400 mg twice daily, 4 times the recommended daily dose, has been shown to significantly prolong the QTc interval of the electrocardiogram [see Drug Interactions ( 7.4 ), Clinical Pharmacology ( 12.2 )] . RUKOBIA should be used with caution in patients with a history of QTc interval prolongation, when coadministered with a drug with a known risk of Torsade de Pointes, or in patients with relevant pre-existing cardiac disease. Elderly patients may be more susceptible to drug-induced QT interval prolongation. 5.3 Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-Infection Monitoring of liver chemistries is recommended in patients with hepatitis B (HBV) and/or C (HCV) virus co-infection. Elevations in hepatic transaminases were observed in a greater proportion of subjects with HBV and/or HCV co-infection compared with those with HIV mono-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn [see Adverse Reactions ( 6.1 )] . Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting RUKOBIA in patients co-infected with hepatitis B. 5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of RUKOBIA and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.3 ), Clinical Pharmacology ( 12.3 )] : • Loss of therapeutic effect of RUKOBIA and possible development of resistance due to reduced exposure of temsavir. • Possible prolongation of QTc interval from increased exposure to temsavir [see Drug Interactions ( 7.4 )] . See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with RUKOBIA, review concomitant medications during therapy with RUKOBIA, and monitor for the adverse reactions associated with the concomitant drugs.
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Immune reconstitution syndrome [see Warnings and Precautions ( 5.1 )] . • QTc prolongation [see Warnings and Precautions ( 5.2 )] . • Elevations in hepatic transaminases in patients with hepatitis B or C virus co-infection [see Warnings and Precautions ( 5.3 )]. The most common adverse reaction (all grades) observed in ≥5% of subjects was nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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 [see Clinical Studies ( 14 )] . 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) OBT = Optimized background therapy. 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 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% 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, d ysgeusia, 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) OBT = Optimized background therapy; 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). 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/mm 3 ) 4% Triglycerides (>500 mg/dL) 5% Urate (>12 mg/dL) 3% 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 pre-existing 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 [see Warnings and Precautions ( 5.3 )] .
adverse reactions table
<table ID="_Ref43893202" width="100%"><caption>Table 1. Adverse Reactions<sup>a</sup> (Grades 1 to 4) Reported in ≥2% of Subjects Receiving RUKOBIA plus OBT in the BRIGHTE Trial, Randomized Cohort (Week 96 Analysis)</caption><col width="57%"/><col width="43%"/><tfoot><tr><td align="left" colspan="2" valign="top">OBT = Optimized background therapy.</td></tr><tr><td align="left" colspan="2" valign="top"><sup>a</sup> Frequencies of adverse reactions are based on all treatment-emergent adverse events attributed to study drug by the investigator. <sup>b</sup> 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. <sup>c</sup> Includes pooled terms: abdominal discomfort, abdominal pain, and abdominal pain upper. <sup>d</sup> Includes pooled terms: fatigue and asthenia. <sup>e</sup> Includes pooled terms: rash, rash generalized, rash maculo-papular, rash pruritic, and dermatitis allergic. <sup>f</sup> Includes pooled terms: insomnia, sleep deficit, sleep disorder, abnormal dreams.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">RUKOBIA plus OBT</content></paragraph><paragraph><content styleCode="bold">(n = 271)</content><sup>b</sup></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>10%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Abdominal pain<sup>c</sup></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyspepsia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fatigue<sup>d</sup></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rash<sup>e</sup></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Sleep disturbance<sup>f </sup></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Immune Reconstitution Inflammatory Syndrome</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Somnolence</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="bottom"><paragraph>2%</paragraph></td></tr></tbody></table>
adverse reactions table
<table ID="_Ref43893228" width="100%"><caption>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)</caption><col width="55%"/><col width="45%"/><tfoot><tr><td align="left" colspan="2" valign="top">OBT = Optimized background therapy; ULN = Upper limit of normal. <sup>a</sup> 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). <sup>b</sup> Grade 3 only (no Grade 4 values reported).</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Laboratory Parameter</content> <content styleCode="bold">Preferred Term</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">RUKOBIA plus OBT</content> <content styleCode="bold">(n = 271</content><sup>a</sup><content styleCode="bold">)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>ALT (>5.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>AST (>5.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Direct bilirubin (>ULN)<sup>b</sup></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Bilirubin (≥2.6 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cholesterol (≥300 mg/dL)<sup>b</sup></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Creatinine (>1.8 x ULN or 1.5 x baseline)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Creatine kinase (≥10 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hemoglobin (<9.0 g/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hyperglycemia (>250 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Lipase (>3.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>LDL cholesterol (≥190 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Neutrophils (≤599 cells/mm<sup>3</sup>)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Triglycerides (>500 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Urate (>12 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>3%</paragraph></td></tr></tbody></table>