Summary Basis of Decision for Tivicay

 

Clinical Pharmacology

Human immunodeficiency virus infection (HIV) is a serious/life-threatening disease affecting thousands of Canadians. Dolutegravir, the medicinal ingredient in Tivicay, is a novel, potent and selective orally bioavailable integrase strand transfer inhibitor (INI). Dolutegravir acts by blocking the actions of HIV 1 integrase (IN) by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration, which is essential for the HIV replication cycle.

The clinical pharmacology analysis of Tivicay included reports on the human pharmacodynamic and pharmacokinetic studies. In these reports, the following topics of interest were noted:

Pharmacokinetics

Drug-Drug Interactions

In vitro, dolutegravir inhibited renal organic cation transporter 2 (OCT2). Therefore, dolutegravir may increase plasma concentrations of drugs dependent upon OCT2 for excretion, [for example (e.g.) metformin]. In vivo, dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase (UGT) 1A1 with cytochrome P450 (CYP) isozyme 3A4 as a minor route. Moderate to strong inducers of UGT1A1 and/or CYP3A4 such as etravirine (ETR), efavirenz (EFV), rifampin, fosamprenavir/ritonavir (FPV/r), and tipranavir/ritonavir (TPV/r) reduced the plasma concentrations of dolutegravir significantly. Tivicay 50 mg twice daily dosing is recommended in INI-naïve patients receiving Tivicay in combination with EFV, rifampin, FPV/r, and TPV/r. Alternative combinations that do not include EFV, rifampin, FPV/r, and TPV/r should be considered for INI-resistant patients.

Special Populations

Renal/Hepatic Impairment

Tivicay exposure was noted to be lower in subjects with severe renal impairment (creatinine clearance <30 mL/min, not on dialysis) than in healthy matched adult controls [single dose area under the curve (AUC) (0-∞), maximum plasma concentration (C_max), and C24 were 40%, 23%, and 43% lower respectively]. Tivicay should therefore be used with caution in antiretroviral treatment (ART)-experienced INI-resistant patients with severe renal impairment.

The single dose total Tivicay plasma exposure was similar between subjects with moderate hepatic impairment and matched healthy adult controls. The effect of severe hepatic impairment on the Tivicay pharmacokinetics was not studied. Tivicay is therefore not recommended for use in patients with severe hepatic impairment.

For further details on Tivicay, please refer to the Tivicay Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Tivicay was derived mainly from four pivotal Phase III studies conducted in HIV infected adult patients. These four pivotal studies were SPRING-2 and SINGLE for antiretroviral treatment (ART) naïve patients; SAILING for ART experienced, INI naïve patients; and VIKING 3 for INI resistant patients. Supportive data from a Phase I/II study (IMPAACT) conducted in children infected with HIV 1 virus was also evaluated.

Pivotal Studies

Antiretroviral Treatment Naïve Patients

The efficacy of Tivicay in HIV-infected, treatment-naïve patients was based on the analyses of 48-week data from two randomized, international, double-blind, active-controlled studies, SPRING-2 and SINGLE.

The SPRING-2 study is an ongoing Phase III, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel group, non-inferiority study. This study was conducted in HIV-1 infected ART-naïve adult patients. A total of 822 HIV-infected patients were randomized and received at least one dose of either Tivicay 50 mg once daily [Number (n) = 411] or Isentress (raltegravir) 400 mg twice daily (n = 411), both in combination with a fixed-dose dual-nucleoside reverse transcriptase inhibitor (NRTI) treatment [open-labelled, either Kivexa (abacavir sulfate/lamivudine) or Truvada (emtricitabine/ tenofovir disoproxil fumarate)] for 96 weeks. Patient randomization was stratified by baseline viral load (HIV-1 ribonucleic acid (RNA) ≤100,000 or >100,000 copies/mL) and background NRTI treatment (Kivexa or Truvada).

The SINGLE study is an ongoing Phase III, multicentre, randomized, double-blind, double-dummy, active-controlled, non-inferiority study. This study was also conducted in HIV-1 infected ART-naïve adult patients. A total of 833 HIV-infected patients were randomized and received either Tivicay 50 mg once daily along with fixed-dose of Kivexa (n = 414) or fixed-dose Atripla (efavirenz/emtricitabine/tenofovir) (n = 419) administered once daily over 96 weeks. Patient randomization was stratified according to screening plasma HIV-1 RNA ≤ or >100,000 copies/mL and the screening CD4+ lymphocyte (CD4+ cell) count ≤ or >200 cells/mm³. For the baseline measurements, most patients had a CD4+ cell count >200 cells/mm³ (86%) and the majority of patients had a baseline HIV-1 RNA equal or less than 100,000 copies/mL (68%).

The primary efficacy endpoint for both the SPRING-2 and SINGLE studies was the proportion of patients with HIV-1 RNA <50 copies/mL (undetectable) at week-48 based on the United States Food and Drug Administration (FDA)-defined 'Snapshot' analysis using a Missing, Switch, or Discontinuation = Failure (MSDF) algorithm.

Results from the SPRING-2 study demonstrated at week-48, the proportion of study participants who were virologically suppressed (HIV-1 RNA <50 copies/mL) was 88% in the Tivicay treatment group and 85% for the Isentress treatment group. Therefore, based on the primary endpoint results, Tivicay was shown to be non-inferior to Isentress. The virologic suppression treatment differences were comparable across baseline characteristics (gender, race, and age) and across ART backbone.

The week-48 SINGLE study data showed that there was a statistically significant difference in the proportion of patients achieving viral suppression (HIV-1 RNA <50 copies/mL) between the treatment group receiving Tivicay + Kivexa (88%) compared to the Atripla treatment group (81%) based on outcomes of MSDF (Snapshot) algorithm.

In SINGLE, the median time to viral suppression in the Tivicay + Kivexa treatment group was statistically significantly shorter compared to the Atripla treatment group. In the first four weeks of treatment, the proportion of patients reaching undetectable levels of HIV-1 RNA was nearly 63% in Tivicay + Kivexa-treated patients compared to only 14% in the Atripla-treated patients. High premature withdrawals due to AEs were observed in the Atripla group (10%) versus (vs.) Tivicay + Kivexa group (2%), which played a major role for lower response rate at week-48 in the Atripla treatment group. Tivicay + Kivexa-treated patients also showed statistically significantly higher CD4+ cell recovery over the 48 weeks measured (adjusted mean difference was 58.9 with 95% CI 33.41, 84.40; p<0.001).

In SINGLE, patients with high baseline viral load (>100,000 copies/mL) were found to have higher CD4+ cell recovery compared to patients with Baseline viral load less than 100,000 copies/mL irrespective of treatment group. Baseline CD4+ cell count level (≤ or >200 cells/mm³) did not seem to affect the immunologic results in terms of CD4+ cell recovery. Patients in Tivicay group with a higher baseline CD4+ cell count level (>200 cells/mm³) achieved much higher viral response rate than that in Atripla group by subgroup analyses.

Protocol defined virological failure was 4% in each treatment group in SINGLE. No INI or NRTI-resistance was observed in the Tivicay + Kivexa-treated patients in either study.

As shown by the results with different baseline strata in HIV-1 RNA and CD4+ cells, the overall efficacy may be affected if more patients with higher viral load, or more patients with a baseline CD4+ cells <200 cells/mm³ were included in the study.

Antiretroviral Treatment Experienced and Integrase Inhibitor Naïve Patients

The SAILING study is an ongoing Phase III, multicentre, randomized, double-blind, active-controlled, parallel-group, non-inferiority study, conducted in HIV-1 infected ART-experienced INI-naïve adults. Enrolled patients had at least two class resistance and one fully active agent available as background regimen (≤2 ARTs total). A total of 719 patients were randomized and received either Tivicay 50 mg once daily (n = 354) or Isentress 400 mg twice daily (n = 361), in addition to the resistance test-guided background regimen (BR)(3 and 1 patients in Tivicay and Isentress groups respectively were excluded from efficacy analyses due to site protocol violations). Patients were stratified according to screening HIV-1 RNA (≤50,000 or >50,000 copies/mL), investigator-specified number of fully active agents as background regimen (2, <2), and darunavir/ritonavir (DRV/r) use (No DRV/r use or DRV/r use with primary inhibitor-resistance mutations vs. DRV/r use without primary inhibitor-resistance mutations).

The efficacy analysis, at time of submission, was based on week-24 study results (the proportion of patients with HIV-1 RNA <50 copies/mL) which was a secondary endpoint and post-hoc analysis of the available interim data for the primary endpoint at week-48.

Based on the week-24 results, virologic suppression (HIV-1 RNA <50 copies/mL) in the Tivicay + BR-treated patients (79%) was statistically significant compared to Isentress + BR-treated patients (70%) (p = 0.003). The week 24 results were further supported by sensitivity analyses. Fewer patients experienced virologic failure at week 24 in Tivicay + BR treatment group (15%) as compared to that in the Isentress + BR treatment group (24%). Statistically fewer patients failed therapy with treatment emergent INI-resistance with Tivicay + BR (0.6%) compared to Isentress + BR (2.8%) (p = 0.016). The median CD4+ cell count increases were similar in both groups (Tivicay: cells/mm³ vs. Isentress: 93 cells/mm³). The week 24 analysis was considered to be a reliable predictor of week-48 results (the primary efficacy endpoint) and further confirmed by week-48 post-hoc analysis of the interim data.

Antiretroviral Treatment Experienced and Integrase Inhibitor Resistant Patients

The VIKING-3 study is an ongoing Phase III, multicentre, open-label, single-arm study conducted in HIV-1 infected, ART-experienced adults with virological failure due to current or historical INI-resistance to raltegravir and/or elvitegravir. This study examined the effect of Tivicay 50 mg administered twice daily over 7 days of functional monotherapy, followed by an optimized background regimen from Day 8 in addition to continued Tivicay twice-daily treatment.

The primary treatment endpoints were to assess the antiviral activity of Tivicay with current failing background regimen for 7 days, and from Day 8 with an optimized background regimen consisting of at least one fully active agent through week 24. Among 183 enrolled patients, 133 had INI-resistance (genotypic or phenotypic) at screening and 50 patients had historic evidence of INI-resistance only (no evidence of INI-resistance at screening). Patients were multiple-class ART-resistant at baseline; 79% had ≥2 NRTI, 75% ≥1 non-nucleoside reverse transcriptase inhibitor (NNRTI), and 70% ≥2 protease inhibitor-resistance mutations; and 62% had non-R5 virus.

Overall, 82% of patients achieved >1.0 log10 copies/mL HIV-1 RNA viral load decrease or <50 copies/mL at Day 8. The mean reduction of viral load from the baseline was 1.43 log10 copies/mL (±0.61).

The virologic response differed depending on the presence of IN mutations at baseline. More than 90% of patients without Q148 primary mutations achieved full response whereas patients with Q148 + 1 or ≥2 secondary mutations showed increasingly less virologic response to Tivicay monotherapy at Day 8.

The week 24 analysis focused on patients who completed 24 weeks of treatment before the data cut-off (n = 114). At week 24, the proportion of patients who achieved HIV-1 RNA <50 copies/mL was 63%. Similar to Day 8 virologic results, the virologic response rates were associated with baseline integrase genotypic resistant mutations. Patients with Q148 + 1 or ≥2 secondary mutations had a lower response at week 24. Susceptibility to background regimen did not appear to affect week 24 response. The most commonly detected additional secondary mutations in the Q148+G140 dual mutants were E138 and L74 mutations. In addition, baseline viral load and Tivicay phenotype could strongly impact week-24 response. As Tivicay FC increased, week-24 responses decreased and no patient with Tivicay FC >10 achieved HIV-1 RNA <50 copies/mL by week-24. The median increase of CD4+ cell count at week-24 over a Baseline value of 120 cells/mm³ was 65 cells/mm³.

Supportive Pediatric Study

A non-pivotal Phase I/II pediatric study, known as IMPAACT P1093, was also conducted. In this ongoing 48-week multicentre, non-comparative, open-label study, the pharmacokinetic parameters, safety, tolerability, and efficacy of Tivicay were evaluated in combination regimens in HIV-1 infected infants, children, and adolescents.

The initial dose-finding stage included intensive pharmacokinetic evaluation in 10 ART treatment-experienced, INI-naive patients (aged 12 to 18 years with 9 patients weighing ≥40 kg). Dose selection was based upon achieving similar dolutegravir plasma exposure and trough concentration as seen in adults. After dose selection, an additional 13 patients were enrolled for evaluation of long-term safety, tolerability, and efficacy.

The primary efficacy endpoint of this study was the proportion of patients with virologic success defined as the proportion of patients with HIV-1 RNA <50 copies/mL at 48 weeks. Given this study remains ongoing, week 24 study results were used for the primary efficacy analysis.

Results of the efficacy analysis showed 8 out of 10 patients achieved virologic suppression at week 24. The two patients who failed to achieve suppression had documented adherence problems and neither patient had INI resistance-associated mutations. The median increase in CD4+cell count was 118 cells/mm³ at week 24.

Revised Sponsor Proposed Indication

For this New Drug Submission, the sponsor initially sought approval for the following indication: Treatment of human immunodeficiency virus (HIV) infection in adults and children 12 years of age and older, in combination with other antiretroviral agents. Health Canada has revised this indication to specify a weight factor in children, in addition to inserting a bullet point consideration prior to initiation treatment as follows:

Tivicay, in combination with other antiviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) infection in adults and children 12 years of age and older and weighing at least 40 kg.

The following should be considered prior to initiating treatment with Tivicay:

• Poor virologic response was observed in subjects treated with Tivicay with 50 mg twice daily with an integrase strand transfer inhibitor (INI)-resistance Q148H/K/R substitution plus 2 or more additional INI-resistance substitutions, including, but not limited to L74I, E138A/K/T, and G140A/C/S.

Clinical studies of Tivicay did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from adult patients <65 years of age.

The safety and efficacy of Tivicay in children younger than 12 years or weighing less than 40 kg have not been established. In addition, the safety and efficacy of Tivicay have not been established in children less than 18 years of age who were infected with suspected or confirmed INI-resistant HIV-1 virus.

Overall, the results of the pivotal studies, in addition to efficacy results from the non-pivotal study demonstrate that Tivicay is non-inferior to the comparators used within the clinical studies analyzed.

For more information, refer to the Tivicay Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The overall safety profile of Tivicay is based on over 1,500 HIV-infected patients treated with a Tivicay-based regimen in Phase II and III clinical studies. In addition to the four Phase III clinical studies previously discussed in the Clinical Efficacy section, additional Phase IIb studies, as well as a Sponsor-submitted 60-day safety update were also reviewed.

Antiretroviral Treatment Naïve Patients

In the SPRING-2 study, over the 48-week period the safety profile for Tivicay was comparable to Isentress, with similar rates of adverse events (AEs) reported in both treatment groups, Tivicay 82% and Isentress 83% respectively. There were also low rates of discontinuation due to AEs in both treatment groups (2% each). Furthermore, there were also similar rates for Serious Adverse Events (SAEs) in both treatment groups, Tivicay 7% and Isentress 8% respectively. Vomiting, diarrhea and gastric erosions observed in Tivicay animal studies were not reported as frequently in the clinical studies conducted. There were more patients in the Tivicay treatment group with maximum treatment-emergent alanine aminotransferase (ALT) levels >10 times the Upper Limit of Normal (ULN) than in the Isentress treatment group [Tivicay 5 (1%) Isentress 2 (<1%)] and all discontinued the investigational product. There were no serious events of rash and no increased risk of psychiatric disorders observed in this study. Similar improvements from Baseline in Health Outcome scores for Tivicay and Isentress were observed; there were no significant differences for Tivicay vs. Isentress in these outcomes.

Similar rates for graded laboratory toxicities were seen in both treatment groups except for the rate of Grade 3 to 4 creatine phosphokinase (CPK) in the Tivicay group (5%) vs. Isentress group (3%). In subjects receiving Tivicay with Grade 4 CPK elevations, the changes were transient without associated AEs, clinically significant symptoms or changes in renal function.There was no evidence of a clinically significant impairment of lipid profile in either treatment group.

In the SINGLE study, over the 48-week period the Tivicay + Kivexa treatment group had favourable safety and tolerability profiles compared to that of the Atripla treatment group. Patients in the Atripla treatment group were significantly more likely to develop dizziness, abnormal dreams, rash, anxiety, and somnolence, whereas patients in the Tivicay + Kivexa treatment group were more likely to develop insomnia. However, the proportion of drug-related insomnia episodes (Grade 2 to 4) was comparable in both treatment groups (Tivicay 3% vs. Atripla 2%) and none of these events were reported as an SAE. Additionally, very few episodes resulted in the permanent discontinuation of the investigational product and patient withdrawal. It was observed however that more Female subjects in the Tivicay + Kivexa treatment group developed at least one episode of insomnia compared to Female subjects in the Atripla treatment group (19% vs 6%). Whereas the proportion of Male subjects developing at least one episode of insomnia was comparable across both treatment groups (15% vs 12%).

Drug-related AEs were overall more commonly reported for the Atripla treatment group, and specifically, episodes of dizziness, abnormal dreams, and rash were more commonly reported for the group, compared to the Tivicay group. There was also a greater frequency of drug-related Grade 3 and 4 AEs assessed as attributable to Atripla. There were no drug-related Grade 4 AEs related to the Tivicay treatment group. Overall, only one patient (<1%) experienced an SAE (drug hypersensitivity) considered to be related to treatment in the Tivicay treatment group. There was no death reported in Tivicay group. Two patients, both HLA B*5701 negative in this double-blind study were considered to have abacavir hypersensitivity reactions in the Tivicay + Kivexa treatment group. Higher rates of discontinuation due to AEs were observed in the Atripla group (10%) than that in the Tivicay group (2%).

Laboratory value analyses showed comparable measurements in both treatment groups with the exception of Grade 2 CPK (4% in Tivicay vs. 2% in Atripla) and Grade 2 hyperglycemia (7% in Tivicay vs. 5% in Atripla).

Antiretroviral Treatment Experienced and Integrase Inhibitor Naïve Patients

In the SAILING study, over the 48-week period, drug-related AEs (Grade 2 to 4) reported by more than one patient in Tivicay-treated patients vs. Isentress-treated patients were as follows: diarrhea (Tivicay 2% vs. Isentress 1%), nausea (Tivicay 1% vs. Isentress <1%), headache (Tivicay <1% vs. Isentress <1%) and upper abdominal pain (Tivicay <1% vs. Isentress 0%). Adverse events leading to discontinuation of investigational product were 2% in the Tivicay group vs. 4% in the Isentress group. Of the 7 patients with AEs leading to withdrawal in the Tivicay group, 4 events (in three patients) were considered to be drug-related: hepatoxicity (2), renal impairment (1) and myositis (1). Two of these events were also considered to be serious. No deaths were reported in the Tivicay group.

In laboratory values, more incidents of total bilirubin post-baseline emergent elevations were found in both treatment groups (Tivicay and Isentress) than that within the ART-naïve clinical studies. Some of these transient total bilirubin elevations observed likely reflect competition between Tivicay and unconjugated bilirubin through the UGT1A pathway and therefore was determined not to be clinically relevant. Total bilirubin elevations (Grade 2 to 4) were reported a little higher in the Tivicay group (12%) and Isentress group (11%) in the SAILING study. This was due largely to concomitant use of atazanavir (ATV) or ritonavir-boosted atazanavir (ATV/r) as part of their background regimen in the majority of these patients (36/44 Tivicay vs. 34/40 Isentress).

The number of patients who experienced post-baseline hepatobiliary laboratory abnormalities (ALT ≥3× ULN) was 19 (5%) in the Tivicay group and 11 (3%) in the Isentress group. Half of these patients had hepatitis B (HBV) and/or hepatitis C (HCV) co-infections when receiving study treatment. Post-baseline ALT > 5× ULN was found in 9 (3%) patients in the Tivicay treatment group and 7 (2%) in the Isentress treatment group. Three patients on Tivicay and no patients on Isentress had a combination of ALT >3× ULN with total bilibubin ≥2× ULN and ALP <2× ULN. They all met the protocol-defined liver stopping criteria and were associated with HBV flare and/ or acute HCV co-infections.Most of the liver ALT elevations were either due to HBV flare and/or Immune Reconstitution Inflammatory Syndrome (IRIS or to HCV IRIS). Maintaining effective HBV treatment and monitoring liver chemistries for IRIS in HBV or HCV co-infected patients when starting Tivicay-based therapy is an important measure. This clinically important safety information has been included in the Warnings and Precautions and in the Adverse Drug Reaction sections of the Tivicay Product Monograph

Adverse drug reactions (ADRs) Grade 1 or 2 were reported in 13% and 6% (respectively) in Tivicay-treated patients compared to 15% and 7% (respectively) in Isentress-treated patients. No drug-related hypersensitivity reaction (HSR) events were reported in either treatment group. In addition, no serious rash was observed in the Tivicay treatment group.

Creatine phosphokinase (CPK) Grade 3 to 4 abnormalities were reported in 2% of Tivicay-treated patients compared to 1% in the Isentress treatment group. Cases of myalgia or myositis with concurrent CPK elevations were noted. At least one case in a Tivicay-treated patient was determined as drug-related following a dechallenge and rechallenge with Tivicay. This case was also associated with acute renal insufficiency. Consequently, myositis or myalgia, and renal impairment issues have been appropriately identified in the Tivicay Product Monograph.

No evidence of an increased risk of Torsades de Pointe was shown with the use of Tivicay. There also was no untoward effect on the overall lipid profile with either use of Tivicay or Isentress. The only pharmacokinetic/pharmacodynamic relationship observed between Tivicay and clinical chemistries was a correlation with total bilirubin and serum creatinine, which was not considered clinically significant.

Antiretroviral Treatment Experienced and Integrase Inhibitor Resistant Patients

Patients in this open label, non-comparative single-arm VIKING 3 study were heavily treatment-experienced adults and multi-class resistant including current or historical evidence of INI resistance to raltegravir and /or elvitegravir. The median exposure to the Tivicay study drug was 169 days. The most commonly reported investigator attributable AEs were diarrhea, nausea, and headache (5% each) and the adverse drug reactions (ADR) with Grade 2 to 4 in severity were diarrhea and headache (2% each). There was one patient with drug-related Grade 4 ADR (ALT increased) leading to discontinuation of Tivicay. Additionally, there was only one SAE reported as Tivicay related (drug eruption/ hypersensitivity) and the patient discontinued Tivicay treatment due to this event. The most common laboratory abnormality noted was Grade 3 to 4 CPK elevations (4%). One percent of patients had a Grade 3 to 4 treatment-emergent neutropenia.

Overall Conclusion

Tivicay's safety profile was shown to be similar across ART-naive, ART-experienced INI-naive and INI-resistant patient populations. The most common adverse reactions of moderate to severe intensity and incidence ≥2% noted in these studies were insomnia, headache, and diarrhea.

Incidence of hypersensitivity reaction (HSR) with or without systemic involvement in Tivicay-treated patients was found at a rate of <1% and these events were mainly Grade 1 to 2 in intensity. Yet, due to its clinical relevance (e.g., skin rash, possibility of systemic involvement or organ dysfunction), Tivicay HSR is recognized as a significant risk for Tivicay regardless of dose or patient population. The risk is adequately presented in the Warnings and Precautions section of the Tivicay Product Monograph.

Hepatobiliary disorder adverse events (AEs) were identified in 2% of the ART-naïve patients, 3% in the ART-experienced INI-naïve patients, and 5% in the INI-resistant patients. Serious AEs or AEs resulting in discontinuation of the study drug/withdrawal were reported in less than 1% of study patients. Post-baseline alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin and alkaline phosphatase (AKP) elevations, indicating drug associated liver injury or hepatotoxic effects of drug hypersensitivity and/or Immune Reconstitution Inflammatory Syndrome (IRIS), were reported in both ART-naïve and ART-experienced patients. Patients with hepatitis B and/or C co-infection at baseline had a higher incidence of post-baseline emergent (Grade 2 to 4) liver toxicities. In hepatitis B co-infected cases, liver damage was associated with hepatitis B flare due to withdrawal or lack of hepatitis B active therapy when starting Tivicay therapy. In hepatitis C co-infected patients, IRIS was a greater risk in the setting of HIV virologic and immunologic responses to Tivicay. Therefore, maintaining effective hepatitis B treatment to prevent hepatitis B flare and monitoring liver chemistries for IRIS in hepatitis C co-infected patients when starting Tivicay-based therapy are emphasized.

Increases in total bilirubin (without clinical jaundice) (Grade 2 to 4) were observed for Tivicay and Isentress (but not efavirenz). These changes of -0.04 µmol/L (range -24 µmol/L to 14 µmol/L) are not considered clinically relevant as they likely reflect competition between dolutegravir and unconjugated bilirubin through uridine diphosphate glucuronosyl transferase (UGT) 1A1 pathway. Total bilirubin elevations were reported high in both the Tivicay treatment group (44/357, 12%) and the Isentress treatment group (40/362, 11%) in the SAILING study. This was due largely to concomitant use of ATV or ATV/r as part of the background regimen in the majority of these patients (36/44 in Tivicay vs. 34/40 in Isentress).

In Phase III studies, Grade 3 to 4 creatine phosphokinase (CPK) abnormalities were reported in 3% to 5% of treatment-naïve patients, 2% of treatment-experienced INI-naive patients, and 4% of INI-resistant patients with Tivicay therapy. Cases of myalgia or myositis with concurrent CPK elevations have been reported.

Overall the renal profile of Tivicay is comparable to the comparators used in clinical studies conducted. Mild or moderate elevation of creatinine, likely related to organic cation transporter 2 (OCT2) receptor inhibition of creatinine tubular secretion by Tivicay, have been reported and appropriately listed in the Tivicay Product Monograph. Clinical cases of renal insufficiency/impairment AEs were reported in less than 1% of Tivicay-treated patients. There was one case deemed as Tivicay-associated which has been appropriately addressed in adverse drug reaction section of the Product Monograph due to its clinical relevance.

Mild to moderate events indicative of general gastrointestinal intolerance (i.e., diarrhea, nausea, vomiting or upper abdominal pain) were seen in most clinical studies and was noted for Tivicay treatment regardless of dose or treatment population. The nature and incidence rate appeared not changed with different Tivicay dosing. This issue has also been addressed in the adverse drug reaction section of the Tivicay Product Monograph.

Supportive Pediatric Study

Pediatric Safety

 

 

Although the pediatric safety data derived from the IMPAACT study is limited (23 patients over 24 week period), the ADR profile was similar to that observed in adults. For all AEs regardless of causality, Grade 2 rash, diarrhea, headache, oropharyngeal pain, abdominal pain, and fatigue were reported in 2 patients each. There were no Grade 3 or 4 AEs, no drug-related AEs, no SAEs, and no deaths reported.

Grade 3 laboratory abnormalities were elevated total bilirubin and lipase in one subject each.  There were no Grade 4 laboratory abnormalities. The change in mean serum creatinine was similar to that observed in adults. There were no AEs leading to withdrawal or discontinuation. Also, no laboratory events were considered related to Tivicay. Small increases in creatinine were noted in the pediatric population (Grade 1 only). The Pediatric 60-day safety update provided additional safety data which further supported a positive safety profile. Therefore, based on limited safety data from 23 patients over 24 weeks, the safety profile in pediatric patients was in general similar to that in adults.

For more information on Tivicay, refer to the Tivicay Product Monograph approved by Health Canada and available through the Drug Product Database.