Safety and Effectiveness Analysis of Dolutegravir in Patients with HIV-1: Interim Report of Post-Marketing Surveillance in Japan.

INTRODUCTION: Dolutegravir (DTG), a novel HIV-integrase strand transfer inhibitor (INSTI), is usually used with multiple antiretrovirals (ARVs) for treatment of HIV. DTG is now approved as Tivicay tablets in over 120 countries and Triumeq combination tablets (DTG/abacavir [ABC]/lamivudine [3TC]) in over 90 countries. In Japan, these formulations have been marketed since 2014 and 2015. The post-marketing prospective surveillance has been conducted as part of the HIV-Related Drug (HRD) cooperative survey aimed to collect actual drug use information in all of these DTG-treated patients in accordance with conditions for initial approvals. METHODS: The survey has been conducted to evaluate long-term safety and effectiveness of DTG since 2014, for approximately 6 years. The safety was evaluated by incidence of adverse drug reactions (ADRs) and change in body weight. The effectiveness was evaluated by plasma HIV RNA copies/mL and peripheral CD4+ cell counts. RESULTS: Of 2292 patients in 30 Japanese sites, 565 (24.65%) reported ADRs. The most common ADR was blood creatinine increased (4.28%). Incidence of ADRs was statistically significantly higher in patients with severe symptoms (Centers for Disease Control and Prevention [CDC] categories B and C) than those with category A, and in patients with comorbidities than those without comorbidities. Whereas incidence of ADRs was statistically significantly lower in antiretroviral therapy (ART)-experienced patients than that in ART-naïve patients. Incidence of ADRs related to suicide or self-injurious behavior was statistically significantly higher in patients with comorbidities of psychiatric disorders than those without comorbidities. The body weight tended to increase over time and those changes and percentage changes from baseline were greater in ART-naïve patients compared with ART-experienced patients. HIV RNA copies/mL and CD4+ cell counts showed favorable shifts from baseline in both ART-naïve and ART-experienced patients. CONCLUSION: The results of the survey identified no new safety and effectiveness risks in Japanese patients with HIV/AIDS treated with DTG.

Safety analysis of Lexiva tablets 700 (fosamprenavir calcium hydrate) in post-marketing surveillance in Japan.

Objective: Fosamprenavir, a protease inhibitor (PI) to treat human immunodeficiency virus (HIV)-infected patients, has been approved in more than 40 countries and mainly used with nucleoside reverse transcriptase inhibitors. In Japan, Lexiva tablet (fosamprenavir calcium hydrate) has been marketed since January 2005 and used in clinical practice. The safety and effectiveness of fosamprenavir in HIV-infected Japanese patients were evaluated in an observational surveillance study (OTH112334).Methods: A post-marketing surveillance study (PMS) of fosamprenavir usage in HIV-infected Japanese subjects evaluating drug safety was conducted under Good Post-marketing Study Practice from January 2005 to December 2014.Results: Of 364 patients receiving fosamprenavir, 51% received emtricitabine/tenofovir disoproxil fumarate. Adverse events whose causal relationship could not be completely ruled out (adverse drug reactions; ADRs) were reported in 43.7%; the most common were diarrhoea (10.4%), hyperlipidaemia (8.5%) and hypertriglyceridaemia (6.9%). Serious ADRs were reported in 26 patients (32 events), including 1 death attributed to hepatic failure. Most ADRs occurred within 180 days after fosamprenavir was started. ADRs were more frequent in patients with the Centers for Disease Control and Prevention category B (AIDS or lipid disorders) or in those taking fosamprenavir combined with abacavir and lamivudine. Although spontaneous bleeding has been reported in hemophiliac patients taking other PIs, in this survey, only one muscle haemorrhage case was reported in 24 hemophiliac patients.Conclusions: The results of this PMS analysis in Japan support its known safety profile and identified no new safety risks for people living with HIV/AIDS in Japan currently on, or beginning treatment with, fosamprenavir.

Safety analysis of Ziagen® (abacavir sulfate) in postmarketing surveillance in Japan.

PURPOSE: Abacavir is a nucleoside reverse transcriptase inhibitor indicated for human immunodeficiency virus (HIV) infection. In Japan, Ziagen® (300-mg abacavir sulfate) has been marketed since 1999. To obtain safety data on Ziagen, a mandatory postmarketing surveillance was conducted between September 1999 and September 2009. METHODS: A joint survey [HIV-related Drug Surveys (HRD)] has been conducted involving manufacturers of drugs for HIV treatment in Japan. Safety data from total 643 cases (1345.7 person-years) registered to the HRD surveys and received Ziagen were obtained. Adverse drug reaction (ADR) was defined as adverse event of which association with abacavir could not be "ruled out." RESULTS: It was found that the overall frequency of ADR was 47.6% (306/643); the common ADRs were "hyperlipidemia," "nausea," "increased γ-glutamyltransferase level," "increased blood triglycerides," "abnormal hepatic function," and so on. Serious adverse events were reported in 65 subjects; however, none of the three fatal cases were clearly associated with Ziagen use. The survey-defined hypersensitivity has been infrequently reported in 15 subjects (2.3%). Although some studies had indicated of the association between abacavir and myocardial infarction, no ischemic heart diseases were reported in the present survey. Two of the three pregnant cases delivered normal neonates (one induced abortion). CONCLUSIONS: During the mandatory postmarketing survey of Ziagen, there were no cases of ischemic heart diseases, and the incidence of hypersensitivity was considerably low. These indicated that abacavir can be safely used in Japanese HIV+ population. However, the safety profile of Ziagen should be continued to be monitored through pharmacovigilance.

Safety analysis of Epzicom® (lamivudine/abacavir sulfate) in post-marketing surveillance in Japan.

PURPOSE: To obtain safety and effectiveness data on a combined anti-HIV drug, Epzicom (abacavir 600 mg/lamivudine 300 mg), a post-marketing surveillance on Epzicom that was required by the Japanese regulatory authority was conducted between January 2005 and December 2010. METHODS: A joint survey (HIV-related drug [HRD] survey) has been conducted involving manufacturers of drugs for treatment of HIV infection in Japan. Safety and effectiveness data from total 624 cases (1107.3 person-years) registered to the HRD surveys and received Epzicom were obtained. Adverse drug reactions (ADRs) were defined as adverse events (AE) of which association with Epzicom could not be 'ruled out'. RESULTS: It was found that the incidence of ADR was 32.4% (202/624 cases) on the case basis. In addition, the frequently reported ADR included hyperlipidaemia (59 cases), hypertriglyceridaemia (21 cases), blood bilirubin increased (19 cases), gamma-glutamyltransferase increase (14 cases), blood triglyceride increase (14 cases) and rash (14 cases). Serious AEs were seen in 19 patients (30 events), including one death (no evident association with Epzicom). There were four cases (0.6%) of survey-defined 'hypersensitivity', and the incidence was 0.9% (4/445) among abacavir naïve patients; none of which was reported as serious. No case of myocardial infarction was reported. One pregnant case who delivered a normal baby by caesarean section was reported to have experienced aggravation of anaemia and nausea. CONCLUSIONS: The post-marketing surveillance indicated that the incidence of both ischaemic heart disease and hypersensitivity associated with Epzicom was considerably low, suggesting that this drug can be safely used in the Japanese population.