Effectiveness of Risk Minimization Measures for Fentanyl Buccal Tablet (FENTORA) in Canada: A Mixed-Methods Evaluation Using Surveys, Medical Chart Records and Web Surveillance.

BACKGROUND: Fentanyl buccal tablet (FBT), a potent opioid, was approved in Canada in 2013 for breakthrough pain in opioid-tolerant adult cancer patients. Additional risk minimization measures (aRMMs), consisting of communications to patients and healthcare providers (HCPs), were implemented from November 2014 through September 2015. OBJECTIVES: The aim of this study was to assess the effectiveness of FBT aRMMs as measured by prescriber knowledge, understanding, and behavior regarding key safety concerns (off-label use, use in non-opioid-tolerant patients, misuse/abuse/diversion, and drug-drug interaction) and to evaluate illicit FBT use. METHODS: The study included three components: (1) a knowledge and understanding (KAU) survey of FBT prescribers conducted in two waves: November 2016-February 2017 and April-September 2018; (2) a retrospective prescription study of medical records of patients treated with FBT by a subgroup of prescribers from the KAU survey; and (3) Web surveillance of illicit FBT use in Canada using the search term FENTORA (May 2014-September 2018). The aRMMs were considered effective if the lower bound of the 95% confidence interval indicated that at least 65% of respondents met or partly met the knowledge objective for each key safety concern. RESULTS: KAU survey: Of 46 eligible HCPs, 97.8% met or partly met the knowledge objective on use in breakthrough pain cancer patients, 97.8% on use in opioid-tolerant patients, 89.1% on dose and titration, 100% on abuse/addiction, and 58.7% on drug-drug interaction. Retrospective prescription study: Of 22 FBT-treated patients identified from 14 HCPs, 45.5% had cancer, 50.0% recorded a breakthrough pain indication, and 36.4% reported opioid tolerance; however, only 13.6% of patients were prescribed FBT according to the approved indication. Web surveillance: Of 932 FBT posts in Canada, only 40 (4.3%) mentioned illicit use. CONCLUSIONS: The aRMMs as measured by the prescriber KAU were effective for most key safety messages; however, not all key messages of the aRMMs were stringently followed in routine practice.

Comparative efficacy and safety of estradiol transdermal preparations for the treatment of vasomotor symptoms in postmenopausal women: an indirect comparison meta-analysis.

OBJECTIVE: Divigel and Estrogel are estradiol gels for the treatment of postmenopausal women with moderate to severe vasomotor symptoms. They differ with respect to several factors including estradiol concentration and surface application, and cannot be compared solely on the basis of their estradiol dose. No randomized clinical trials have compared them head to head, but both have been compared with placebo. Therefore, the objective of this study was to conduct a systematic review and network meta-analysis of the two estradiol gels. METHODS: We performed a comprehensive systematic literature review. One publication reporting on one Divigel trial, three publications reporting on two Estrogel trials, and five publications reporting on other estradiol transdermal preparations were identified. Efficacy outcomes were change from baseline in daily hot flush frequency and change from baseline in daily hot flush severity. Safety outcomes were frequency of treatment-related adverse events (AEs) and frequency of treatment-emergent AEs leading to discontinuation. Bayesian indirect treatment comparison meta-analysis of trial-level data was performed in accordance with the International Society for Pharmacoeconomics and Outcomes Research, Academy of Managed Care Pharmacy, National Pharmaceutical Council (ISPOR-AMCP-NPC) Good Practice Questionnaire. All outcomes were compared with respect to doses of the considered preparations. RESULTS: For hot flush frequency, Divigel 0.25 mg was similar to Divigel 0.5 mg and to Estrogel 0.75 mg, and was statistically significantly superior to Estrogel 1.5 mg. The largest effect was observed with Divigel 1.0 mg (mean difference of 3.91 hot flushes/wk vs placebo), and was statistically significantly superior to all other interventions. The 1.5 mg Estrogel dose was associated with the smallest estimate of efficacy. For hot flush severity, Divigel 0.25 mg was similar to the efficacy of Divigel 0.5 mg, and for 0.25 mg and 0.5 mg of other estradiol gels, but was statistically inferior to Divigel 1.0 mg, Estrogel 0.75 mg, Estrogel 1.5 mg, and the 1.0 and 1.5 mg doses of all other estradiol gels. The estimated efficacy of Divigel 0.5 mg was similar to that of Estrogel 0.75 mg, Estrogel 1.5 mg, and the 0.25 and 0.5 mg doses of other transdermal estradiol preparations. Risks of treatment-related AEs for Divigel 0.25 mg, Divigel 0.5 mg, Estrogel 0.75 mg, and Estrogel 1.5 mg were similar and all were of a slightly higher risk than placebo. Among these, Divigel 1.0 mg, Estrogel 1.5 mg, and other gels 0.5 mg were statistically significantly less safe than placebo. However, for treatment-emergent AEs leading to discontinuation, none of the gels were associated with statistically significantly higher relative risks compared with placebo. In this study, statistically significant refers to the 95% credible intervals used in the Bayesian Network Analysis. CONCLUSIONS: Using network meta-analysis for indirect treatment comparison, we have shown that the efficacy of Divigel 0.25 mg, as measured by reduced hot flush frequency and severity, was similar to that of Divigel 0.5 mg and of Estrogel 0.75 and 1.5 mg. Overall, our analysis showed that Divigel 1.0 mg provided the best efficacy profile, but that this treatment was also associated with a higher risk of AEs. The network meta-analysis also showed that treatment with Estrogel 1.5 mg was associated with the smallest estimate of reduction in frequency of hot flushes.

A comparative study of manganese and lead levels in human umbilical cords and maternal blood from two urban centers exposed to different gasoline additives.

Manganese (Mn) and lead (Pb) are two neurotoxic chemicals and experimental evidence suggests that they can cross the placental barrier. Tetraethyl lead was still in use as an antiknock agent in Paris during the sampling period of the study, while it has been replaced by methylcyclopentadienyl manganese tricarbonyl (MMT) in Canada since 1977. By 1990, MMT was in 100% of gasoline in Canada. In a study of 160 pairs of mothers-neonates in Montreal and 206 pairs in Paris, we compared levels of Mn and Pb in the umbilical cord and in maternal blood. Neonates and mothers had significantly higher Pb levels in Paris where lead additives were still used in gasoline. Geometric mean maternal blood Pb levels were 5.4 microg/dl compared to 2.1 microg/dl in Montreal and cord blood Pb levels were 3.2 microg/dl in Parisian mothers compared to 1.7 microg/dl in Montreal. The prevalence of Paris Pb values superior to the 95th percentile of the Montreal distribution was highly elevated in all media studied. The prevalence of high Mn levels in umbilical cord blood was also significantly higher in Montreal. Surveillance programs are important to limit Pb overexposure and associated neurological effects in neonates where tetraethyl Pb is still in use as a gasoline additive. Since Mn is an essential element and dietary Mn intake may differ between Montreal and Paris, the difference observed with regard to high Mn values between Montreal and Paris cannot, at this time, be attributed to MMT in Montreal's gasoline. Further studies are needed to infer an association between Mn emissions from MMT and prenatal exposure to Mn.