FDA Drug Approvals — 2019 Midyear Review

Mary L Windle, PharmD


August 09, 2019

Infectious Disease Agents

Egaten (triclabendazole)

Triclabendazole is an antihelmintic agent indicated for the treatment of fascioliasis in patients aged 6 years or older caused by Fasciola hepatica or Fasciola gigantica. The mechanism by which triclabendazole exhibits its effect against Fasciola species is not fully elucidated. Studies in vitro and/or in infected animals suggest that triclabendazole and its active metabolites (sulfoxide and sulfone) are absorbed by the tegument of the immature and mature worms, leading to a decrease of the resting membrane potential and inhibition of tubulin function and protein and enzyme synthesis.

Prior to its approval in 2019, triclabendazole was available for many years via investigational protocols from the US Centers for Disease Control and Prevention. An open label, randomized trial conducted in Vietnam compared the efficacy of triclabendazole (two 10-mg/kg doses given 12 hours apart with food) with oral artesunate (4 mg/kg, given once daily for 10 days) (N=100). Patients (age range, 9-74 years) with acute symptomatic fascioliasis were randomized, 50 in each treatment group. At 3 months after treatment, 92% and 76% (difference 16%; 95% confidence interval, 1.7-30.8; P=.035) of patients in the triclabendazole and artesunate arms, respectively, reported no clinical symptoms. Six open-labeled studies showed a dose response at 20 mg/kg was superior to that of lower doses.[10]

Dengvaxia (dengue vaccine)

Dengue vaccine was approved by the FDA for individuals aged 9-16 years with laboratory-confirmed previous dengue infection and living in endemic areas. It elicits dengue-specific immune responses against the 4 dengue virus serotypes (ie, serotypes 1, 2, 3, and 4). It is only approved for individuals previously infected by any dengue virus serotype or for whom this information is unknown. Those not previously infected are at increased risk for severe dengue disease when vaccinated and subsequently infected with dengue virus.

The approval was based on data from 2 placebo-controlled studies in patients (N>35,000) living in dengue-endemic areas. Patients were randomized 2:1 to receive either the vaccine or saline placebo and monitored for symptomatic virologically confirmed dengue (VCD) starting at day 0. Vaccine efficacy was assessed beginning 28 days after the third vaccination for 12 months. The vaccine was approximately 76% effective in preventing symptomatic VCD disease among patients aged 9-16 years who were seropositive for dengue at baseline.[11]

Recarbrio (imipenem/cilastatin/relebactam)

Imipenem/cilastatin/relebactam contains previously approved imipenem/cilastatin and relebactam, a new beta-lactamase inhibitor. It is indicated for complicated urinary tract infections (cUTIs), including pyelonephritis, and complicated intra-abdominal infections (cIAIs) in adults with limited or no other treatment options.

Imipenem is a carbapenem that inhibits bacterial cell-wall synthesis by binding to penicillin-binding proteins resulting in bacterial cell lysis. Cilastatin prevents renal metabolism of imipenem by competing with dehydropeptidase in the renal tubules to improve systemic exposure of imipenem. Relebactam has no intrinsic antibacterial activity. It protects imipenem from degradation by certain serine beta-lactamases such as sulfhydryl variable (SHV), temoneira (TEM), cefotaximase-Munich (CTX-M), E cloacae P99 (P99), Pseudomonas-derived cephalosporinase (PDC), and K pneumoniae carbapenemase (KPC).

Efficacy of the antibiotic combination was supported in part by the findings of the efficacy and safety of imipenem-cilastatin for the treatment of cUTIs and cIAIs. Relebactam was assessed based on data from in vitro studies and animal models of infection. Safety was studied in two clinical trials, one each for cUTIs and cIAIs. The cUTI trial included 298 adult patients, with 99 treated with the proposed dose. The cIAI trial included 347 patients, with 117 treated with the proposed dose. Dosage modifications are necessary for patients who have renal impairment.[12]

Other notable infectious disease approvals

Dovato (dolutegravir/lamivudine) is the first 2-drug, fixed-dose complete regimen for treatment-naive adults with HIV-1 infection with no known substitutions associated with resistance to dolutegravir or lamivudine.

Zerbaxa (ceftolozane/tazobactam) was approved for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.

Avycaz (ceftazidime/avibactam) was approved for complicated urinary tract infections, including pyelonephritis, in adults and children as young as 3 months.


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