Plazomicin

Risk Summary

Aminoglycosides, including plazomicin, can cause fetal harm when administered to a pregnant woman. There are no available data on the use of plazomicin in pregnant women to inform a drug associated risk of adverse developmental outcomes. Published literature reports of streptomycin, an aminoglycoside, state that it can cause total, irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. No drug-related visceral or skeletal malformations were observed in pregnant rats and rabbits administered subcutaneous plazomicin during organogenesis at maternal exposures approximately 0.8-fold (rats) and 2.5-fold (rabbits) of the human AUC at the clinical dose of 15 mg/kg/day. Auditory function of offspring was not measured in animal studies (see Data). Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In an embryo-fetal development study in rats, plazomicin doses of 0, 8, 25, or 50 mg/kg/day administered subcutaneously during organogenesis did not cause drug-related visceral or skeletal malformations, or reduce survival of fetuses. The mid and high doses caused maternal toxicity (reductions in food consumption and body weight gain; increased kidney weight). The high dose resulted in maternal exposure (AUC) approximately 0.8-fold the human AUC at the clinical dose of 15 mg/kg once daily.

In an embryo-fetal development study in rabbits, plazomicin administered subcutaneously at doses of 0, 10, 30, or 50 mg/kg/day did not cause visceral or skeletal malformations or reduced fetal survival. At the high dose, significant maternal toxicity was observed (including renal injury and lethality) and exposure was approximately 2.5-fold the human AUC at the recommended clinical dose.

In a pre- and postnatal development study in rats, maternal animals received subcutaneous plazomicin at 0, 3, 8, or 30 mg/kg/day from the start of organogenesis through lactation. There were no adverse effects on maternal function or pre- and postnatal survival, development, behavior, or reproductive function of the offspring at up to 30 mg/kg/day (0.32-fold human AUC at the clinical daily dose of 15 mg/kg).

Risk Summary

There are no data on the presence of plazomicin in human milk, the effects on the breastfed infant, or the effects on milk production. Plazomicin was detected in rat milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for plazomicin and any potential adverse effects on the breastfed infant from plazomicin or from the underlying maternal condition.

Data

In a pre- and postnatal development study in rats, low concentrations of plazomicin in maternal milk were detected, with mean concentrations representing 2% to 4% of maternal plasma concentrations. In nursing pups, the systemic exposure (AUC) to plazomicin through lactational exposure was approximately 0.04% of maternal systemic exposure.

Carcinogenesis

Long term carcinogenicity studies in animals have not been conducted with plazomicin.

Mutagenesis

Plazomicin was negative for mutagenicity in an Ames test and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes. In vivo, a mouse bone marrow micronucleus assay showed no evidence of clastogenic potential.

Impairment of Fertility

In a fertility and early embryonic development study, male and female rats received subcutaneous plazomicin at 0, 8, 25, or 50 mg/kg/day from prior to pairing through the mating and postmating period. Parental toxicity (reduced food consumption and body weight gain, and gross kidney changes) was observed at the mid and high doses. Plazomicin had no adverse effects on fertility in male rats at up to 50 mg/kg/day, resulting in an exposure (AUC) approximately 0.8-fold the human AUC at the clinical dose of 15 mg/kg once daily. In female rats, there were no effects on estrous cyclicity or reproductive performance including mating indices, fertility and fecundity indices, and copulatory intervals. At 25 and 50 mg/kg/day, female rats had fewer corpora lutea, leading to fewer uterine implantation sites and viable embryos per dam. The no observed effect level (NOEL) for fertility and reproductive performance in female rats was 8 mg/kg/day (0.1-fold human AUC).

• Nephrotoxicity
• Ototoxicity
• Neuromuscular Blockade
• Fetal Harm
• Hypersensitivity Reactions
• Clostridium difficile-Associated Diarrhea

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 compared directly to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Plazomicin was evaluated in two comparator-controlled clinical trials (Trial 1, NCT02486627 and Trial 2, NCT01096849) in patients with cUTI, including pyelonephritis. In both trials, patients with CLcr greater than 60 mL/min received plazomicin 15 mg/kg IV once daily as a 30-minute infusion.

Trial 1 included 303 patients treated with plazomicin and 301 patients treated with meropenem. Patients were to receive 4 to 7 days of plazomicin (mean duration of 5.1 days). In some patients, parenteral therapy was followed by a switch to an oral antibacterial drug.

The median age of patients treated with plazomicin in Trial 1 was 62 years (range 18 to 90 years) and 45.2% of patients were 65 years of age or older. Patients treated with plazomicin were predominantly female (56.1%) and White (99.3%). A majority of patients (68.0%) had mild or moderate renal impairment (CLcr >30 to 90 mL/min) at baseline. Patients with CLcr of 30 mL/min or less were excluded.

Adverse Reactions Leading to Treatment Discontinuations in Trial 1

In Trial 1, treatment discontinuation from IV study drug due to an adverse reaction occurred in 2.0% of patients receiving plazomicin (6/303) and meropenem (6/301), respectively.

Common Adverse Reactions in Trial 1

Table 1 lists adverse reactions occurring in 1% or more of patients receiving plazomicin in Trial 1.

Table 1. Incidence () of Adverse Reactions Occurring in 1 or More of cUTI Adult Patients Treated With Plazomicin in Trial 1:

* 1 g IV every 8 hours.
^† Combined term that corresponds to adverse reactions associated with renal function described in Nephrotoxicity section below

The adverse reactions profile for the cUTI patients in Trial 2 were similar to those observed in Trial 1.

Nephrotoxicity Reported in Trial 1

In Trial 1, serum creatinine increases of 0.5 mg/dL or greater above baseline occurred in 7.0% (21/300) of plazomicin-treated patients compared with 4.0% (12/297) of meropenem-treated patients. Of these, the incidence during IV therapy was 3.7% (11/300) vs 3.0% (9/297) in plazomicin- and meropenem-treated patients, respectively. By the last follow-up visit (between 8 to 43 days after completion of IV therapy), the majority of plazomicin-treated patients (9/11) and all meropenem treated patients (9/9) with serum creatinine increases while on therapy had fully recovered renal function. Serum creatinine increases of 0.5 mg/dL or greater above baseline were observed following completion of IV therapy. These increases were generally ≤1.0 mg/dL above baseline and recovered by the next measurement.

In cUTI patients with CLcr of greater than 30 and less than or equal to 90 mL/min, 9.7% (20/207) plazomicin-treated and 4.1% (9/217) meropenem-treated patients had serum creatinine increases of 0.5 mg/dL or greater above baseline. In cUTI patients with CLcr greater than 90 mL/min, 1.1% (1/93) plazomicin-treated and 3.8% (3/80) of meropenem-treated patients had serum creatinine increases of 0.5 mg/dL or greater above baseline.

Ototoxicity

Pure tone audiometry was evaluated in Phase 1 trials and in Trial 2. Treatment associated ototoxicity could not be definitively excluded according to the American Speech-Language-Hearing Association criteria ¹ in 2.2% (4/182) of plazomicin-exposed and 2.0% (1/49) of comparator- or placebo-exposed adults.

Other Adverse Reactions Reported with Plazomicin

The following selected adverse reactions were reported in more than one plazomicin-treated patient in Trials 1 and 2 and are not described elsewhere in the labeling:

Gastrointestinal disorders: constipation, gastritis

Laboratory Investigations: alanine aminotransferase increased

Metabolism and nutrition disorders: hypokalemia

Nervous system disorders: dizziness

Renal and urinary disorders: hematuria

Respiratory, thoracic and mediastinal disorders: dyspnea