Zemdri

• Nephrotoxicity has been reported with ZEMDRI. The risk of nephrotoxicity is greater in patients with impaired renal function, the elderly, and in those receiving concomitant nephrotoxic medications. Assess creatinine clearance in all patients prior to initiating therapy and daily during therapy
  [see

  2.2 Monitoring of Renal Function

  Assess creatinine clearance in all patients prior to initiating therapy and daily during therapy with ZEMDRI

  [see Dosage and Administration (2.3), Warnings and Precautions (5.1)and Use in Specific Populations (8.6)]

  .

  and

  5.1 Nephrotoxicity

  Nephrotoxicity has been reported with the use of ZEMDRI

  [see Adverse Reactions (6.1)].

  Most serum creatinine increases were ≤ 1 mg/dL above baseline and reversible.

  In Trial 1, the incidence of adverse reactions associated with renal function (acute kidney injury, serum creatinine increased, chronic kidney disease, creatinine clearance decreased, renal failure, renal impairment) was 3.6% (11/303) in ZEMDRI-treated patients compared with 1.3% (4/301) in meropenem-treated patients

  [see Adverse Reactions (6.1)].

  Serum creatinine increases of 0.5 mg/dL or greater above baseline occurred in 7% (21/300) of ZEMDRI-treated patients compared with 4% (12/297) of meropenem-treated patients. These increases mainly occurred in patients with CLcr ≤ 90 mL/min and were associated with a plazomicin trough level (C_min) greater than or equal to 3 mcg/mL

  [see Adverse Reactions (6.1)and Clinical Pharmacology (12.2)]

  .

  Assess CLcr in all patients prior to initiating therapy and daily during therapy with ZEMDRI, particularly in those at increased risk of nephrotoxicity, such as those with renal impairment, the elderly, and those receiving concomitant potentially nephrotoxic medications. In the setting of worsening renal function, the benefit of continuing ZEMDRI should be assessed

  [see Dosage and Administration (2.2, 2.4), Adverse Reactions (6.1)and Use in Specific Populations (8.5, 8.6)]

  .

  Adjust the initial dosage regimen in cUTI patients with CLcr ≥ 15 mL/min and < 60 mL/min

  [see Dosage and Administration (2.3)]

  . For subsequent doses, TDM is recommended for patients with CLcr ≥15 mL/min and < 90 mL/min

  [see Dosage and Administration (2.4)]

  .

  ]
  . Therapeutic Drug Monitoring (TDM) is recommended for complicated urinary tract infection (cUTI) patients with CLcr less than 90 mL/min to avoid potentially toxic levels
  [see

  2.3 Dosage in Adult Patients With Renal Impairment

  The recommended initial dosage regimen of ZEMDRI in adult patients with CLcr greater than or equal to 15 and less than 90 mL/min, estimated by the Cockcroft-Gault formula, is described in Table 2.

  Patients with CLcr greater than or equal to 15 and less than 90 mL/min receiving ZEMDRI may require subsequent dosage adjustments based on change in renal function and/or Therapeutic Drug Monitoring (TDM) as appropriate [

  see Dosage and Administration (2.4)]

  .

  Table 2: Dosage Regimen of ZEMDRI in Adults With CLcr Less Than 90 mL/min

  Estimated CLcrCLcr estimated by the Cockcroft-Gault formula using total body weight (TBW). For patients with TBW greater than ideal body weight (IBW) by 25% or more, use IBW.(mL/min)	DosageCalculate dosage using TBW. For patients with TBW greater than IBW by 25% or more, use adjusted body weight based on the equation: Adjusted body weight = IBW + 0.4 × [TBW – IBW].	Dosing Interval
  Greater than or equal to 60 to less than 90	15 mg/kg	Every 24 hours
  Greater than or equal to 30 to less than 60	10 mg/kg	Every 24 hours
  Greater than or equal to 15 to less than 30	10 mg/kg	Every 48 hours

  There is insufficient information to recommend a dosage regimen in patients with CLcr less than 15 mL/min or on renal replacement therapy, including hemodialysis or continuous renal replacement therapy.

  ,

  2.4 TDM in cUTI Patients With Renal Impairment

  For cUTI patients with CLcr greater than or equal to 15 mL/min and less than 90 mL/min, TDM is recommended to maintain plasma trough concentrations below 3 mcg/mL. Measure plazomicin plasma trough concentration within approximately 30 minutes before administration of the second dose of ZEMDRI. Adjustment of the ZEMDRI dosage regimen based on TDM involves extending ZEMDRI dosing interval by 1.5 fold (i.e., from every 24 hours to every 36 hours or from every 48 hours to every 72 hours) for patients with plasma trough concentrations greater than or equal to 3 mcg/mL [

  see Warnings and Precautions (5.1)and Clinical Pharmacology (12.2)]

  .

  ]
  .
• Ototoxicity, manifested as hearing loss, tinnitus, and/or vertigo, has been reported with ZEMDRI. Symptoms of aminoglycoside-associated ototoxicity may be irreversible and may not become evident until after completion of therapy. Aminoglycoside-associated ototoxicity has been observed primarily in patients with a family history of hearing loss, patients with renal impairment, and in patients receiving higher doses and/or longer durations of therapy than recommended

  [see

  5.2 Ototoxicity

  Ototoxicity with use of ZEMDRI

  Ototoxicity, manifested as hearing loss, tinnitus, and/or vertigo, has been reported with ZEMDRI. Symptoms of aminoglycoside-associated ototoxicity may be irreversible and may not become evident until after completion of therapy.

  Regarding the incidence of adverse reactions associated with cochlear or vestibular function, in Trial 1, there was one case of reversible hypoacusis (1/303;0.3%) in ZEMDRI-treated patients and one case of tinnitus (1/301;0.3%) in meropenem-treated patients

  [see Adverse Reactions (6.1)]

  . In Trial 2, one case each of irreversible tinnitus and reversible vertigo was reported in ZEMDRI-treated patients, and one case of an abnormal audiogram occurred in a levofloxacin-treated patient

  [see Adverse Reactions (6.1)]

  .

  Aminoglycoside-associated ototoxicity has been observed primarily in patients with a family history of hearing loss (excluding age-related hearing loss), patients with renal impairment, and in patients receiving higher doses and/or for longer periods than recommended. In Trial 1 and Trial 2, patients with a history of hearing loss, with the exception of age-related hearing loss, were excluded. The benefit-risk of ZEMDRI therapy should be considered in these patients.

  Risk of Ototoxicity Due to Mitochondrial DNA Variants

  Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (

  MT-RNR1

  ), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

  ]

  .
• Aminoglycosides have been associated with neuromuscular blockade. During therapy with ZEMDRI, monitor for adverse reactions associated with neuromuscular blockade, particularly in high-risk patients, such as patients with underlying neuromuscular disorders (including myasthenia gravis) or in patients concomitantly receiving neuromuscular blocking agents
  [see

  5.3 Neuromuscular Blockade

  Aminoglycosides have been associated with exacerbation of muscle weakness in patients with underlying neuromuscular disorders, or delay in recovery of neuromuscular function in patients receiving concomitant neuromuscular blocking agents.

  During therapy with ZEMDRI, monitor for adverse reactions associated with neuromuscular blockade, particularly in high-risk patients, such as patients with underlying neuromuscular disorders (including myasthenia gravis) or those patients concomitantly receiving neuromuscular blocking agents.

  ]
  .
• Aminoglycosides, including ZEMDRI, can cause fetal harm when administered to a pregnant woman
  [see

  5.4 Fetal Harm

  Aminoglycosides, including ZEMDRI, can cause fetal harm when administered to a pregnant woman. Aminoglycosides cross the placenta, and streptomycin has been associated with several reports of total, irreversible, bilateral congenital deafness in pediatric patients exposed

  in utero

  . Patients who use ZEMDRI during pregnancy, or become pregnant while taking ZEMDRI should be apprised of the potential hazard to the fetus

  [see Use in Specific Populations (8.1)]

  .

  ,

  8.1 Pregnancy

  Risk Summary

  Aminoglycosides, including ZEMDRI, can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ZEMDRI 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).

  ]
  .

ZEMDRI is an aminoglycoside antibacterial indicated for the treatment of patients 18 years of age or older with Complicated Urinary Tract Infections (cUTI) including Pyelonephritis. (

As only limited clinical safety and efficacy data are available, reserve ZEMDRI for use in patients who have limited or no alternative treatment options. (

To reduce the development of drug-resistant bacteria and maintain effectiveness of ZEMDRI and other antibacterial drugs, ZEMDRI should be used only to treat infections that are proven or strongly suspected to be caused by susceptible microorganisms. (

• Administer ZEMDRI 15 mg/kg every 24 hours by intravenous (IV) infusion over 30 minutes to patients 18 years of age or older with creatinine clearance greater than or equal to 90 mL/min. (
  2.1 Recommended Dosage

  The recommended dosage regimen of ZEMDRI is 15 mg/kg administered every 24 hours by intravenous (IV) infusion over 30 minutes in patients 18 years of age or older and with creatinine clearance (CLcr) greater than or equal to 90 mL/min (Table 1). The duration of therapy should be guided by the severity of infection and the patient's clinical status for up to 7 days. During treatment, dosage adjustments may be required based on change in renal function

  [see Dosage and Administration (2.3, 2.4)].

  Table 1: Dosage Regimen of ZEMDRI in Adults With CLcrCLcr estimated by the Cockcroft-Gault formula using total body weight (TBW). For patients with TBW greater than ideal body weight (IBW) by 25% or more, use IBW.Greater Than or Equal to 90 mL/min

  cUTI Infection	Dosage RegimenCalculate dosage using TBW. For patients with TBW greater than IBW by 25% or more, use adjusted body weight based on the equation: Adjusted body weight = IBW + 0.4 × [TBW – IBW].	Duration of Treatment
  Complicated Urinary Tract Infections, including Pyelonephritis	15 mg/kg every 24 hours	4 to 7 daysAn appropriate oral therapy may be considered after 4 to 7 days of ZEMDRI therapy to complete a total duration of 7 to 10 days (IV plus oral). The maximum duration of ZEMDRI for cUTI is 7 days.
  )
• Recommended duration of treatment is 4 to 7 days for cUTI, including pyelonephritis. (
  2.1 Recommended Dosage

  The recommended dosage regimen of ZEMDRI is 15 mg/kg administered every 24 hours by intravenous (IV) infusion over 30 minutes in patients 18 years of age or older and with creatinine clearance (CLcr) greater than or equal to 90 mL/min (Table 1). The duration of therapy should be guided by the severity of infection and the patient's clinical status for up to 7 days. During treatment, dosage adjustments may be required based on change in renal function

  [see Dosage and Administration (2.3, 2.4)].

  Table 1: Dosage Regimen of ZEMDRI in Adults With CLcrCLcr estimated by the Cockcroft-Gault formula using total body weight (TBW). For patients with TBW greater than ideal body weight (IBW) by 25% or more, use IBW.Greater Than or Equal to 90 mL/min

  cUTI Infection	Dosage RegimenCalculate dosage using TBW. For patients with TBW greater than IBW by 25% or more, use adjusted body weight based on the equation: Adjusted body weight = IBW + 0.4 × [TBW – IBW].	Duration of Treatment
  Complicated Urinary Tract Infections, including Pyelonephritis	15 mg/kg every 24 hours	4 to 7 daysAn appropriate oral therapy may be considered after 4 to 7 days of ZEMDRI therapy to complete a total duration of 7 to 10 days (IV plus oral). The maximum duration of ZEMDRI for cUTI is 7 days.
  )
• Assess creatinine clearance in all patients prior to initiating therapy and daily during therapy. (
  2.2 Monitoring of Renal Function

  Assess creatinine clearance in all patients prior to initiating therapy and daily during therapy with ZEMDRI

  [see Dosage and Administration (2.3), Warnings and Precautions (5.1)and Use in Specific Populations (8.6)]

  .
  )
• Recommended initial dosage regimen for patients with renal impairment is shown in the table below. (
  2.3 Dosage in Adult Patients With Renal Impairment

  The recommended initial dosage regimen of ZEMDRI in adult patients with CLcr greater than or equal to 15 and less than 90 mL/min, estimated by the Cockcroft-Gault formula, is described in Table 2.

  Patients with CLcr greater than or equal to 15 and less than 90 mL/min receiving ZEMDRI may require subsequent dosage adjustments based on change in renal function and/or Therapeutic Drug Monitoring (TDM) as appropriate [

  see Dosage and Administration (2.4)]

  .

  Table 2: Dosage Regimen of ZEMDRI in Adults With CLcr Less Than 90 mL/min

  Estimated CLcrCLcr estimated by the Cockcroft-Gault formula using total body weight (TBW). For patients with TBW greater than ideal body weight (IBW) by 25% or more, use IBW.(mL/min)	DosageCalculate dosage using TBW. For patients with TBW greater than IBW by 25% or more, use adjusted body weight based on the equation: Adjusted body weight = IBW + 0.4 × [TBW – IBW].	Dosing Interval
  Greater than or equal to 60 to less than 90	15 mg/kg	Every 24 hours
  Greater than or equal to 30 to less than 60	10 mg/kg	Every 24 hours
  Greater than or equal to 15 to less than 30	10 mg/kg	Every 48 hours

  There is insufficient information to recommend a dosage regimen in patients with CLcr less than 15 mL/min or on renal replacement therapy, including hemodialysis or continuous renal replacement therapy.
  )

• See Full Prescribing Information for subsequent dosage adjustment based on changes in renal function or Therapeutic Drug Monitoring (TDM). (
  2.3 Dosage in Adult Patients With Renal Impairment

  The recommended initial dosage regimen of ZEMDRI in adult patients with CLcr greater than or equal to 15 and less than 90 mL/min, estimated by the Cockcroft-Gault formula, is described in Table 2.

  Patients with CLcr greater than or equal to 15 and less than 90 mL/min receiving ZEMDRI may require subsequent dosage adjustments based on change in renal function and/or Therapeutic Drug Monitoring (TDM) as appropriate [

  see Dosage and Administration (2.4)]

  .

  Table 2: Dosage Regimen of ZEMDRI in Adults With CLcr Less Than 90 mL/min

  Estimated CLcrCLcr estimated by the Cockcroft-Gault formula using total body weight (TBW). For patients with TBW greater than ideal body weight (IBW) by 25% or more, use IBW.(mL/min)	DosageCalculate dosage using TBW. For patients with TBW greater than IBW by 25% or more, use adjusted body weight based on the equation: Adjusted body weight = IBW + 0.4 × [TBW – IBW].	Dosing Interval
  Greater than or equal to 60 to less than 90	15 mg/kg	Every 24 hours
  Greater than or equal to 30 to less than 60	10 mg/kg	Every 24 hours
  Greater than or equal to 15 to less than 30	10 mg/kg	Every 48 hours

  There is insufficient information to recommend a dosage regimen in patients with CLcr less than 15 mL/min or on renal replacement therapy, including hemodialysis or continuous renal replacement therapy.
  ,
  2.4 TDM in cUTI Patients With Renal Impairment

  For cUTI patients with CLcr greater than or equal to 15 mL/min and less than 90 mL/min, TDM is recommended to maintain plasma trough concentrations below 3 mcg/mL. Measure plazomicin plasma trough concentration within approximately 30 minutes before administration of the second dose of ZEMDRI. Adjustment of the ZEMDRI dosage regimen based on TDM involves extending ZEMDRI dosing interval by 1.5 fold (i.e., from every 24 hours to every 36 hours or from every 48 hours to every 72 hours) for patients with plasma trough concentrations greater than or equal to 3 mcg/mL [

  see Warnings and Precautions (5.1)and Clinical Pharmacology (12.2)]

  .
  ).
• See Full Prescribing Information for instructions on preparation of the solution, stability in intravenous fluids and drug compatibilities. (
  2.5 Preparation of Diluted Solutions of ZEMDRI

  ZEMDRI is supplied as a single-dose fliptop 10-mL vial that contains plazomicin sulfate equivalent to 500 mg plazomicin freebase in 10 mL Water for Injection (concentration of 50 mg/mL). The appropriate volume of ZEMDRI solution (50 mg/mL) for the required dose should be diluted in 0.9% Sodium Chloride Injection, USP or Lactated Ringer's Injection, USP to achieve a final volume of 50 mL for intravenous infusion. The stability of ZEMDRI solution in the compatible diluents is described below

  [see Dosage and Administration (2.7)]

  .

  ZEMDRI does not contain preservatives. Aseptic technique must be followed in preparing the infusion solution. Discard unused portion of the ZEMDRI vial.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
  ,
  2.6 Stability of ZEMDRI Solution in Intravenous Fluids

  After dilution, ZEMDRI solution for administration is stable for 24 hours at room temperature, and for up to 7 days when refrigerated at 2°C to 8°C (36°F to 46°F), at concentrations of 2.5 mg/mL to 45 mg/mL in the following solutions:

  • 0.9% Sodium Chloride Injection, USP
  • Lactated Ringer's Injection, USP
  ,
  2.7 Drug Compatibility

  Compatibility of ZEMDRI for administration with other drugs has not been established. ZEMDRI should not be mixed with other drugs or physically added to solutions containing other drugs. Other medications should not be infused simultaneously with ZEMDRI through the same IV line.
  )

ZEMDRI injection 500 mg/10 mL (50 mg/mL) is a sterile, clear, colorless to yellow solution supplied in a single-dose vial. Each single-dose vial contains plazomicin sulfate equivalent to 500 mg plazomicin freebase.

Aminoglycosides, including ZEMDRI, can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ZEMDRI 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

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.