Dosage & Administration
| Estimated CLcr * (mL/min) | Recommended Dosage for ZEMDRI † | 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 |
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Zemdri Prescribing Information
- 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 Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. 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 Dosage and Administration (2.3, 2.4)].
- 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 Warnings and Precautions (5.2)].
- 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 Warning and Precautions (5.3)].
- Aminoglycosides, including ZEMDRI, can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].
Complicated Urinary Tract Infections (cUTI), including Pyelonephritis
ZEMDRI is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis caused by the following susceptible microorganism(s): Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae.
As only limited clinical safety and efficacy data for ZEMDRI are currently available, reserve ZEMDRI for use in cUTI patients who have limited or no alternative treatment options [see Clinical Studies (14.1)].
Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZEMDRI and other antibacterial drugs, ZEMDRI should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
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)].
| cUTI Infection | Dosage Regimen † | Duration of Treatment |
|---|---|---|
| ||
| Complicated Urinary Tract Infections, including Pyelonephritis | 15 mg/kg every 24 hours | 4 to 7 days ‡ |
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)].
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)].
| Estimated CLcr * (mL/min) | Dosage † | 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.
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)].
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.
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
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.
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).
Lactation
Risk Summary
There are no data on the presence of ZEMDRI 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 ZEMDRI and any potential adverse effects on the breastfed infant from ZEMDRI 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.
. Pediatric Use
The safety and effectiveness of ZEMDRI in patients less than 18 years of age have not been established.
Geriatric Use
Of the 425 patients treated with ZEMDRI in Trials 1 and 2, 40% (170/425) were 65 years of age and older, including 17.2% (73/425) patients 75 years of age and older. In Trial 1, for ZEMDRI- treated patients ≥ 65 years old, the incidence rate of adverse reactions was 27% (37/137) versus 18.9% (27/143) in the meropenem-treated patients ≥ 65 years old. For ZEMDRI- treated patients < 65 years old, the incidence rate of adverse reactions was 13.3% (22/166) versus 24.1% (38/158) in the meropenem-treated patients < 65 years old.
The rate of adverse reactions associated with renal function for the ZEMDRI-treated patients ≥ 65 years old was 6.6% (9/137) versus 2.8% (4/143) in the meropenem-treated patients. For ZEMDRI- treated patients < 65 years old, the incidence rate of adverse reactions associated with renal function was 1.2% (2/166), versus 0% (0/158) in the meropenem-treated patients [see Clinical Studies (14.1) and Adverse Reactions (6.1)].
ZEMDRI is substantially excreted by the kidneys, and the risk of adverse reactions to ZEMDRI may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored. Dosage adjustment in elderly patients should take into account renal function and plazomicin concentrations as appropriate [see Dosage and Administration (2.2, 2.3, 2.4) and Clinical Pharmacology (12.3)].
Renal Impairment
Plazomicin total body clearance was significantly decreased in patients with CLcr greater than or equal to 15 to less than 60 mL/min compared to patients with CLcr greater than or equal to 60 mL/min [see Clinical Pharmacology (12.3)]. Monitor CLcr daily and adjust ZEMDRI dosage accordingly [see Dosage and Administration (2.2)]. 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.
For patients with CLcr greater than or equal to 15 mL/min and less than 90 mL/min, TDM is recommended. Monitor plazomicin trough concentrations and adjust ZEMDRI dosage accordingly [see Dosage and Administration (2.3, 2.4)].
ZEMDRI is contraindicated in patients with known hypersensitivity to any aminoglycoside [see Warnings and Precautions (5.5)].