ZEMDRI (plazomicin) injection

ZEMDRI ™ (plazomicin) injection

Usual Diluents

Standard Dilutions   [Amt of drug] [Infusion vol] [Infusion rate]

Renal dosing: Additional info.
[10 mg/kg ]   [50 ml total volume]  [30 minutes]

Based on the wide range of compatible concentrations, keeping the total volume at 50 mL appears unnecessary:
Stability of ZEMDRI Solution in Intravenous Fluids:   After dilution, ZEMDRI solution for administration is stable for 24 hours at room temperature 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.

Supplied: ZEMDRI injection 500 mg/10 mL (50 mg/mL)

WARNINGS  ASSOCIATED WITH ZEMDRI (plazomicin) 

WARNING: NEPHROTOXICITY, OTOTOXICITY, NEUROMUSCULAR BLOCKADE and FETAL HARM

• 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)].

DESCRIPTION 

intravenous administration supplied in 10-mL single-dose Type 1 glass vials. Each vial contains plazomicin sulfate equivalent to 500 mg plazomicin freebase at a concentration of 50 mg/mL adjusted to pH 6.5. Each vial also contains Water for Injection and sodium hydroxide for pH adjustment. This sterile, nonpyrogenic solution is formulated without preservatives.

CLINICAL PHARMACOLOGY:

Plazomicin is an aminoglycoside that acts by binding to bacterial 30S ribosomal subunit, thereby inhibiting protein synthesis. Plazomicin has concentration-dependent bactericidal activity as measured by time kill studies. In vitro studies demonstrated a plazomicin post-antibiotic effect ranging from 0.2 to 2.6 hours at 2x MIC against Enterobacteriaceae.

INDICATIONS AND USAGE 

1.1 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)].

1.2 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.

CONTRAINDICATIONS OF ZEMDRI

ZEMDRI is contraindicated in patients with known hypersensitivity to any aminoglycoside [see Warnings and Precautions (5.5)].

PRECAUTIONS

ADVERSE REACTIONS

See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide. Drug information

ZEMDRI (plazomicin) DOSAGE AND ADMINISTRATION 

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 CLcr * Greater Than or Equal to 90 mL/min

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)].

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

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)].

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 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.

HOW ZEMDRI (plazomicin) IS SUPPLIED 

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.

Storage and Stability

ZEMDRI injection 500 mg/10 mL (50 mg/mL) is supplied in single-dose, 10-mL vials fitted with flip-off seals with royal blue polypropylene buttons as a clear, colorless to yellow, sterile solution. Each vial contains plazomicin sulfate equivalent to 500 mg plazomicin freebase at a concentration of 50 mg/mL plazomicin in Water for Injection. Each vial contains sodium hydroxide for pH adjustment to 6.5. The solution may become yellow in color; this does not indicate a decrease in potency.

16.2 Storage and Handling

Store ZEMDRI injection 500 mg/10 mL (50 mg/mL) refrigerated at 2°C to 8°C (36°F to 46°F).
16.2 Storage and Handling

Store ZEMDRI injection 500 mg/10 mL (50 mg/mL) refrigerated at 2°C to 8°C (36°F to 46°F).

Manufactured for:
Achaogen, Inc.
South San Francisco, CA 94080

NDC 71045-010-02
Rx ONLY

ZEMDRI™
(plazomicin) Injection

10 (10 mL) Single-dose vials
500 mg/10 mL per vial (50 mg/mL)

For Intravenous Infusion Only
Must dilute before use
To report SUSPECTED ADVERSE REACTIONS, contact Achaogen at 1-833-252-6402 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Revised: 6/2018