PRINCIPAL DISPLAY PANEL

NDC 80735-820-37
** Rx ONLY**

ZEMDRI®
(plazomicin)
Injection

500 mg/10 mL per vial*****
(50 mg/mL)

For Intravenous Infusion Only
Must dilute before use
Single-dose vial
Discard unused portion
Cipla
THERAPEUTICS

NDC 80735-820-96
** 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
Cipla
THERAPEUTICS

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

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).

2. 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

cUTI Infection	Dosage Regimen †	Duration of Treatment
CLcr 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. † Calculate 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]. ‡ An 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.
Complicated Urinary Tract Infections, including Pyelonephritis	15 mg/kg every 24 hours	4 to 7 days ‡

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

Estimated CLcr * (mL/min)	Dosage †	Dosing Interval
CLcr 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. † Calculate 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].
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)].

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.