Discover the efficacy data vs meropenem (mMITT)

EPIC, Evaluating Plazomicin In cUTI; mMITT, microbiologic modified intent-to-treat.

ZEMDRI—Noninferior to meropenem for the co-primary endpoints1

Composite cure rates (mMITT)

Point estimate for difference
(ZEMDRI minus meropenem) with 95% CIa

Composite cure rates (mMITT)

Point estimate for difference (ZEMDRI minus meropenem) with 95% CIa

CI, confidence interval; mMITT, microbiologic modified intent-to-treat; NI, noninferiority; TOC, test of cure.

aCI=95% confidence interval based on Newcombe method with continuity correction.

Numerically higher composite cure rate at TOC in patients with concomitant bacteremia at baseline (mMITT)1

  • ZEMDRI 72.0% (18/25) vs meropenem 56.5% (13/23); treatment difference 15.5% (ZEMDRI - meropenem)

In the mMITT population...

Microbiologic persistenceb data vs meropenem at TOC2

CFU, colony-forming unit; mMITT, microbiologic modified intent-to-treat; TOC, test of cure (Day 17 ± 2 from the first dose of study drug).

bAn overall per-patient microbiologic response was determined based on individual outcomes for each baseline pathogen. If the outcome for any pathogen was persistence (ie, urine culture grew ≥104 CFU/mL of the original pathogen), the patient was considered to have a microbiologic response of persistence.

Microbiologic eradication rates at TOC by baseline pathogen (mMITT)1

  • There were 52 baseline Enterobacterales isolates in 27% (51/189) of patients in the ZEMDRI group that were nonsusceptible (defined as intermediate or resistant) to gentamicin or tobramycin or both
    • All of these isolates were susceptible to ZEMDRI, and all but 1 was susceptible to amikacin (1 isolate was intermediate to amikacin)
    • The microbiologic eradication rate at the TOC visit in this subset was 78.9% (41/52) in the ZEMDRI group

mMITT, microbiologic modified intent-to-treat; TOC, test of cure (Day 17 ± 2 from the first dose of study drug).

Relapse and microbiologic recurrence data vs meropenem at LFU (mMITT)2

Relapse definition: new or worsening clinical cUTI symptoms relative to baseline, or no return to premorbid status in patients with clinical cure or an indeterminate clinical response at TOC. Patients with clinical failure at TOC are included in the denominator.2

Recurrence definition: urine culture grew ≥104 CFU/mL of the original pathogen(s) at any time after documented eradication at TOC through LFU.2 Approximately 32% (61/191) and 20% (40/197) of ZEMDRI and meropenem patients, respectively, had an LFU visit conducted by telephone and, per protocol, were presumed to have sustained eradication based on resolution or return to premorbid status of all clinical cUTI symptoms.3

CFU, colony-forming unit; cUTI, complicated urinary tract infection; LFU, late follow-up (Day 28 ± 4 from the first dose of study drug); mMITT, microbiologic modified intent-to-treat; TOC, test of cure (Day 17 ± 2 from the first dose of study drug).

EPIC, Evaluating Plazomicin In cUTI.

References: 1. ZEMDRI® (plazomicin) injection Prescribing Information. Cipla USA, Inc. 2. Wagenlehner FME, Cloutier DJ, Komirenko AS, et. al. Once-Daily Plazomicin for Complicated Urinary Tract Infections. N Engl J Med. 2019 Feb 1;380(8):729-740. 3. Data on file, MC. Cipla Therapeutics, a division of Cipla USA, Inc.

EPIC Study Design EPIC Efficacy

Discover the efficacy data vs meropenem (mMITT)

EPIC, Evaluating Plazomicin In cUTI; mMITT, microbiologic modified intent-to-treat.

ZEMDRI—Noninferior to meropenem for the co-primary endpoints1

Composite cure rates (mMITT)

Point estimate for difference
(ZEMDRI minus meropenem) with 95% CIa

Composite cure rates (mMITT)

Point estimate for difference (ZEMDRI minus meropenem) with 95% CIa

CI, confidence interval; mMITT, microbiologic modified intent-to-treat; NI, noninferiority; TOC, test of cure.

aCI=95% confidence interval based on Newcombe method with continuity correction.

Numerically higher composite cure rate at TOC in patients with concomitant bacteremia at baseline (mMITT)1

In the mMITT population...

Microbiologic persistenceb data vs meropenem at TOC2

CFU, colony-forming unit; mMITT, microbiologic modified intent-to-treat; TOC, test of cure (Day 17 ± 2 from the first dose of study drug).

bAn overall per-patient microbiologic response was determined based on individual outcomes for each baseline pathogen. If the outcome for any pathogen was persistence (ie, urine culture grew ≥104 CFU/mL of the original pathogen), the patient was considered to have a microbiologic response of persistence.

Microbiologic eradication rates at TOC by baseline pathogen (mMITT)1

mMITT, microbiologic modified intent-to-treat; TOC, test of cure (Day 17 ± 2 from the first dose of study drug).

Relapse and microbiologic recurrence data vs meropenem at LFU (mMITT)2

Relapse definition: new or worsening clinical cUTI symptoms relative to baseline, or no return to premorbid status in patients with clinical cure or an indeterminate clinical response at TOC. Patients with clinical failure at TOC are included in the denominator.2

Recurrence definition: urine culture grew ≥104 CFU/mL of the original pathogen(s) at any time after documented eradication at TOC through LFU.2 Approximately 32% (61/191) and 20% (40/197) of ZEMDRI and meropenem patients, respectively, had an LFU visit conducted by telephone and, per protocol, were presumed to have sustained eradication based on resolution or return to premorbid status of all clinical cUTI symptoms.3

CFU, colony-forming unit; cUTI, complicated urinary tract infection; LFU, late follow-up (Day 28 ± 4 from the first dose of study drug); mMITT, microbiologic modified intent-to-treat; TOC, test of cure (Day 17 ± 2 from the first dose of study drug).

EPIC, Evaluating Plazomicin In cUTI.

References: 1. ZEMDRI [prescribing information]; 2018. 2. Data on file, Clinical Study Report: A phase 3, randomized, multicenter, double-blind study to evaluate the efficacy and safety of plazomicin compared with meropenem followed by optional oral therapy for the treatment of complicated urinary tract infection (cUTI), including acute pyelonephritis (AP), in adults. Cipla Therapeutics, a division of Cipla USA, Inc. 3. Data on file, MC. Cipla Therapeutics, a division of Cipla USA, Inc.

INDICATION AND IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNINGS

Indications & Usage

ZEMDRI® (plazomicin) injection 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.

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.

Important Safety Information

BOXED WARNINGS: 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. 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.
  • 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.
  • 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.
  • Aminoglycosides, including ZEMDRI, can cause fetal harm when administered to a pregnant woman.

Contraindications

ZEMDRI is contraindicated in patients with known hypersensitivity to any aminoglycoside.

Additional Warnings and Precautions

    Nephrotoxicity

  • Nephrotoxicity has been reported with the use of ZEMDRI. Most serum creatinine increases were ≤1 mg/dL above baseline and reversible.
  • 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 (Cmin) greater than or equal to 3 mcg/mL.
  • 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.
  • Adjust the initial dosage regimen in cUTI patients with CLcr ≥15 mL/min and <60 mL/min. For subsequent doses, TDM is recommended for patients with CLcr ≥15 mL/min and <90 mL/min.
  • Ototoxicity

  • 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 (excluding age-related hearing loss), patients with renal impairment, and in patients receiving higher doses and/or for longer periods than recommended. The benefit-risk of ZEMDRI therapy should be considered in these patients.
  • 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.
  • 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.
  • Hypersensitivity Reactions

  • Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving aminoglycoside antibacterial drugs. Before therapy with ZEMDRI is instituted, careful inquiry about previous hypersensitivity reactions to other aminoglycosides should be made. A history of hypersensitivity to other aminoglycosides is a contraindication to the use of ZEMDRI, because cross-sensitivity among aminoglycoside antibacterial drugs has been established. Discontinue ZEMDRI if an allergic reaction occurs.
  • Clostridium difficile-Associated Diarrhea

  • Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit overgrowth of C. difficile.
  • Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs.
  • If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued.
  • Development of Drug-Resistant Bacteria

  • Prescribing ZEMDRI in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Adverse Reactions

The most common adverse reactions (≥1% of patients treated with ZEMDRI) are decreased renal function, diarrhea, hypertension, headache, nausea, vomiting and hypotension.

Please see the full Prescribing Information, including BOXED WARNINGS, for additional Important Safety Information.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Cipla Therapeutics, a division of Cipla USA, Inc., at (866) 604-3268 or drugsafety@cipla.com

INDICATION AND IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNINGS

Indications & Usage

ZEMDRI® (plazomicin) injection 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.

To reduce the development of drug-resistant bacteria and maintain 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 microorganisms.

Important Safety Information

BOXED WARNINGS: 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. 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.

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