Plazomicin

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# Black Box Warning

# Overview
Plazomicin is an aminoglycoside antibacterial that is FDA approved for the treatment of patients 18 years of age or older with Complicated Urinary Tract Infections (cUTI) including Pyelonephritis. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include decreased renal function, diarrhea, hypertension, headache, nausea, vomiting and hypotension.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Indication
- Plazomicin 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 plazomicin are currently available, reserve plazomicin for use in cUTI patients who have limited or no alternative treatment options.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of plazomicin and other antibacterial drugs, plazomicin 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.
Dosage
- Administer plazomicin 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.
- Recommended duration of treatment is 4 to 7 days for cUTI, including pyelonephritis.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding plazomicin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding plazomicin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness of plazomicin in patients less than 18 years of age have not been established.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding plazomicin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding plazomicin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- Plazomicin is contraindicated in patients with known hypersensitivity to any aminoglycoside.

# Warnings
- Nephrotoxicity has been reported with the use of plazomicin. 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 plazomicin-treated patients compared with 1.3% (4/301) in meropenem-treated patients.
- Serum creatinine increases of 0.5 mg/dL or greater above baseline occurred in 7% (21/300) of plazomicin-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 plazomicin, 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 plazomicin 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, manifested as hearing loss, tinnitus, and/or vertigo, has been reported with plazomicin. 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 plazomicin-treated patients and one case of tinnitus (1/301;0.3%) in meropenem-treated patients. In Trial 2, one case each of irreversible tinnitus and reversible vertigo was reported in plazomicin-treated patients, and one case of an abnormal audiogram occurred in a levofloxacin-treated patient.
- 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 plazomicin therapy should be considered in these patients.
- 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 plazomicin, 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 plazomicin, 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 plazomicin during pregnancy, or become pregnant while taking plazomicin should be apprised of the potential hazard to the fetus.
- Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving aminoglycoside antibacterial drugs. Before therapy with plazomicin 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 plazomicin, because cross-sensitivity among aminoglycoside antibacterial drugs has been established. Discontinue plazomicin if an allergic reaction occurs.
- 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.
- C. difficile produces toxins A and B that contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. 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. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.
- Prescribing plazomicin 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

## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Plazomicin was evaluated in two comparator-controlled clinical trials (Trial 1, NCT02486627 and Trial 2, NCT01096849) in patients with cUTI, including pyelonephritis. In both trials, patients with CLcr greater than 60 mL/min received plazomicin 15 mg/kg IV once daily as a 30-minute infusion.
- Trial 1 included 303 patients treated with plazomicin and 301 patients treated with meropenem. Patients were to receive 4 to 7 days of plazomicin (mean duration of 5.1 days). In some patients, parenteral therapy was followed by a switch to an oral antibacterial drug.
- The median age of patients treated with plazomicin in Trial 1 was 62 years (range 18 to 90 years) and 45.2% of patients were 65 years of age or older. Patients treated with plazomicin were predominantly female (56.1%) and White (99.3%). A majority of patients (68.0%) had mild or moderate renal impairment (CLcr >30 to 90 mL/min) at baseline. Patients with CLcr of 30 mL/min or less were excluded.
Adverse Reactions Leading to Treatment Discontinuations in Trial 1
- In Trial 1, treatment discontinuation from IV study drug due to an adverse reaction occurred in 2.0% of patients receiving plazomicin (6/303) and meropenem (6/301), respectively.
Common Adverse Reactions in Trial 1
- Table 3 lists adverse reactions occurring in 1% or more of patients receiving plazomicin in Trial 1.
- The adverse reactions profile for the cUTI patients in Trial 2 were similar to those observed in Trial 1.
Nephrotoxicity Reported in Trial 1
- In Trial 1, serum creatinine increases of 0.5 mg/dL or greater above baseline occurred in 7.0% (21/300) of plazomicin-treated patients compared with 4.0% (12/297) of meropenem-treated patients. Of these, the incidence during IV therapy was 3.7% (11/300) vs 3.0% (9/297) in plazomicin- and meropenem-treated patients, respectively. By the last follow-up visit (between 8 to 43 days after completion of IV therapy), the majority of plazomicin-treated patients (9/11) and all meropenem treated patients (9/9) with serum creatinine increases while on therapy had fully recovered renal function. Serum creatinine increases of 0.5 mg/dL or greater above baseline were observed following completion of IV therapy. These increases were generally  1.0 mg/dL above baseline and recovered by the next measurement.
- In cUTI patients with CLcr of greater than 30 and less than or equal to 90 mL/min, 9.7% (20/207) plazomicin-treated and 4.1% (9/217) meropenem-treated patients had serum creatinine increases of 0.5 mg/dL or greater above baseline. In cUTI patients with CLcr greater than 90 mL/min, 1.1% (1/93) plazomicin-treated and 3.8% (3/80) of meropenem-treated patients had serum creatinine increases of 0.5 mg/dL or greater above baseline.
Ototoxicity
- Pure tone audiometry was evaluated in Phase 1 trials and in Trial 2. Treatment associated ototoxicity could not be definitively excluded according to the American Speech-Language-Hearing Association criteria1 in 2.2% (4/182) of plazomicin-exposed and 2.0% (1/49) of comparator- or placebo-exposed adults.
Other Adverse Reactions Reported with plazomicin
- The following selected adverse reactions were reported in more than one plazomicin-treated patient in Trials 1 and 2 and are not described elsewhere in the labeling:
Gastrointestinal disorders: constipation, gastritis
Laboratory Investigations: alanine aminotransferase increased
Metabolism and nutrition disorders: hypokalemia
Nervous system disorders: dizziness
Renal and urinary disorders: hematuria
Respiratory, thoracic and mediastinal disorders: dyspnea
- Gastrointestinal disorders: constipation, gastritis
- Laboratory Investigations: alanine aminotransferase increased
- Metabolism and nutrition disorders: hypokalemia
- Nervous system disorders: dizziness
- Renal and urinary disorders: hematuria
- Respiratory, thoracic and mediastinal disorders: dyspnea

## Postmarketing Experience
There is limited information regarding Plazomicin Postmarketing Experience in the drug label.

# Drug Interactions
There is limited information regarding Plazomicin Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Risk Summary
- Aminoglycosides, including plazomicin, can cause fetal harm when administered to a pregnant woman. There are no available data on the use of plazomicin 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. 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.
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).
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Plazomicin in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Plazomicin during labor and delivery.

### Nursing Mothers
Risk Summary
- There are no data on the presence of plazomicin 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 plazomicin and any potential adverse effects on the breastfed infant from plazomicin 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 plazomicin in patients less than 18 years of age have not been established.

### Geriatic Use
- Of the 425 patients treated with plazomicin 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 plazomicin- 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 plazomicin- 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 plazomicin-treated patients  65 years old was 6.6% (9/137) versus 2.8% (4/143) in the meropenem-treated patients. For plazomicin- 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.
- Plazomicin is substantially excreted by the kidneys, and the risk of adverse reactions to plazomicin 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.

### Gender
There is no FDA guidance on the use of Plazomicin with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Plazomicin with respect to specific racial populations.

### 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. Monitor CLcr daily and adjust plazomicin dosage accordingly. 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 plazomicin dosage accordingly.

### Hepatic Impairment
There is no FDA guidance on the use of Plazomicin in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Plazomicin in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Plazomicin in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Recommended Dosage
- The recommended dosage regimen of plazomicin 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.
Dosage in Adult Patients With Renal Impairment
- The recommended initial dosage regimen of plazomicin 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 plazomicin may require subsequent dosage adjustments based on change in renal function and/or Therapeutic Drug Monitoring (TDM) as appropriate.
- 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 plazomicin. Adjustment of the plazomicin dosage regimen based on TDM involves extending plazomicin 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.
Preparation of Diluted Solutions of plazomicin
- Plazomicin 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 plazomicin 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 plazomicin solution in the compatible diluents is described below.
- Plazomicin does not contain preservatives. Aseptic technique must be followed in preparing the infusion solution. Discard unused portion of the plazomicin vial.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Stability of plazomicin Solution in Intravenous Fluids
- After dilution, plazomicin 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
- 0.9% Sodium Chloride Injection, USP
- Lactated Ringer's Injection, USP
Drug Compatibility
- Compatibility of plazomicin for administration with other drugs has not been established. Plazomicin should not be mixed with other drugs or physically added to solutions containing other drugs. Other medications should not be infused simultaneously with plazomicin through the same IV line.

### Monitoring
Monitoring of Renal Function
- Assess creatinine clearance in all patients prior to initiating therapy and daily during therapy with plazomicin.

# IV Compatibility
- Plazomicin is administered by intravenous infusion.

# Overdosage
- In the event of overdosage, plazomicin should be discontinued and supportive care is advised. Maintenance of glomerular filtration and careful monitoring of renal function is recommended. Hemodialysis may aid in the removal of plazomicin from the blood, especially if renal function is, or becomes, compromised. No clinical information is available on the use of hemodialysis to treat plazomicin overdosage.

# Pharmacology

## Mechanism of Action
- Plazomicin is an antibacterial drug.

## Structure
- Plazomicin contains plazomicin sulfate, a semi-synthetic aminoglycoside antibacterial derived from sisomicin.
- Plazomicin sulfate contains a theoretical 2.5 molar equivalents of sulfate relative to the freebase, based on complete protonation. The molecular weight of plazomicin sulfate is calculated based on 1:2.5 stoichiometry. The corresponding empirical formula is C25H48N6O102.5 H2SO4 (plazomicin sulfate) and the molecular weight of the plazomicin sulfate salt is 837.89 g/mol and the molecular weight of the freebase is 592.69 g/mol.

## Pharmacodynamics
- The ratio of area under the plasma concentration-time curve to the minimum inhibitory concentration (AUC:MIC) for plazomicin has been shown to best correlate with efficacy in animal and in vitro models of infection against Enterobacteriaceae.
Exposure- Response Relationship for Nephrotoxicity in cUTI Patients
- Based on exposure-response analysis for nephrotoxicity, defined as serum creatinine increases greater than or equal to 0.5 mg/dL from baseline, using the data from two cUTI clinical trials (Trial 1 and Trial 2), development of nephrotoxicity was associated with estimated plazomicin exposure (i.e., the plasma trough concentration ) in patients with CLcr greater than 30 mL/min and less than or equal to 90 mL/min (N=243). The incidence of nephrotoxicity was higher in patients with plazomicin Cmin greater than or equal to 3 mcg/mL (36%, 10/28) compared to patients with plazomicin Cmin less than 3 mcg/mL (5%, 11/215).
Cardiac Electrophysiology
- The effect of plazomicin on the QTc interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, single-dose, crossover thorough QTc study in 56 healthy adult subjects. At a single dose of 20 mg/kg (1.3 times the maximum recommended dose), plazomicin did not prolong the QTc interval to any clinically relevant extent.

## Pharmacokinetics
- The pharmacokinetic (PK) parameters of plazomicin are similar for single- and multiple-dose administration of plazomicin in healthy subjects. No appreciable accumulation of plazomicin was observed following multiple IV infusions of 15 mg/kg administered every 24 hours in subjects with normal renal function. The AUC, maximum plasma concentration (Cmax), and Cmin increased in proportion to the dose over the dose range of 4 to 15 mg/kg. The plazomicin AUC, Cmax, and Cmin are summarized in Table 4.
Distribution
- The mean (SD) volume of distribution of plazomicin in healthy adults and cUTI patients is 17.9 (4.8) and 30.8 (12.1) L, respectively. The average binding of plazomicin to human plasma proteins is approximately 20%. The degree of protein binding was concentration-independent across the range tested in vitro (5 to 100 mcg/mL).
Elimination
- The mean (SD) total body clearance of plazomicin in healthy adults and cUTI patients is 4.5 (0.9) and 5.1 (2.01) L/h, respectively. The mean (SD) half-life of plazomicin was 3.5 h (0.5) in healthy adults with normal renal function (n=54).
Metabolism
- Plazomicin does not appear to be metabolized to any appreciable extent.
Excretion
- Plazomicin is primarily excreted by the kidneys. Following a single 15 mg/kg IV dose of radiolabeled plazomicin in healthy subjects, 56% of the total administered radioactivity was recovered in urine within 4 hours, 89.1% was recovered within 168 hours, with less than 0.2% in feces. In total, 97.5% of the dose was recovered in the urine as unchanged plazomicin. The mean renal clearance (SD) of plazomicin (4.6  L/h) was similar to total body clearance, suggesting that plazomicin is eliminated by the kidneys.
Specific Populations
- No clinically significant differences in the pharmacokinetics of plazomicin were observed based on age (18 to 90 years of age), sex, or race/ethnicity. The pharmacokinetics of plazomicin in patients with hepatic impairment is unknown.
Patients with Renal Impairment
- Following a single 7.5 mg/kg IV dose (0.5 times the recommended dose) of plazomicin as a 30-minute infusion, the geometric mean AUC0-inf of plazomicin in subjects with mild (CLcr 60 to <90 mL/min, n=6), moderate (CLcr 30 to <60 mL/min, n=6), and severe (CLcr 15 to <30 mL/min, n=6) renal impairment was 1.01-fold, 1.98-fold, and 4.42-fold higher, respectively, compared to subjects with normal renal function (CLcr 90 mL/min, n=6).
- Based on the population PK model, the recommended dosage of plazomicin was associated with a mean (SD) Cmin of 1.0 (1.3) and 1.7 (1.4) mcg/mL in cUTI patients with mild (CLcr 60 to <90 mL/min, n=104) and moderate (CLcr 30 to <60 mL/min, n=89) renal impairment, respectively. The mean (SD) area under the curve from time zero to 24 hours (AUC0-24h) was 261 (102) and 224 (147) mcgh/mL in cUTI patients with mild (CLcr 60 to <90 mL/min, n=104) and moderate (CLcr 30 to <60 mL/min, n=89) renal impairment, respectively. There were insufficient data to calculate Cmin and AUC0-24h for patients with severe renal impairment (CLcr 15 to <30 mL/min).
Geriatric Patients
- No clinically relevant trend in plazomicin exposure (Cmax and AUC0-24h) was observed with regard to age alone. Higher Cmin in elderly subjects (65 to 90 years of age) as compared to non-elderly adult subjects (18 to 64 years of age) was mainly attributable to age-related changes in renal function.
Drug Interaction Studies
Clinical Studies
- Based on the results of a clinical drug-drug interaction (DDI) study that evaluated the effect of a single dose of plazomicin (15 mg/kg) on the single dose plasma PK of metformin, plazomicin did not affect the PK of metformin, which is a substrate of OCT and MATE transporters.
In Vitro Studies
Drug-Metabolizing Enzymes
- Plazomicin does not inhibit the following cytochrome P450 isoforms: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Plazomicin does not induce CYP1A2, CYP2B6, and CYP3A4.
Membrane Transporters
- Plazomicin is not a substrate of P-gp or BCRP transporters. Plazomicin does not inhibit the following hepatic and renal transporters in vitro at clinically relevant concentrations: P-gp, BCRP, BSEP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and OCT2. Plazomicin selectively inhibited the MATE1 and MATE2-K renal transporter in vitro with an IC50 value of 1300 and 338 mcg/mL, respectively.

## Microbiology
Mechanism of Action
- 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 2 MIC against Enterobacteriaceae.
Resistance
- Resistance to aminoglycosides includes production of aminoglycoside modifying enzymes (AMEs), alteration of the ribosomal target through production of 16S rRNA methyltransferases, up-regulation of efflux pumps and reduced permeability into bacterial cell due to loss of outer membrane porins.
- Plazomicin is not inhibited by most AMEs known to affect gentamicin, amikacin and tobramycin, including acetyltransferases (AACs), phosphotransferases (APHs) and nucleotidyltransferases (ANTs). Plazomicin, like other aminoglycosides, is inactive against bacterial isolates that produce 16S rRNA methyltransferases. Plazomicin may have reduced activity against Enterobacteriaceae that overexpress certain efflux pumps (e.g., acrAB-tolC) or lower expression of porins (e.g., ompF or ompK36).
- Plazomicin has no in vitro activity against streptococci (including Streptococcus pneumonia), enterococci (including Enterococcus faecalis, E. faecium), anaerobes, Stenotrophomonas maltophilia and Acinetobacter spp and variable activity against Pseudomonas aeruginosa.
- Activity of plazomicin was demonstrated in vitro against Enterobacteriaceae in the presence of certain beta-lactamases, including extended-spectrum beta-lactamases (TEM, SHV, CTX-M, AmpC), serine carbapenemases (KPC-2, KPC-3), and oxacillinase (OXA-48). Bacteria producing metallo-beta-lactamases often co-express 16S rRNA methyltransferase, conferring resistance to plazomicin.
Interaction With Other Antimicrobials
- In vitro studies have demonstrated that against Enterobacteriaceae isolates, no antagonism was observed for plazomicin in combination with clindamycin, colistin, daptomycin, fosfomycin, levofloxacin, linezolid, rifampin, tigecycline and vancomycin; few isolates showed synergy with ceftazidime, meropenem and piperacillin-tazobactam. The clinical significance of these findings is unknown.
Animal Infection Models
- Plazomicin demonstrated activity in animal models of infection (e.g., thigh infection, lung infection, and septicemia) caused by either amikacin-non-susceptible, gentamicin-non-susceptible, or beta-lactamase producing Enterobacteriaceae.
Antimicrobial Activity
- Plazomicin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections:
- Aerobic Bacteria
- Gram-negative Bacteria
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Enterobacter cloacae
- Escherichia coli
- Klebsiella pneumoniae
- Proteus mirabilis
- Enterobacter cloacae
- The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for plazomicin against isolates of similar genus or organism group. However, the efficacy of plazomicin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.
- Aerobic Bacteria
- Gram-negative Bacteria
Citrobacter freundii
Citrobacter koseri
Enterobacter aerogenes
Klebsiella oxytoca
Morganella morganii
Proteus vulgaris
Providencia stuartii
Serratia marcescens
- Citrobacter freundii
- Citrobacter koseri
- Enterobacter aerogenes
- Klebsiella oxytoca
- Morganella morganii
- Proteus vulgaris
- Providencia stuartii
- Serratia marcescens

## Nonclinical Toxicology
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).

# Clinical Studies
- A total of 609 adults hospitalized with cUTI (including pyelonephritis) were randomized in a multinational, double-blind, noninferiority trial comparing plazomicin (15 mg/kg IV once daily as a 30-minute infusion) to meropenem (1 g intravenously every 8 hours as a 30-minute infusion) (Trial 1, NCT02486627). Switch to an oral antibacterial drug, such as levofloxacin, was allowed after a minimum of 4 and maximum of 7 days of IV therapy for a total of 7 to 10 days of treatment.
- Efficacy was assessed in the microbiological modified intent-to-treat (mMITT) population, which included all patients who received study medication and had at least 1 baseline uropathogen. The mMITT population excluded patients with organisms resistant to study drugs. Patient demographic and baseline characteristics were balanced between treatment groups in the mMITT population. The mMITT population consisted of 388 patients with cUTI, including 162 (41.8%) with pyelonephritis. The median age was 64 years, 52.8% were female and 99.5% were White. The majority of the patients (99%) were from Eastern Europe; 3 patients were from the United States. Concomitant bacteremia was identified in 25 (13.1%) and 23 (11.7%) patients at baseline in the plazomicin and meropenem groups, respectively. The median treatment duration of IV study drug was 6 days in both groups.
- Plazomicin demonstrated efficacy for composite cure at Day 5 and the Test of Cure (TOC) visit (Table 5). Composite cure at Day 5 was defined as resolution or improvement of clinical cUTI symptoms and a microbiological outcome of eradication (all baseline uropathogens reduced to <104 colony-forming units /mL). Composite cure at the TOC visit (Day 17  2 from the first dose of study drug) was defined as resolution of clinical cUTI symptoms and a microbiological outcome of eradication.
- Microbiological eradication rates at the TOC visit by baseline uropathogen in the mMITT population are presented in Table 6. Composite Cure at the TOC visit in individuals with concomitant bacteremia at baseline was achieved in 72.0% (18/25) of patients in the plazomicin group and 56.5% (13/23) of patients in the meropenem group.
- There were 52 baseline Enterobacteriaceae isolates in 51/189 (27%) patients in the plazomicin group that were non-susceptible (defined as intermediate or resistant) to gentamicin, or tobramycin or both. All of these isolates were susceptible to plazomicin and all but one was susceptible to amikacin (one isolate was intermediate to amikacin). The microbiological eradication rate at the TOC visit in this subset was 78.9% (41/52) in the plazomicin group. Note that certain resistance mechanisms can confer resistance to all aminoglycosides, including plazomicin.

# How Supplied
- Plazomicin 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.

## Storage
- Store plazomicin injection 500 mg/10 mL (50 mg/mL) refrigerated at 2C to 8C (36F to 46F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Nephrotoxicity
- Advise patients, their families, or caregivers that nephrotoxicity has been reported with plazomicin therapy. Counsel patients to follow their physician's directions regarding renal function laboratory tests, maintenance of adequate hydration, and avoidance of potentially nephrotoxic agents while receiving plazomicin therapy.
Ototoxicity
- Advise patients, their families, or caregivers that hearing loss, vertigo, and tinnitus have been reported with plazomicin therapy. Counsel patients to inform their physician if they experience changes in hearing or balance, or if they experience new onset or changes in preexisting buzzing or roaring in their ear(s), even if it occurs after the completion of plazomicin therapy.
Aggravation of Neuromuscular Disorders
- Advise patients, their families, or caregivers that aggravation of muscle weakness has been reported for other aminoglycosides, particularly in patients with underlying neuromuscular disease or receiving neuromuscular blocking agents. Counsel patients to inform their physician if they have an underlying neuromuscular disorder such as myasthenia gravis or are receiving neuromuscular blocking agents.
Fetal Harm
- Aminoglycosides, including plazomicin, can cause fetal harm when administered to a pregnant woman. Counsel women of childbearing potential about the potential risk of fetal harm if plazomicin is used during pregnancy. Advise pregnant women that aminoglycosides can cause irreversible congenital deafness when administered to a pregnant woman. Tell women of childbearing potential to notify their prescribing physician/ healthcare provider if they become pregnant during plazomicin treatment.
Hypersensitivity Reactions
- Advise patients, their families, or caregivers that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask them about any previous hypersensitivity reactions to plazomicin or other aminoglycosides.
Potentially Serious Diarrhea
- Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including plazomicin. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, tell patient to contact his or her healthcare provider.
Antibacterial Resistance
- Counsel patients, their families, or caregivers that antibacterial drugs, including plazomicin, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When plazomicin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by plazomicin or other antibacterial drugs in the future.

# Precautions with Alcohol
Alcohol-Plazomicin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
Zemdri

# Look-Alike Drug Names
There is limited information regarding Plazomicin Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price