Plazomicin

1. INDICATIONS AND USAGE ZEMDRI is an aminoglycoside antibacterial indicated for the treatment of patients 18 years of age or older with Complicated Urinary Tract Infections (cUTI) including Pyelonephritis. ( 1.1 ) As only limited clinical safety and efficacy data are available, reserve ZEMDRI for use in patients who have limited or no alternative treatment options. ( 1.1 ) 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. ( 1.2 )

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.

3. DOSAGE FORMS AND STRENGTHS 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. ZEMDRI injection 500 mg/10 mL (50 mg/mL) is a single-dose vial containing plazomicin sulfate equivalent to 500 mg plazomicin free base. ( 3 )

4. CONTRAINDICATIONS ZEMDRI is contraindicated in patients with known hypersensitivity to any aminoglycoside [see Warnings and Precautions (5.5) ] . ZEMDRI is contraindicated in patients with known hypersensitivity to any aminoglycoside ( 4 , 5.4 )

5. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions, including anaphylaxis: Reported for aminoglycosides. If an allergic reaction occurs, discontinue ZEMDRI. ( 5.4 ) Clostridium difficile -Associated Diarrhea : Reported for nearly all systemic antibacterial drugs. Evaluate if diarrhea occurs. ( 5.5 )

5.1 Nephrotoxicity Nephrotoxicity has been reported with the use of ZEMDRI [see Adverse Reactions (6.1) ]. 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 ZEMDRI-treated patients compared with 1.3% (4/301) in meropenem-treated patients [see Adverse Reactions (6.1) ]. 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 (C min ) greater than or equal to 3 mcg/mL [see Adverse Reactions (6.1) and Clinical Pharmacology (12.2) ] . 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 [see Dosage and Administration (2.2 , 2.4) , Adverse Reactions (6.1) and Use in Specific Populations (8.5 , 8.6) ] . Adjust the initial dosage regimen in cUTI patients with CLcr ≥ 15 mL/min and < 60 mL/min [see Dosage and Administration (2.3) ] . For subsequent doses, TDM is recommended for patients with CLcr ≥15 mL/min and < 90 mL/min [see Dosage and Administration (2.4) ] .

5.2 Ototoxicity Ototoxicity with use of ZEMDRI 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. 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 ZEMDRI-treated patients and one case of tinnitus (1/301;0.3%) in meropenem-treated patients [see Adverse Reactions (6.1) ] . In Trial 2, one case each of irreversible tinnitus and reversible vertigo was reported in ZEMDRI-treated patients, and one case of an abnormal audiogram occurred in a levofloxacin-treated patient [see Adverse Reactions (6.1) ] . 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 ZEMDRI therapy should be considered in these patients. Risk of Ototoxicity Due to Mitochondrial DNA Variants Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene ( MT-RNR1 ), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

5.3 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.

5.4 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 [see Use in Specific Populations (8.1) ] .

5.5 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.

5.6 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. 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.

5.7 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 .

6. ADVERSE REACTIONS The following important adverse reactions are discussed in greater detail in the Warnings and Precautions section: Nephrotoxicity [see Warnings and Precautions (5.1) ] Ototoxicity [see Warnings and Precautions (5.2) ] Neuromuscular Blockade [see Warnings and Precautions (5.3) ] Fetal Harm [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Clostridium difficile -Associated Diarrhea [see Warnings and Precautions (5.6) ] Most common adverse reactions (≥ 1% of patients treated with ZEMDRI) are decreased renal function, diarrhea, hypertension, headache, nausea, vomiting and hypotension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cipla USA, Inc. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial 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. ZEMDRI 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 ZEMDRI 15 mg/kg IV once daily as a 30-minute infusion [ see Clinical Studies (14.1) ] . Trial 1 included 303 patients treated with ZEMDRI and 301 patients treated with meropenem. Patients were to receive 4 to 7 days of ZEMDRI (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 ZEMDRI 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 ZEMDRI 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 ZEMDRI (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 ZEMDRI in Trial 1. Table 3: Incidence (%) of Adverse Reactions Occurring in 1% or More of cUTI Adult Patients Treated With ZEMDRI in Trial 1 Adverse Reactions ZEMDRI (N=303) n (%) Meropenem 1 g IV every 8 hours. (N=301) n (%) Decreased Renal Function Combined term that corresponds to adverse reactions associated with renal function described in Nephrotoxicity section below. 11 (3.6) 4 (1.3) Diarrhea 7 (2.3) 5 (1.7) Hypertension 7 (2.3) 7 (2.3) Headache 4 (1.3) 9 (3.0) Nausea 4 (1.3) 4 (1.3) Vomiting 4 (1.3) 3 (1.0) Hypotension 3 (1.0) 2 (0.7) 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 ZEMDRI-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 ZEMDRI- and meropenem-treated patients, respectively. By the last follow-up visit (between 8 to 43 days after completion of IV therapy), the majority of ZEMDRI-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) ZEMDRI-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) ZEMDRI-treated and 3.8% (3/80) of meropenem-treated patients had serum creatinine increases of 0.5 mg/dL or greater above baseline [see Use in Specific Populations (8.6) ] . 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 criteria 1 in 2.2% (4/182) of ZEMDRI-exposed and 2.0% (1/49) of comparator- or placebo-exposed adults. Other Adverse Reactions Reported with ZEMDRI The following selected adverse reactions were reported in more than one ZEMDRI-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

8. USE IN SPECIFIC POPULATIONS

8.1 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).

8.2 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. 8.4. Pediatric Use The safety and effectiveness of ZEMDRI in patients less than 18 years of age have not been established.

8.5 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) ] .

8.6 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 an antibacterial drug [see Microbiology (12.4) ] .