BRIEF SUMMARY

18/19. Plazomicin- (June 2019)

Indn     To treat adults with complicated urinary tract infections                                                                                                 

Comp-    injection 500 mg/10 mL (50 mg/mL) is a single-dose vial containing plazomicin sulfate equivalent to 500 mg plazomicin free base.    -   Administer   I 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

ADR-   Most common adverse reactions  are decreased renal function, diarrhea, hypertension, headache, nausea, vomiting and hypotension.

CI-   I is contraindicated in patients with known hypersensitivity to any aminoglycoside

 WARNINGS -

· Hypersensitivity Reactions, including anaphylaxis: Reported for aminoglycosides. If an allergic reaction occurs, discontinue .                                                                     · Clostridium difficile-Associated Diarrhea: Reported for nearly all systemic antibacterial drugs. Evaluate if diarrhea occurs.

Pat inform-                                                                                                           Nephrotoxicity-                                                                                                           Advise patients, their families, or caregivers that nephrotoxicity has been reported with I 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 therapy

Ototoxicity-                                                                                                                           Advise patients, their families, orcaregivers that hearing loss, vertigo, and tinnitus have been reported with  therapy.

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  18

 ADVERSE REACTIONS

 Most common adverse reactions (³ 1% of patients treated with ZEMDRI) are decreased renal function, diarrhea, hypertension, headache, nausea, vomiting and hypotension.

CONTRAINDICATIONS

 ZEMDRI is contraindicated in patients with known hypersensitivity to any aminoglycoside

 WARNINGS AND PRECAUTIONS-

· Hypersensitivity Reactions, including anaphylaxis: Reported for aminoglycosides. If an allergic reaction occurs, discontinue ZEMDRI.                                                                     · Clostridium difficile-Associated Diarrhea: Reported for nearly all systemic antibacterial drugs. Evaluate if diarrhea occurs.

 ADVERSE REACTIONS

 Most common adverse reactions (³ 1% of patients treated with ZEMDRI) are decreased renal function, diarrhea, hypertension, headache, nausea, vomiting and hypotension.

 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.

 As only limited clinical safety and efficacy data are available, reserve ZEMDRI for use in 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.

DOSAGE AND ADMINISTRATION

 -·Administer ZEMDRI 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. 

  - Assess creatinine clearance in all patients prior to initiating therapy and daily during therapy.

- See Full Prescribing Information for subsequent dosage adjustment based on changes in renal function or Therapeutic Drug Monitoring (TDM).                                                                                             · See Full Prescribing Information for instructions on preparation of the solution, stability in intravenous fluids and drug compatibilities.

 DOSAGE FORMS AND STRENGTHS

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

 PATIENT COUNSELING INFORMATION

 Nephrotoxicity-                                                                                                           Advise patients, their families, or caregivers that nephrotoxicity has been reported with ZEMDRI 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 ZEMDRI therapy

Ototoxicity-                                                                                                                           Advise patients, their families, orcaregivers that hearing loss, vertigo, and tinnitus have been reported with ZEMDRI 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 ZEMDRI 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 ZEMDRI, can cause fetal harm when administered to a pregnant woman. Counsel women of childbearing potential about the potential risk of fetal harm if ZEMDRI 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 ZEMDRI 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 ZEMDRI or other aminoglycosides

 Potentially Serious Diarrhea-                                                                                             Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including ZEMDRI. 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 ZEMDRI, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).

When ZEMDRI 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 ZEMDRI or other antibacterial drugs in the future

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

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                                     ZEMDRI is an antibacterial drug

2. 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 [Cmin]) in patients with CLcr greater than 30 mL/min and less than or equal to 90 mL/min (N=243).

3. Pharmacokinetics-                                                                                                          The pharmacokinetic (PK) parameters of plazomicin are similar for single- and multiple-dose administration of ZEMDRI 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.                                                           

 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.

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 ZEMDRI 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)

  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 nonelderly 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.

 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.

USE IN SPECIFIC POPULATIONS

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.

 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.

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                                                                                                                                              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.

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

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 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.

Dosage adjustment in elderly patients should take into account renal function and plazomicin concentrations as appropriate

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. Monitor CLcr daily and adjust ZEMDRI 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 ZEMDRI dosage accordingly

 OVERDOSAGE-                                                                                                                   In the event of overdosage, ZEMDRI 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 ZEMDRI from the blood, especially if renal function is, or becomes, compromised.

No clinical information is available on the use of hemodialysis to treat ZEMDRI overdosage.