Plazomicin
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From MedlinePlus, U.S. National Library of Medicine
Boxed warning
WARNING: 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 [see Dosage and Administration (2.2) and Warnings and Precautions (5.1) ] . 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 [see Dosage and Administration (2.3 , 2.4) ] .
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 [see Warnings and Precautions (5.2) ] . 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 [see Warning and Precautions (5.3) ] . Aminoglycosides, including ZEMDRI, can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ] . WARNING: NEPHROTOXICITY, OTOTOXICITY, NEUROMUSCULAR BLOCKADE and FETAL HARM See full prescribing information for complete boxed warning. 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. ( 5.1 ) 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. ( 5.2 ) Aminoglycosides have been associated with neuromuscular blockade. During therapy with ZEMDRI, monitor for adverse reactions associated with neuromuscular blockade particularly in high-risk patients. ( 5.3 ) Aminoglycosides, including ZEMDRI can cause fetal harm when…
Dosing in kidney impairment
Monitoring of Renal Function Assess creatinine clearance in all patients prior to initiating therapy and daily during therapy with ZEMDRI [see Dosage and Administration , Warnings and Precautions and Use in Specific Populations ] .
Dosage in Adult Patients With Renal Impairment The recommended initial dosage regimen of ZEMDRI in adult patients with CLcr greater than or equal to 15 and less than 90 mL/min, estimated by the Cockcroft-Gault formula, is described in Table 2. Patients with CLcr greater than or equal to 15 and less than 90 mL/min receiving ZEMDRI may require subsequent dosage adjustments based on change in renal function and/or Therapeutic Drug Monitoring (TDM) as appropriate [ see Dosage and Administration ] . [See table below.] 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 ZEMDRI.
Adjustment of the ZEMDRI dosage regimen based on TDM involves extending ZEMDRI dosing interval by 1.5 fold (i.e., from every 24 hours to every 36 hours or from every 48 hours to every 72 hours) for patients with plasma trough concentrations greater than or equal to 3 mcg/mL [ see Warnings and Precautions and Clinical Pharmacology ] .
| Estimated CLcr CLcr estimated by the Cockcroft-Gault formula. (2.3) (mL/min) | Recommended Dosage for ZEMDRI Calculate dosage using Total Body Weight (TBW). For patients with TBW greater than IBW by 25% or more, use adjusted body weight. (2.3) | Dosing Interval |
|---|---|---|
| Greater than or equal to 60 to less than 90 | 15 mg/kg | Every 24 hours |
| Greater than or equal to 30 to less than 60 | 10 mg/kg | Every 24 hours |
| Greater than or equal to 15 to less than 30 | 10 mg/kg | Every 48 hours |
| cUTI Infection | Dosage Regimen Calculate dosage using TBW. For patients with TBW greater than IBW by 25% or more, use adjusted body weight based on the equation: Adjusted body weight = IBW + 0.4 × [TBW – IBW]. | Duration of Treatment |
|---|---|---|
| Complicated Urinary Tract Infections, including Pyelonephritis | 15 mg/kg every 24 hours | 4 to 7 days An appropriate oral therapy may be considered after 4 to 7 days of ZEMDRI therapy to complete a total duration of 7 to 10 days (IV plus oral). The maximum duration of ZEMDRI for cUTI is 7 days. |
| Estimated CLcr CLcr estimated by the Cockcroft-Gault formula using total body weight (TBW). For patients with TBW greater than ideal body weight (IBW) by 25% or more, use IBW. (mL/min) | Dosage Calculate dosage using TBW. For patients with TBW greater than IBW by 25% or more, use adjusted body weight based on the equation: Adjusted body weight = IBW + 0.4 × [TBW – IBW]. | Dosing Interval |
|---|---|---|
| Greater than or equal to 60 to less than 90 | 15 mg/kg | Every 24 hours |
| Greater than or equal to 30 to less than 60 | 10 mg/kg | Every 24 hours |
| Greater than or equal to 15 to less than 30 | 10 mg/kg | Every 48 hours |
Preparation and administration
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Preparation of Diluted Solutions of ZEMDRI ZEMDRI is supplied as a single-dose fliptop 10-mL vial that contains plazomicin sulfate equivalent to 500 mg plazomicin freebase in 10 mL Water for Injection (concentration of 50 mg/mL). The appropriate volume of ZEMDRI solution (50 mg/mL) for the required dose should be diluted in 0.9% Sodium Chloride Injection, USP or Lactated Ringer's Injection, USP to achieve a final volume of 50 mL for intravenous infusion.
The stability of ZEMDRI solution in the compatible diluents is described below [see Dosage and Administration ] . ZEMDRI does not contain preservatives. Aseptic technique must be followed in preparing the infusion solution. Discard unused portion of the ZEMDRI vial. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Stability of ZEMDRI Solution in Intravenous Fluids After dilution, ZEMDRI solution for administration is stable for 24 hours at room temperature, and for up to 7 days when refrigerated at 2°C to 8°C (36°F to 46°F), at concentrations of 2.5 mg/mL to 45 mg/mL in the following solutions: 0.9% Sodium Chloride Injection, USP Lactated Ringer's Injection, USP
Drug Compatibility Compatibility of ZEMDRI for administration with other drugs has not been established. ZEMDRI should not be mixed with other drugs or physically added to solutions containing other drugs. Other medications should not be infused simultaneously with ZEMDRI through the same IV line.
Contraindications
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 )
Pregnancy and lactation
Pregnancy
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).
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
Supply and cost
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