Zemdri

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.

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 (Cmin) 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)].

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.

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.

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 [see Use in Specific Populations (8.1)].

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.

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.

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.

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).

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.

. Pediatric Use

The safety and effectiveness of Zemdri in patients less than 18 years of age have not been established.

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)].

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)].

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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).

How Supplied

Zemdri 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 and Handling

Store Zemdri injection 500 mg/10 mL (50 mg/mL) refrigerated at 2°C to 8°C (36°F to 46°F).

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 [see Warnings and Precautions (5.1)].

Ototoxicity

Advise patients, their families, or caregivers 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 [see Warnings and Precautions (5.2)].

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 [see Warnings and Precautions (5.3)].

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 [see Use in Specific Populations (8.1)]. Tell women of childbearing potential to notify their prescribing physician/ healthcare provider if they become pregnant during Zemdri treatment [see Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.5)].

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 [see Warnings and Precautions (5.6)].

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 [see Warnings and Precautions (5.7)].

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

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of plazomicin in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of plazomicin in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require caution for patients receiving this medicine.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Hearing loss, family history of or
• Kidney disease or
• Nerve or muscle disorder (eg, myasthenia gravis)—Use with caution. May make these conditions worse.