Zemdri (plazomicin sulfate)

Plazomicin is commercially available as plazomicin sulfate; dosage is expressed in terms of plazomicin.

Dosage of plazomicin should be calculated using total body weight. If total body weight exceeds ideal body weight by 25% or more, adjusted body weight should be used to calculate dosage.

Plazomicin sulfate is administered by IV infusion.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Aminoglycosides/Ataluren

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The mechanism of this interaction is not known.

CLINICAL EFFECTS: The combination of an aminoglycoside and ataluren may increase risk for serious nephrotoxicity.(1)

PREDISPOSING FACTORS: Preexisting renal impairment, dehydration, extended duration of aminoglycoside therapy, greater than one aminoglycoside dose per day, or concomitant use of additional nephrotoxic agents such as iodinated contrast media or vancomycin appear to increase the risk for nephrotoxicity.(1-5).

PATIENT MANAGEMENT: The manufacturer states that ataluren should not be co-administered with intravenous aminoglycosides based upon cases of decreased renal function observed in a clinical trial with cystic fibrosis patients. If aminoglycoside therapy is required, stop ataluren and resume therapy 2 days after aminoglycoside therapy has ended.(1)

DISCUSSION: In a clinical trial with cystic fibrosis patients, 18 of 118 (15%) patients in the ataluren group developed increased creatinine concentrations compared with one of 120 patients in the placebo group.(2)

Antibiotics/Fecal Microbiota

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Aminoglycosides/Anesthetics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The neuromuscular blocking activity of aminoglycosides results from a decreased sensitivity at the postjunctional membrane and interfere with transmitter release.(1) These actions produce a synergistic effect with anesthetic agents that produce neuromuscular blockade.(2,3) Some anesthetics cause renal failure due to release of fluoride ion. Aminoglycosides cause nephrotoxicity when high doses are given.(4,5)

CLINICAL EFFECTS: Increased neuromuscular blockade activity, profound sedation, respiratory depression, coma, and/or death. Circulatory collapse may also occur secondary to the neuromuscular blockade.(6-10) Decreased urinary output and increased BUN and serum creatinine may indicate renal impairment.

PREDISPOSING FACTORS: Patients in respiratory distress, history of renal impairment and high doses of aminoglycosides and anesthetics.

PATIENT MANAGEMENT: Monitor neuromuscular blockade with train-of-four stimulus. Monitor vital signs, and respiratory rate. Intravenous neostigmine (0.2 to 2.5 mg), calcium (1 G), and possibly sodium bicarbonate (dose not reported) may be beneficial in reversal of neuromuscular blockade and respiratory depression.(6-10) Supportive care and ventilation should be utilized until the neuromuscular blockade is resolved. Volume replacement may be necessary for circulatory collapse.(6-10) Monitor BUN, serum creatinine, and urinary output and adjust aminoglycoside and anesthetic doses according to renal function.

DISCUSSION: Aminoglycosides including kanamycin(6,11), streptomycin(6,13), amikacin(13), gentamicin(7,13-15), neomycin, and tobramycin(13) have been documented to have neuromuscular blocking activity. There is no documentation with netilmicin and paromomycin, though it is assumed that they produce the same effects as the other members of this class. Neomycin has been shown to interact with cyclopropane(8,9), halothane(6), methoxyflurane(6), and nitrous oxide(6). Enflurane, ethylene, and isoflurane share similar properties to the previous inhalation anesthetics and would likely interact with neomycin. Kanamycin(6,11) and streptomycin (6,12) are known to interact with ether. Gentamicin has been reported to potentiate atracurium.(16) Therefore it is hypothesized that all aminoglycosides interact with the inhaled anesthetics. One study evaluating gentamicin and halothane in animals did not exhibit a decrease in muscle strength.(17) Aminoglycosides have been proven to be nephrotoxic at high doses. Anesthetics containing fluoride also produce renal dysfunction. Nephrotoxicity occurred more often when gentamicin or tobramycin were given with enflurane than when enflurane was given alone or in patients who received nitrous oxide and opioid anesthesia.(4)

Aminoglycosides/Cyclosporine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cyclosporine and aminoglycosides can both cause nephrotoxicity. Concurrent administration may result in an additive or synergistic risk of nephrotoxicity.(1-3)

CLINICAL EFFECTS: Concurrent use of cyclosporine with aminoglycosides may result in a higher risk of renal dysfunction, including structural kidney damage.(1-3)

PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include pre-existing renal impairment, older age, higher doses or longer treatment duration of either drug, and dehydration.(1-3)

PATIENT MANAGEMENT: Avoid the concurrent use of cyclosporine and aminoglycosides whenever possible.(2,3) If concurrent use cannot be avoided, it should be undertaken with great caution. Minimize the cyclosporine dose and monitor renal function carefully. Frequent dose adjustment may be indicated. If renal function deteriorates, the aminoglycoside may need to be decreased or discontinued.(1-4)

DISCUSSION: Coadministration of cyclosporine with other drugs that may impair renal function, like aminoglycosides, may cause additive or synergistic impairment of renal function. A meta-analysis of 30 studies that evaluated the correlation and risk factors between cyclosporine and kidney injury in allogeneic hematopoietic stem cell transplant (allo-HSCT) patients included 7 studies that examined the role of the combination with other drugs in the development of nephrotoxicity. Coadministration of aminoglycosides and amphotericin B were independent risk factors for acute or chronic kidney diseases related to cyclosporine in allo-HSCT patients.(5)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Aminoglycosides/Loop Diuretics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The coadministration of aminoglycosides and loop diuretics may result in additive or synergistic ototoxicity and/or nephrotoxicity.

CLINICAL EFFECTS: The combination of an aminoglycoside and a loop diuretic may increase risk for serious nephrotoxicity or ototoxicity.(1,2) Vestibular or auditory ototoxicity may be permanent.(1,3)

PREDISPOSING FACTORS: Preexisting renal impairment, extended duration of aminoglycoside therapy, greater than one aminoglycoside dose per day, rapid injection or high doses of loop diuretics, concomitant use of additional nephrotoxic agents such as iodinated contrast media or vancomycin, or sepsis appear to increase the risk for nephrotoxicity and ototoxicity.(1-6). Patients carrying certain variants in the MT-RNR1 gene (m.1555A>G, m.1095T>C, and m.1494C>T) are at increased risk of developing ototoxicity. An additional risk factor includes patients with a maternal relative known to have a clinically relevant MT-RNR1 variant. The risk of ototoxicity can occur at standard recommended doses of aminoglycosides.(7)

PATIENT MANAGEMENT: Administer aminoglycoside dosage every 24 to > 48 hours based upon renal function and continue therapy for less than 4 to 7 days, whenever possible.(4,5) The recommended maximal infusion rate for high dose furosemide therapy is 4 mg/minute.(2) When concurrent therapy is necessary monitor renal, hearing, and vestibular function. Signs of vestibular dysfunction include loss of balance and/or the visual sensation that stationary objects are moving (oscillopsia). In hospitalized or bedbound patients these symptoms may not be noticed or may be ascribed to other etiologies.(3)

DISCUSSION: Several studies and case reports have documented altered aminoglycoside levels, nephrotoxicity, and ototoxicity with concurrent therapy.(8-14) Otic aminoglycosides are included in this interaction because high aminoglycoside concentrations in the ear have been associated with an increased risk for hearing loss.

Aminoglycosides/Select Cephalosporins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Nephrotoxicity may occur.

PREDISPOSING FACTORS: Preexisting renal impairment, older age, and large doses of either drug.

PATIENT MANAGEMENT: Try to avoid this combination in patients at risk of developing nephrotoxicity. Elderly patients, patients receiving large doses of either drug, and renal patients should be considered at risk. Monitor renal function if this combination is used.

DISCUSSION: This interaction is likely to occur in some patients, but clinical documentation is limited. This interaction is usually not a problem in patients with normal renal function.

Selected Nephrotoxic Agents/Cisplatin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The nephrotoxic effects of aminoglycosides or non-steroidal anti-inflammatory drugs (NSAIDs) may be additive to those of cisplatin.

CLINICAL EFFECTS: The concurrent administration of amikacin, gentamicin, tobramycin, or NSAIDs with cisplatin may result in additive nephrotoxic effects.(1,2,5,6)

PREDISPOSING FACTORS: Pre-existing renal insufficiency, advanced age, dehydration may increase the risk of nephrotoxicity.(1,5,6)

PATIENT MANAGEMENT: The US labeling for aminoglycosides and cisplatin states that the concurrent use of aminoglycosides and cisplatin should be avoided.(1,3,4,6) Inform patients that concurrent cisplatin and aminoglycosides or NSAIDs can cause nephrotoxicity and that renal function and electrolyte monitoring during treatment is necessary.(2)

DISCUSSION: The US manufacturers of amikacin, gentamicin and tobramycin state that since the nephrotoxic effects of these medications may be additive, avoid concurrent or sequential use of other neurotoxic and/or nephrotoxic agents including cisplatin.(1,3,6)

*Known hypersensitivity to any aminoglycoside.

• Mt-RNr1 increased risk of aminoglycoside-induced hearing loss

• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Clostridioides difficile infection
• Disorder of the vestibulocochlear nerve
• Myasthenia gravis
• Pregnancy

• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Tinnitus
• Vertigo

Adverse effects reported in 1% or more of patients receiving plazomicin include decreased renal function, diarrhea, hypertension, headache, nausea, vomiting, and hypotension.

More Frequent

• Hypertension
• Hypotension
• Kidney disease with reduction in glomerular filtration rate (GFr)

Less Frequent

• Auditory neurotoxicity
• Nephrotoxicity

Rare or Very Rare

• Abnormal hepatic function tests
• Clostridioides difficile infection
• Hypersensitivity drug reaction
• Hypokalemia
• Neuromuscular blockade
• Ototoxicity

More Frequent

• Diarrhea
• Headache disorder
• Nausea
• Vomiting

Rare or Very Rare

• Constipation
• Dizziness
• Dyspnea
• Gastritis
• Hematuria
• Tinnitus

No enhanced messaging available.

Safety and efficacy of plazomicin have not been established in patients younger than 18 years of age.

Aminoglycosides, including plazomicin, can cause fetal harm when administered to pregnant women.

Data are not available regarding use of plazomicin in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Pregnant women should be advised of the potential risk to a fetus.

In animal studies, no plazomicin-related visceral or skeletal malformations were observed in pregnant rats or rabbits receiving plazomicin at doses that resulted in maternal exposures 0.8- or 2.5-fold higher, respectively, than human exposures at the recommended dosage; auditory function was not measured in the offspring of these animals.

Plazomicin is distributed into milk in rats. It is not known if the drug is distributed into human milk, affects the breast-fed infant, or affects milk production.

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for plazomicin and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.

Dosage should be selected with caution because of age-related decreases in renal function, and plasma concentrations of plazomicin should be monitored as appropriate.

In phase 2 and 3 clinical studies evaluating plazomicin, 40% of patients were 65 years of age and older; 17.2% of patients were 75 years of age and older. In patients 65 years of age or older in the phase 3 study (Trial 1), adverse effects were reported in 27 or 18.9% of those receiving plazomicin or meropenem, respectively; in those younger than 65 years of age, adverse effects were reported in 13.3 or 24.1%, respectively. The rate of adverse renal effects in patients 65 years and older was 6.6 or 2.8% in those receiving plazomicin or meropenem, respectively; in those younger than 65 years of age, such adverse effects were reported in 1.2 or 0%, respectively.

Clinically relevant age-related differences in plazomicin exposures have not been observed. Although trough plasma concentrations of plazomicin reported in geriatric patients 65-90 years of age were higher than those reported in younger adults, these increased trough plasma concentrations were mainly attributed to age-related changes in renal function.

Since the risk of adverse effects may be greater in patients with renal impairment and geriatric patients are more likely to have decreased renal function, plazomicin dosage should be selected carefully in geriatric patients and renal function should be monitored. Dosage adjustments in geriatric patients should take into account renal function and plazomicin plasma concentrations as appropriate.