Arikayce (amikacin sulfate liposomal with nebulizer accessories)

Dosage of amikacin sulfate is expressed in terms of amikacin. IM and IV dosage is identical.

Like other aminoglycosides, dosage of amikacin should be individualized taking into consideration the patient's pretreatment body weight, renal status, severity of the infection, and susceptibility of the causative organism. Many clinicians recommend that amikacin dosage be determined using appropriate pharmacokinetic methods for calculating dosage requirements and patient-specific pharmacokinetic parameters (e.g., elimination rate constant, volume of distribution) derived from serum concentration-time data.

Whenever possible, especially in patients with life-threatening infections, suspected toxicity or nonresponse to treatment, decreased or varying renal function, and/or when increased aminoglycoside clearance (e.g., patients with cystic fibrosis, burns) or prolonged therapy is likely, peak and trough serum concentrations of amikacin should be determined periodically and dosage should be adjusted to maintain desired serum concentrations. (See Dosage and Administration: Dosage, in the Aminoglycosides General Statement 8:12.02.) A causal relationship between maintenance of certain peak or trough serum concentrations or other pharmacodynamic endpoints and clinical response or toxicity has not been established to date for amikacin dosing regimens. However, for amikacin administered in conventional dosage regimens (i.e., multiple daily doses), peak serum concentrations of 15-30 and trough concentrations less than 5-10 mcg/mL have been suggested. Amikacin serum concentrations greater than 30-35 mcg/mL may be associated with toxicity. The manufacturers recommend that peak serum concentrations (30-90 minutes after injection) greater than 35 mcg/mL and trough serum concentrations (just prior to the next dose) greater than 10 mcg/mL should be avoided.

Parenteral aminoglycosides historically have been administered in dosage regimens that include multiple daily doses, and current prescribing information for IM or IV amikacin only includes dosage regimens that involve multiple daily doses (usually 2 or 3 doses daily). However, there is evidence that once-daily+ (single-daily) aminoglycoside dosage regimens are at least as effective as, may provide superior pharmacokinetics, and may be less toxic than conventional dosage regimens employing multiple daily doses. Once-daily parenteral aminoglycoside regimens should not be used in all patients. Additional controlled studies in children, patients with renal dysfunction, and other appropriate patient groups are needed to fully define the optimal use of once-daily aminoglycoside dosing regimens. In addition, the most appropriate methods for optimizing dosage selection for once-daily regimens and monitoring serum aminoglycoside concentrations in patients receiving such regimens have not been clearly established. (See Dosage and Administration: Dosage, in the Aminoglycosides General Statement 8:12.02.)

The usual duration of amikacin treatment is 7-10 days. The manufacturers state that safety of amikacin treatment for longer than 14 days has not been established. If a clinical response does not occur within 3-5 days, amikacin should be discontinued and in vitro susceptibility to the drug should be reassessed. In difficult and complicated infections, use of amikacin should be re-evaluated if treatment longer than 10 days is being considered. If the drug is continued, serum amikacin concentrations and renal, auditory, and vestibular functions should be monitored closely.

The maximum dosage of amikacin recommended by the manufacturers is 15 mg/kg (up to 1.5 g) daily.

In patients with impaired renal function, doses and/or frequency of administration of amikacin must be modified in response to serum concentrations of the drug and the degree of renal impairment. There are various methods to determine dosage and a wide variation in dosage recommendations for these patients. However, even when one of these methods is used, peak and trough serum concentrations of the drug should be monitored, especially in patients with changing renal function.

The manufacturers recommend an initial amikacin loading dose of 7.5 mg/kg. For subsequent therapy, the manufacturers state that 7.5-mg/kg doses can be given at intervals (in hours) calculated by multiplying the patient's steady-state serum creatinine (in mg/dL) by 9. Alternatively, many clinicians recommend the dosing method of Sarubbi and Hull, which is based on corrected creatinine clearance. (See Dosage and Administration: Dosage in Renal Impairment, in the Aminoglycosides General Statement 8:12.02.)

In adults with renal failure undergoing hemodialysis, some clinicians recommend supplemental doses of 50-75% of the initial loading dose at the end of each dialysis period. Others suggest that supplemental amikacin doses may not be necessary in patients undergoing short-term hemodialysis. Serum amikacin concentrations should be monitored in dialysis patients and dosage adjusted as needed to maintain desired serum concentrations.

For the treatment of active tuberculosis+ in adults with renal impairment, the ATS, CDC, and IDSA recommend that usual doses be given at less frequent intervals since use of lower doses may reduce efficacy of the drug. These experts recommend that adults with renal impairment receive amikacin in a dosage of 12-15 mg/kg daily given 2 or 3 times weekly. In addition, if the patient is receiving hemodialysis, the dose should be given after the procedure is finished and serum concentrations of the drug monitored to avoid toxicity.

Amikacin sulfate is administered by IM injection or IV infusion.

Amikacin sulfate has been given intrathecally+ or intraventricularly+ as an adjunct to IM or IV administration of the drug for the treatment of meningitis and other CNS infections.

Although amikacin has been given intraperitoneally+, the risk of toxicity associated with this route should be considered. (See Cautions in the Aminoglycosides General Statement 8:12.02.)

Patients should be well hydrated prior to and during amikacin therapy to minimize chemical irritation of renal tubules which may occur as the result of high urine amikacin concentrations.

Renal function should be assessed prior to and daily during amikacin therapy. Patients should be under close clinical observation because of the risk of ototoxicity and nephrotoxicity. (See Cautions in the Aminoglycosides General Statement 8:12.02.)

Prior to administration, amikacin solutions should be inspected visually for particulate matter or discoloration.

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

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.

Antimicrobials/Live Typhoid Vaccine

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 antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Selected Nephrotoxic Agents/Bacitracin

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: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3)

CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3)

PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1)

PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3)

DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3)

Selected Nephrotoxic Agents/Polymyxin B

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: Polymyxin B can cause nephrotoxicity with a slight degree of tubular damage. Concurrent administration of other nephrotoxic agents may result in an increased risk of nephrotoxicity.(1)

CLINICAL EFFECTS: Concurrent use of polymyxin B with other nephrotoxic agents may result in additive nephrotoxic effects. Polymyxin B nephrotoxicity is characterized by albuminuria, cellular casts, azotemia, diminished urine output, elevated BUN and rising blood levels usually after about 4 days of therapy.(1,2)

PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include higher cumulative doses and longer duration of therapy of polymyxin B and exposure to multiple nephrotoxins.(2)

PATIENT MANAGEMENT: Concurrent or sequential use of potentially nephrotoxic agents with polymyxin B should be avoided. If concurrent use is necessary, it should be undertaken with great caution. Check renal function at baseline and monitor renal function and polymyxin B blood levels frequently during therapy.(1)

DISCUSSION: Polymyxin B is associated with high rates of nephrotoxicity. Concurrent use with other nephrotoxins may increase the risk of nephrotoxicity.

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

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)

Selected Antimycobacterials/Live Bcg

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

MECHANISM OF ACTION: Bacillus Calmette-Guerin (BCG) is a live, attenuated strain of Mycobacterium bovis (M.bovis) used to induce a granulomatous response in the treatment of localized bladder cancer and as a vaccine to prevent tuberculosis.(1-2) Co-treatment with antibacterial agents active against M.bovis may lead to an attenuation of the immune response associated with BCG administration.(1-2)

CLINICAL EFFECTS: The effectiveness of chemotherapy may be impaired, or the vaccine may be ineffective. Agents linked to this monograph may have activity against M.bovis: amikacin, capreomycin, ciprofloxacin, clofazimine, cycloserine, ethambutol, ethionamide, gatifloxacin, isoniazid, kanamycin, levofloxacin, moxifloxacin, ofloxacin, rifabutin, rifampin, rifapentine, and streptomycin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Intravesical instillation of BCG should be postponed during treatment with antibacterials which may decrease effectiveness.(2) Administration of BCG vaccine to patients receiving antibiotic therapy should only be done under close medical supervision.(1) If a patient develops a systemic BCG infection due to intravesicular or vaccine administration, treatment with multiple antimycobacterial agents may be required.

DISCUSSION: Because antibiotic therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of BCG vaccine states that administration of BCG vaccine to patients receiving antibiotic therapy should only be done under close medical supervision.(1) Pyrazinamide is not included in this interaction as BCG is not sensitive to pyrazinamide.(2)

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

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.

Gentamicin, Amikacin, Tobramycin/Amphotericin

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

MECHANISM OF ACTION: The ototoxic or nephrotoxic effects of gentamicin, amikacin, or tobramycin may be additive with those of amphotericin.

CLINICAL EFFECTS: The concurrent administration of gentamicin, amikacin, or tobramycin with amphotericin may result in additive ototoxic or nephrotoxic effects.(1)

PREDISPOSING FACTORS: Preexisting renal impairment, sepsis, 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 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: The Australian manufacturer of gentamicin, amikacin, and tobramycin state that the concurrent use of gentamicin, amikacin, or tobramycin and amphotericin should be avoided.(1,4,5)

DISCUSSION: The Australian and U.K. manufacturers of gentamicin, amikacin, and tobramycin state that since the ototoxic or nephrotoxic effects of gentamicin, amikacin, or tobramycin may be additive, avoid concurrent or sequential use of other neurotoxic and/or nephrotoxic agents including amphotericin.(1,3,4,5)

Gentamicin, Amikacin, Tobramycin/Vancomycin

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

MECHANISM OF ACTION: The ototoxic or nephrotoxic effects of gentamicin, amikacin, or tobramycin may be additive with those of vancomycin.

CLINICAL EFFECTS: The concurrent administration of gentamicin, amikacin, or tobramycin with vancomycin may result in additive ototoxic or nephrotoxic effects.(1)

PREDISPOSING FACTORS: Preexisting renal impairment, sepsis, 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 and ototoxicity.(1-5). 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.

PATIENT MANAGEMENT: The Australian manufacturer of gentamicin, amikacin, and tobramycin state that the concurrent use of gentamicin, amikacin, or tobramycin and vancomycin should be avoided.(1,4,5)

DISCUSSION: The Australian and U.K. manufacturers of gentamicin, amikacin, and tobramycin state that since the ototoxic or nephrotoxic effects of gentamicin, amikacin, or tobramycin may be additive, avoid concurrent or sequential use of other neurotoxic and/or nephrotoxic agents including vancomycin.(1,3,4,5)

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)

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

• Chronic obstructive pulmonary disease
• Myasthenia gravis

• Asthma
• Disorder of the vestibulocochlear nerve
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Parkinsonism
• Tinnitus
• Vertigo

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More Frequent

• Bronchospastic pulmonary disease
• Hemoptysis
• Ototoxicity

Less Frequent

• Exacerbation of chronic obstructive pulmonary disease
• Hypersensitivity pneumonitis
• Pneumonia
• Pneumothorax

Rare or Very Rare

• Acute kidney injury
• Acute renal failure
• Anaphylaxis
• Lip swelling
• Nephrotoxicity
• Neuromuscular blockade
• Tongue swelling
• Urticaria

More Frequent

• Cough
• Diarrhea
• Fatigue
• General weakness
• Musculoskeletal pain
• Nausea
• Voice change

Less Frequent

• Ataxia
• Chest discomfort
• Dysgeusia
• Epistaxis
• Fever
• Headache disorder
• Increased sputum
• Laryngitis
• Oral candidiasis
• Pain in oropharynx
• Pharyngeal edema
• Pharyngitis
• Skin rash
• Symptoms of anxiety
• Vomiting
• Weight loss
• Xerostomia

Rare or Very Rare

• Abdominal distension
• Abdominal pain with cramps
• Dry nose
• Dysphagia
• Dyspnea
• Glossitis
• Nasal congestion
• Oral pruritus
• Rhinorrhea
• Sialorrhea
• Sneezing
• Sore tongue
• Stomatitis
• Syncope
• Tachycardia

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