AMIKACIN: 11,312 Adverse Event Reports & Safety Profile

The active ingredient in ARIKAYCE (amikacin liposome inhalation suspension) is amikacin sulfate USP, an aminoglycoside antibacterial. Its chemical name is D-Streptamine, O -3-amino-3-deoxy-α-D-glucopyranosyl-(1→6)- O -[6-amino-6-deoxy-α-D-glucopyranosyl-(1→4)]- N 1 -(4-amino-2-hydroxy-1-oxobutyl)-2-deoxy-, ( S )-, sulfate (1:2) salt with a chemical formula of C 22 H 43 N 5 O 13 ∙2H 2 SO 4 with a molecular weight of 781.76. Its structural formula is: ARIKAYCE is a white milky suspension consisting of amikacin sulfate encapsulated in liposomes and is supplied in a unit-dose 10 mL clear glass vial containing amikacin 590 mg/8.4 mL (equivalent to amikacin sulfate 788 mg/8.4 mL) as a sterile aqueous liposomal suspension for oral inhalation. ARIKAYCE consists of amikacin sulfate encapsulated in liposomes at a targeted concentration of 70 mg amikacin/mL with the pH range of 6.1 to 7.1 and lipid to amikacin weight ratio in the range of 0.60 to 0.79. The inactive ingredients are cholesterol, dipalmitoylphosphatidylcholine (DPPC), sodium chloride, sodium hydroxide (for pH adjustment), and water for injection. ARIKAYCE is administered only using a Lamira Nebulizer System [see Dosage and Administration (2.1) ]. Like all other nebulized treatments, the amount delivered to the lungs will depend upon patient factors. Under standardized in vitro testing per USP<1601> adult breathing pattern (500 mL tidal volume, 15 breaths per minute, and inhalation: exhalation ratio of 1:1), the mean delivered dose from the mouthpiece was approximately 312 mg of amikacin sulfate (53% of label claim). The mass median aerodynamic diameter (MMAD) of the nebulized aerosol droplets is about 4.7 µm (4.1 – 5.3 µm) as determined using the Next Generation Impactor (NGI) method. A percentage of the amikacin in the liposome is released by the nebulization process, thus nebulized ARIKAYCE delivers a combination of free and liposomal amikacin.

Chemical

Structure

INDICATIONS AND USAGE Amikacin Sulfate Injection, USP is indicated in the short-term treatment of serious infections due to susceptible strains of Gram-negative bacteria, including Pseudomonas species, Escherichia coli , species of indole-positive and indole-negative Proteus , Providencia species, Klebsiella-Enterobacter-Serratia species, and Acinetobacter ( Mima-Herellea ) species. Clinical studies have shown Amikacin Sulfate Injection, USP to be effective in bacterial septicemia (including neonatal sepsis); in serious infections of the respiratory tract, bones and joints, central nervous system (including meningitis) and skin and soft tissue; intra-abdominal infections (including peritonitis); and in burns and postoperative infections (including post-vascular surgery). Clinical studies have shown amikacin also to be effective in serious complicated and recurrent urinary tract infections due to those organisms. Aminoglycosides, including Amikacin Sulfate Injection, USP are not indicated in uncomplicated initial episodes of urinary tract infections unless the causative organisms are not susceptible to antibiotics having less potential toxicity. Bacteriologic studies should be performed to identify causative organisms and their susceptibilities to amikacin. Amikacin may be considered as initial therapy in suspected Gram-negative infections and therapy may be instituted before obtaining the results of susceptibility testing. Clinical trials demonstrated that amikacin was effective in infections caused by gentamicin and/or tobramycin-resistant strains of Gram-negative organisms, particularly Proteus rettgeri , Providencia stuartii , Serratia marcescens , and Pseudomonas aeruginosa . The decision to continue therapy with the drug should be based on results of the susceptibility tests, the severity of the infection, the response of the patient and the important additional considerations contained in the WARNINGS box above. Amikacin has also been shown to be effective in staphylococci infections and may be considered as initial therapy under certain conditions in the treatment of known or suspected staphylococcal disease such as, severe infections where the causative organism may be either a Gram-negative bacterium or a staphylococcus, infections due to susceptible strains of staphylococci in patients allergic to other antibiotics, and in mixed staphylococci/Gram-negative infections. In certain severe infections such as neonatal sepsis, concomitant therapy with a penicillin-type drug may be indicated because of the possibility of infections due to Gram-positive organisms such as streptococci or pneumococci. To reduce the development of drug-resistant bacteria and maintain the effectiveness of amikacin and other antibacterial drugs, amikacin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION The patient's pretreatment body weight should be obtained for calculation of correct dosage.

Amikacin Sulfate

Injection USP may be given intramuscularly or intravenously. The status of renal function should be estimated by measurement of the serum creatinine concentration or calculation of the endogenous creatinine clearance rate. The blood urea nitrogen (BUN) is much less reliable for this purpose. Reassessment of renal function should be made periodically during therapy. Whenever possible, amikacin concentrations in serum should be measured to assure adequate but not excessive levels. It is desirable to measure both peak and trough serum concentrations intermittently during therapy. Peak concentrations (30 to 90 minutes after injection) above 35 micrograms per mL and trough concentrations (just prior to the next dose) above 10 micrograms per mL should be avoided. Dosage should be adjusted as indicated. Since the vials are for single-dose only, any unused portion remaining in the vial should be discarded.

Intramuscular

Administration for Patients with Normal Renal Function The recommended dosage for adults, children and older infants (see WARNINGS box) with normal renal function is 15 mg/kg/day divided into 2 or 3 equal doses administered at equally-divided intervals, i.e., 7.5 mg/kg q12h or 5 mg/kg q8h. Treatment of patients in the heavier weight classes should not exceed 1.5 gram/day. When amikacin is indicated in newborns (see WARNINGS box), it is recommended that a loading dose of 10 mg/kg be administered initially to be followed with 7.5 mg/kg every 12 hours. The usual duration of treatment is 7 to 10 days. It is desirable to limit the duration of treatment to short term whenever feasible. The total daily dose by all routes of administration should not exceed 15 mg/kg/day. In difficult and complicated infections where treatment beyond 10 days is considered, the use of amikacin should be reevaluated. If continued, amikacin serum levels, and renal, auditory, and vestibular functions should be monitored. At the recommended dosage level, uncomplicated infections due to amikacin-sensitive organisms should respond in 24 to 48 hours. If definite clinical response does not occur within 3 to 5 days, therapy should be stopped and the antibiotic susceptibility pattern of the invading organism should be rechecked. Failure of the infection to respond may be due to resistance of the organism or to the presence of septic foci requiring surgical drainage. When amikacin is indicated in uncomplicated urinary tract infections, a dose of 250 mg twice daily may be used.

Dosage Guidelines Adults And Children With Normal Renal Function

Patient Weight Dosage lbs kg 7.5 mg/kg 5 mg/kg q12h OR q8h 99 45 337.5 mg 225 mg 110 50 375 mg 250 mg 121 55 412.5 mg 275 mg 132 60 450 mg 300 mg 143 65 487.5 mg 325 mg 154 70 525 mg 350 mg 165 75 562.5 mg 375 mg 176 80 600 mg 400 mg 187 85 637.5 mg 425 mg 198 90 675 mg 450 mg 209 95 712.5 mg 475 mg 220 100 750 mg 500 mg Intramuscular Administration for Patients with Impaired Renal Function Whenever possible, serum amikacin concentrations should be monitored by appropriate assay procedures. Doses may be adjusted in patients with impaired renal function either by administering normal doses at prolonged intervals or by administering reduced doses at a fixed interval. Both methods are based on the patient's creatinine clearance or serum creatinine values since these have been found to correlate with aminoglycoside half-lives in patients with diminished renal function. These dosage schedules must be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary. Neither method should be used when dialysis is being performed.

Normal

Dosage at Prolonged Intervals If the creatinine clearance rate is not available and the patient's condition is stable, a dosage interval in hours for the normal dose can be calculated by multiplying the patient's serum creatinine by 9, e.g., if the serum creatinine concentration is 2 mg/100 mL, the recommended single dose (7.5 mg/kg) should be administered every 18 hours.

Reduced

Dosage at Fixed Time Intervals When renal function is impaired and it is desirable to administer amikacin at a fixed time interval, dosage must be reduced. In these patients, serum amikacin concentrations should be measured to assure accurate administration of amikacin and to avoid concentrations above 35 mcg/mL. If serum assay determinations are not available and the patient's condition is stable, serum creatinine and creatinine clearance values are the most readily available indicators of the degree of renal impairment to use as a guide for dosage. First, initiate therapy by administering a normal dose, 7.5 mg/kg, as a loading dose. This loading dose is the same as the normally recommended dose which would be calculated for a patient with a normal renal function as described above. To determine the size of maintenance doses administered every 12 hours, the loading dose should be reduced in proportion to the reduction in the patient's creatinine clearance rate: observed CC in mL/min Maintenance Dose Every 12 Hours = ---------------------------x calculate loading dose in mg normal CC in mL/min (CC-creatinine clearance rate) An alternate rough guide for determining reduced dosage at 12-hour intervals (for patients whose steady state serum creatinine values are known) is to divide the normally recommended dose by the patient's serum creatinine. The above dosage schedules are not intended to be rigid recommendations but are provided as guides to dosage when the measurement of amikacin serum levels is not feasible.

Intravenous Administration

The individual dose, the total daily dose, and the total cumulative dose of amikacin sulfate are identical to the dose recommended for intramuscular administration. The solution for intravenous use is prepared by adding the contents of a 500 mg vial to 100 or 200 mL of sterile diluent such as 0.9% sodium chloride injection or 5% dextrose injection or any of the compatible solutions listed below. The solution is administered to adults over a 30 to 60 minute period. The total daily dose should not exceed 15 mg/kg/day and may be divided into either 2 or 3 equally-divided doses at equally-divided intervals. In pediatric patients the amount of fluid used will depend on the amount of amikacin ordered for the patient. It should be a sufficient amount to infuse the Amikacin Sulfate Injection USP over a 30 to 60 minute period. Infants should receive a 1 to 2 hour infusion. Amikacin should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route. Stability in IV Fluids Amikacin sulfate is stable for 24 hours at room temperature at concentrations of 0.25 and 5 mg/mL in the following solutions: 5% Dextrose Injection 5% Dextrose and 0.2% Sodium Chloride Injection 5% Dextrose and 0.45% Sodium Chloride Injection 0.9% Sodium Chloride Injection Lactated Ringer's Injection Normosol ® M in 5% Dextrose Injection (or Plasma-Lyte 56 Injection in 5% Dextrose in Water) Normosol ® R in 5% Dextrose Injection (or Plasma-Lyte 148 Injection in 5% Dextrose in Water) In the above solutions with Amikacin Sulfate Injection USP concentrations of 0.25 and 5 mg/mL, solutions aged for 60 days at 4°C and then stored at 25°C had utility times of 24 hours. At the same concentrations, solutions frozen and aged for 30 days at - 15°C, thawed, and stored at 25°C had utility times of 24 hours.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Aminoglycosides administered by any of the above routes should not be physically premixed with other drugs but should be administered separately.Because of the potential toxicity of aminoglycosides, "fixed dosage" recommendations which are not based upon body weight are not advised. Rather, it is essential to calculate the dosage to fit the needs of each patient.

CONTRAINDICATIONS: A history of hypersensitivity to amikacin is a contraindication for its use. A history of hypersensitivity or serious toxic reactions to aminoglycosides may contraindicate the use of any other aminoglycoside because of the known cross-sensitivities of patients to drugs in this class.

REACTIONS The following clinically significant adverse reactions are described in greater detail in other sections of labeling: Hypersensitivity pneumonitis [see Boxed Warning and Warnings and Precautions (5.1) ] Hemoptysis [see Boxed Warning and Warnings and Precautions (5.2) ] Bronchospasm [see Boxed Warning and Warnings and Precautions (5.3) ] Exacerbation of Underlying Pulmonary Disease [see Boxed Warning and Warnings and Precautions (5.4) ] Anaphylaxis and Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Ototoxicity [see Warnings and Precautions (5.6) ] Nephrotoxicity [see Warnings and Precautions (5.7) ]

Neuromuscular

Blockade [see Warnings and Precautions (5.8) ] Most common adverse reactions (incidence ≥10% and higher than control) in the patients with refractory MAC lung disease were: dysphonia, cough, bronchospasm, hemoptysis, musculoskeletal pain, upper airway irritation, ototoxicity, fatigue/asthenia, exacerbation of underlying pulmonary disease, diarrhea, nausea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Insmed Incorporated at 1-844-4-INSMED or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Overview of Clinical Trials for Safety Evaluation Within the refractory NTM clinical program, 404 patients that participated in three clinical trials were treated with ARIKAYCE at the dose of 590 mg/day (median duration of exposure to ARIKAYCE was 236.5 days).

Trial

1 (NCT#02344004) was an open-label, randomized (2:1), multi-center Phase 3 trial in patients with refractory Mycobacterium avium complex (MAC) lung disease. Patients were randomized to either 8 months of ARIKAYCE plus a background regimen (n=223) or background regimen alone (n=112).

Trial

2 (NCT#02628600) was a single-arm extension of Trial 1 for refractory MAC lung disease patients that failed to achieve negative sputum cultures after 6 months of treatment or had a relapse or recurrence by Month 6 from either study arm of Trial 1. A total of 163 patients (n=90 from the prior background regimen alone arm of Trial 1, and n=73 from the prior ARIKAYCE plus background regimen arm in Trial 1) participated in the trial.

Trial

3 (NCT#01315236) was a double-blind, randomized, placebo-controlled Phase 2 study in patients with refractory nontuberculous mycobacterial (NTM) lung disease caused by MAC and Mycobacterium abscessus . Patients were randomized to either ARIKAYCE plus background regimen (N=44) or an inhaled diluted empty liposome placebo plus background regimen (N=45) for 84 days. Across all clinical trials of patients with and without refractory NTM lung infection, 818 patients were exposed to multiple doses of ARIKAYCE.

Adverse Reactions

Leading to Treatment Discontinuation In the three NTM studies, there was a higher incidence of premature discontinuation of ARIKAYCE.

In Trial

1, 34.5% discontinued ARIKAYCE prematurely; most were due to adverse reactions (18.8%) and withdrawal by subject (9.9%). In the comparator arm, 10.7% of subjects discontinued their background regimen, with 0.9% due to adverse reactions and 5.4% due to withdrawal by subject.

In Trial

2 (the single-arm extension of Trial 1), 37.8% of patients starting on ARIKAYCE discontinued prematurely with 24.4% discontinuing due to adverse reactions.

In Trial

3, all 9 (20.5%) premature discontinuations occurred in the ARIKAYCE plus background regimen-treated patients and there were no premature discontinuations in the placebo plus background regimen arm.

Serious Adverse

Reactions in Trials 1 and 3 In Trial 1, 19.7% of patients treated with ARIKAYCE plus background regimen reported SAR as compared to 16.1% of patients treated with background regimen alone. In addition, in Trial 1 [2 to 1 randomization, ARIKAYCE plus background regimen versus background regimen alone], there were 80 hospitalizations in 41 patients (18.4%) treated with ARIKAYCE plus background regimen compared to 29 hospitalizations in 15 patients (13.4%) treated with background regimen alone. The most common SARs and reasons for hospitalization in the ARIKAYCE plus background regimen arm were related to exacerbation of underlying pulmonary disease and lower respiratory tract infections, such as pneumonia.

In Trial

3, 18.2% of patients treated with ARIKAYCE plus background regimen reported SARs compared to 8.9% of patients treated with background regimen plus inhaled placebo.

Common Adverse Reactions

The incidence of adverse reactions in Trial 1 are displayed in Table 1. Only those adverse reactions with a rate of at least 5% in the ARIKAYCE plus background regimen group and greater than the background regimen alone group, are shown.

Table

1: Adverse Reactions in ≥ 5% of ARIKAYCE-treated MAC Patients and More Frequent than Background Regimen Alone in Trial 1 Adverse Reaction ARIKAYCE plus Background Regimen Background Regimen Alone (N=223) n (%) (N=112) n (%)

Dysphonia

Includes aphonia and dysphonia 106 (48) 2 (2)

Cough

Includes cough, productive cough, and upper airway cough syndrome 88 (40) 19 (17)

Bronchospasm

Includes asthma, bronchial hyperreactivity, bronchospasm, dyspnea, dyspnea exertional, prolonged expiration, throat tightness, and wheezing 64 (29) 12 (11)

Hemoptysis

41 (18) 15 (13) Musculoskeletal pain Includes back pain, arthralgia, myalgia, pain/body aches, muscle spasm and musculoskeletal pain 40 (18) 10 (9) Upper airway irritation Includes oropharyngeal pain, oropharyngeal discomfort, throat irritation, pharyngeal erythema, upper airway inflammation, pharyngeal edema , vocal cord inflammation, laryngeal pain, laryngeal erythema, laryngitis 39 (18) 2 (2)

Ototoxicity

Includes deafness, deafness neurosensory, deafness unilateral, dizziness, hypoacusis, presyncope, tinnitus, vertigo, balance disorders 38 (17) 11 (10) Fatigue and asthenia 36 (16) 11 (10) Exacerbation of underlying pulmonary disease Includes COPD, infective exacerbation of COPD, infective exacerbation of bronchiectasis 34 (15) 11 (10)

Diarrhea

28 (13) 5 (5)

Nausea

26 (12) 4 (4)

Headache

22 (10) 5 (5)

Pneumonia

Includes atypical pneumonia, empyema, infection pleural effusion, lower respiratory tract infection, lung infection, lung infection pseudomonas, pneumonia, pneumonia aspiration, pneumonia pseudomonas, pseudomonas infection, and respiratory tract infection 20 (9) 10 (9)

Pyrexia

17 (8) 5 (5) Weight decreased 16 (7) 1 (1)

Vomiting

Includes vomiting and post-tussive vomiting 15 (7) 4 (4)

Rash

Includes rash, rash maculo-papular, drug eruption, and urticaria 14 (6) 1 (1) Change in sputum Includes increased sputum, sputum purulent, and sputum discolored 13 (6) 1 (1) Chest discomfort 12 (5) 3 (3) Selected adverse drug reactions that occurred in <5% of patients and at higher frequency in ARIKAYCE-treated patients in Trial 1 are presented in Table 2.

Table

2: Selected Adverse Reactions in < 5% of ARIKAYCE-treated MAC Patients and More Frequent than Background Regimen Alone in Trial 1 Adverse Reaction ARIKAYCE plus Background Regimen N=223 n (%)

Background Regimen

Alone N=112 n (%)

Anxiety

Includes anxiety and anxiety disorder 10 (5) 0 (0) Oral fungal infection Includes oral candidiasis and oral fungal infection 9 (4) 2 (2)

Bronchitis

8 (4) 3 (3)

Dysgeusia

7 (3) 0 (0) Hypersensitivity pneumonitis Includes allergic alveolitis, interstitial lung disease, and pneumonitis 7 (3) 0 (0) Dry mouth 6 (3) 0 (0)

Epistaxis

6 (3) 1 (1) Respiratory failure Includes acute respiratory failure and respiratory failure 6 (3) 2 (2)

Pneumothorax

Includes pneumothorax, pneumothorax spontaneous and pneumomediastinum 5 (2) 1 (1) Exercise tolerance decreased 3 (1) 0 (0) Balance disorder 3 (1) 0 (0) Neuromuscular disorder Includes muscle weakness and neuropathy peripheral 2 (1) 0 (0) Refer to Table 1 and Table 2 for the incidence rate of hypersensitivity pneumonitis, bronchospasm, cough, dysphonia, exacerbation of underlying disease, hemoptysis, ototoxicity, upper airway irritation, and neuromuscular disorders [see Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.4 , 5.6 , 5.7) ].

6.2 Postmarketing Experience The following adverse reactions have been identified from postmarketing surveillance. Because these adverse reactions are reported voluntarily from a population of unknown size, precise estimates of frequency cannot be made and a causal relationship to drug exposure cannot be established. Gastrointestinal disorders: dysphagia, glossitis, glossodynia, salivary hypersecretion, stomatitis, abdominal pain, abdominal distension Immune system disorders: hypersensitivity, anaphylaxis, pharyngeal swelling <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span> Respiratory, thoracic, and mediastinal disorders: nasal dryness, rhinorrhea, sneezing, nasal congestion

AND PRECAUTIONS Hypersensitivity Pneumonitis : Reported with ARIKAYCE treatment; if hypersensitivity pneumonitis occurs, discontinue ARIKAYCE and manage patients as medically appropriate. ( 5.1 ) Hemoptysis : Higher frequency of hemoptysis has been reported with ARIKAYCE treatment. If hemoptysis occurs, manage the patients as medically appropriate. ( 5.2 ) Bronchospasm : Higher frequency of bronchospasm has been reported with ARIKAYCE treatment. Treat patients as medically appropriate if this occurs during treatment with ARIKAYCE. ( 5.3 ) Exacerbations of Underlying Pulmonary Disease: Higher frequency of exacerbations of underlying pulmonary disease has been reported with ARIKAYCE treatment. Treat patients as medically appropriate if this occurs during treatment with ARIKAYCE. ( 5.4 ) Anaphylaxis and Hypersensitivity Reactions : Serious and potentially life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients taking ARIKAYCE. If anaphylaxis or a hypersensitivity reaction occurs, discontinue ARIKAYCE and institute appropriate supportive measures. ( 5.5 ) Ototoxicity: Higher frequency of ototoxicity has been reported with ARIKAYCE treatment. Closely monitor patients with known or suspected auditory or vestibular dysfunction. If patients develop tinnitus this may be an early symptom of ototoxicity. ( 5.6 ) Nephrotoxicity : Nephrotoxicity was observed during the clinical trials of ARIKAYCE in patients with MAC lung disease but not at a higher frequency than the background regimen alone. Aminoglycosides have been associated with nephrotoxicity. Close monitoring of patients with known or suspected renal dysfunction may be needed when prescribing ARIKAYCE. ( 5.7 )

Neuromuscular

Blockade: Aminoglycosides may aggravate muscle weakness by blocking the release of acetylcholine at neuromuscular junctions. Closely monitor patients with known or suspected neuromuscular disorders, such as myasthenia gravis. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical respiratory assistance may be necessary. ( 5.8 ) Embryo-Fetal Toxicity : Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides, including ARIKAYCE, may be associated with total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero . Advise pregnant women of the potential risk to a fetus. ( 5.9 , 8.1 )

5.1 Hypersensitivity Pneumonitis Hypersensitivity pneumonitis has been reported with the use of ARIKAYCE in the clinical trials. Hypersensitivity pneumonitis (reported as allergic alveolitis, pneumonitis, interstitial lung disease, allergic reaction to ARIKAYCE) was reported at a higher frequency in patients treated with ARIKAYCE plus a background regimen (3.1%) compared to patients treated with a background regimen alone (0%). Most patients with hypersensitivity pneumonitis discontinued treatment with ARIKAYCE and received treatment with corticosteroids <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . If hypersensitivity pneumonitis occurs, discontinue ARIKAYCE and manage the patient as medically appropriate .

5.2 Hemoptysis Hemoptysis has been reported with the use of ARIKAYCE in the clinical trials. Hemoptysis was reported at a higher frequency in patients treated with ARIKAYCE plus a background regimen (18.4%) compared to patients treated with a background regimen alone (13.4%) <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . If hemoptysis occurs, manage the patients as medically appropriate .

5.3 Bronchospasm Bronchospasm has been reported with the use of ARIKAYCE in the clinical trials. Bronchospasm (reported as asthma, bronchial hyperreactivity, bronchospasm, dyspnea, dyspnea exertional, prolonged expiration, throat tightness, wheezing) was reported at a higher frequency in patients treated with ARIKAYCE plus a background regimen (28.7%) compared to patients treated with a background regimen alone (10.7%) <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . If bronchospasm occurs during the use of ARIKAYCE, treat the patients as medically appropriate .

5.4 Exacerbation of Underlying Pulmonary Disease Exacerbations of underlying pulmonary disease have been reported with the use of ARIKAYCE in the clinical trials. Exacerbations of underlying pulmonary disease (reported as chronic obstructive pulmonary disease, infective exacerbation of chronic obstructive pulmonary disease, infective exacerbation of bronchiectasis) have been reported at a higher frequency in patients treated with ARIKAYCE plus a background regimen (15.2%) compared to patients treated with background regimen alone (9.8%) <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . If exacerbations of underlying pulmonary disease occur during the use of ARIKAYCE, treat the patients as medically appropriate .

5.5 Anaphylaxis and Hypersensitivity Reactions Serious and potentially life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients taking ARIKAYCE <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 , 6.2) ]</span> . Signs and symptoms include acute onset of skin and mucosal tissue hypersensitivity reactions (hives, itching, flushing, swollen lips/tongue/uvula), respiratory difficulty (shortness of breath, wheezing, stridor, cough), gastrointestinal symptoms (nausea, vomiting, diarrhea, crampy abdominal pain), and cardiovascular signs and symptoms of anaphylaxis (tachycardia, low blood pressure, syncope, incontinence, dizziness). Before therapy with ARIKAYCE is instituted, evaluate for previous hypersensitivity reactions to aminoglycosides. If anaphylaxis or a hypersensitivity reaction occurs, discontinue ARIKAYCE and institute appropriate supportive measures.

5.6 Ototoxicity Ototoxicity with use of ARIKAYCE Ototoxicity has been reported with the use of ARIKAYCE in the clinical trials. Ototoxicity (including deafness, dizziness, presyncope, tinnitus, and vertigo) were reported with a higher frequency in patients treated with ARIKAYCE plus a background regimen (17%) compared to patients treated with background regimen alone (9.8%). This was primarily driven by tinnitus (8.1% in ARIKAYCE plus background regimen vs. 0.9% in the background regimen alone arm) and dizziness (6.3% in ARIKAYCE plus background regimen vs. 2.7% in the background regimen alone arm) <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Closely monitor patients with known or suspected auditory or vestibular dysfunction during treatment with ARIKAYCE. If ototoxicity occurs, manage the patient as medically appropriate, including potentially discontinuing ARIKAYCE. Risk of Ototoxicity Due to Mitochondrial DNA Variants Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene ( MT-RNR1 ), particularly the m.1555A&gt;G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

5.7 Nephrotoxicity Nephrotoxicity was observed during the clinical trials of ARIKAYCE in patients with MAC lung disease but not at a higher frequency than the background regimen alone <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Nephrotoxicity has been associated with the aminoglycosides. Close monitoring of patients with known or suspected renal dysfunction may be needed when prescribing ARIKAYCE.

5.8 Neuromuscular Blockade Patients with neuromuscular disorders were not enrolled in ARIKAYCE clinical trials. Aminoglycosides may aggravate muscle weakness by blocking the release of acetylcholine at neuromuscular junctions. Closely monitor patients with known or suspected neuromuscular disorders, such as myasthenia gravis. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical respiratory assistance may be necessary.

5.9 Embryo-Fetal Toxicity Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides, including ARIKAYCE, may be associated with total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero . Patients who use ARIKAYCE during pregnancy, or become pregnant while taking ARIKAYCE should be apprised of the potential hazard to the fetus <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> .

PRECAUTIONS General Prescribing amikacin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Aminoglycosides are quickly and almost totally absorbed when they are applied topically, except to the urinary bladder, in association with surgical procedures. Irreversible deafness, renal failure, and death due to neuromuscular blockade have been reported following irrigation of both small and large surgical fields with an aminoglycoside preparation.

Amikacin Sulfate

Injection, USP is potentially nephrotoxic, ototoxic and neurotoxic. The concurrent or serial use of other ototoxic or nephrotoxic agents should be avoided either systemically or topically because of the potential for additive effects. Increased nephrotoxicity has been reported following concomitant parenteral administration of aminoglycoside antibiotics and cephalosporins. Concomitant cephalosporins may spuriously elevate creatinine determinations. Since amikacin is present in high concentrations in the renal excretory system, patients should be well hydrated to minimize chemical irritation of the renal tubules. Kidney function should be assessed by the usual methods prior to starting therapy and daily during the course of treatment. If signs of renal irritation appear (casts, white or red cells, or albumin), hydration should be increased. A reduction in dosage (see DOSAGE AND ADMINISTRATION ) may be desirable if other evidence of renal dysfunction occurs such as decreased creatinine clearance; decreased urine specific gravity; increased BUN, creatinine, or oliguria. If azotemia increases or if a progressive decrease in urinary output occurs, treatment should be stopped. Note: When patients are well-hydrated and kidney function is normal the risk of nephrotoxic reactions with amikacin is low if the dosage recommendations (see DOSAGE AND ADMINISTRATION ) are not exceeded . Elderly patients may have reduced renal function which may not be evident in routine screening tests such as BUN or serum creatinine. A creatinine clearance determination may be more useful. Monitoring of renal function during treatment with aminoglycosides is particularly important. Aminoglycosides should be used with caution in patients with muscular disorders such as myasthenia gravis or parkinsonism since these drugs may aggravate muscle weakness because of their potential curare-like effect on the neuromuscular junction. In vitro mixing of aminoglycosides with beta-lactam antibiotics (penicillin or cephalosporin) may result in a significant mutual inactivation. A reduction in serum half-life or serum level may occur when an aminoglycoside or penicillin-type drug is administered by separate routes. Inactivation of the aminoglycoside is clinically significant only in patients with severely impaired renal function. Inactivation may continue in specimens of body fluids collected for assay, resulting in inaccurate aminoglycoside readings. Such specimens should be properly handled (assayed promptly, frozen, or treated with beta-lactamase). Cross-allergenicity among aminoglycosides has been demonstrated. As with other antibiotics, the use of amikacin may result in overgrowth of nonsusceptible organisms. If this occurs, appropriate therapy should be instituted. Aminoglycosides should not be given concurrently with potent diuretics (see WARNINGS box). Information for Patients Patients should be counseled that antibacterial drugs including amikacin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amikacin 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 amikacin or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Carcinogenesis, Mutagenesis, Impairment of Fertility Long term studies in animals to evaluate carcinogenic potential have not been performed, and mutagenicity has not been studied. Amikacin administered subcutaneously to rats at doses up to 4 times the human daily dose did not impair male or female fertility.

Pregnancy Teratogenic

Effects; Pregnancy Category D (See WARNINGS section.)

Nursing

Mothers It is not known whether amikacin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from amikacin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Aminoglycosides should be used with caution in premature and neonatal infants because of the renal immaturity of these patients and the resulting prolongation of serum half-life of these drugs.

INTERACTIONS

7.1 Drugs with Neurotoxic, Nephrotoxic, or Ototoxic Potential Avoid concomitant use of ARIKAYCE with medications associated with neurotoxicity, nephrotoxicity, and ototoxicity.

7.2 Ethacrynic Acid, Furosemide, Urea, or Mannitol Some diuretics can enhance aminoglycoside toxicity by altering aminoglycoside concentrations in serum and tissue. Avoid concomitant use of ARIKAYCE with ethacrynic acid, furosemide, urea, or intravenous mannitol.