• Introduction
  • Boxed Warning
  • Indications and Usage
  • Dosage and Administration and Dosage Forms and Strengths
  • Contraindictions and Warnings and Precautions
  • Adverse Reactions
  • Drug Interactions
  • Use in Specific Populations and Overdosage
  • Description, Clinical Pharmacology, and Nonclinical Toxicology
  • Clinical Studies
  • How Supplied / Storage and Handling
  • Patient Counseling Information
  • Medication Guide
  • Progress Check
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INTRODUCTION

Welcome to the ARIKAYCE® (amikacin liposome inhalation suspension) Prescribing Information educational magazine. In this eMagazine, you will explore the key elements of the ARIKAYCE Prescribing Information (PI), which is sometimes referred to as the Package Insert. The PI contains all of the information needed for physicians to prescribe ARIKAYCE to appropriate patients, and is also the foundation for all promotional activity.

After reviewing the contents of this eMagazine, you should be able to:

  • Describe the Limited Population Pathway for antibacterial and antifungal drugs, and its relevance to ARIKAYCE
  • Describe the following sections of the ARIKAYCE PI:
    • Boxed Warning
    • Indications and Usage
    • Dosage and Administration and Dosage Forms and Strengths
    • Contraindications and Warnings and Precautions
    • Adverse Reactions
    • Drug Interactions
    • Use in Specific Populations and Overdosage
    • Description, Clinical Pharmacology, and Nonclinical Toxicology
    • Clinical Studies
    • How Supplied/Storage and Handling
    • Patient Counseling
    • Medication Guide

Instructions on eMagazine Icons

Throughout this eMagazine, you will encounter the following icons. When you see these icons, make sure to select them to access sections of the ARIKAYCE PI as well as additional important information.

Note that you may download and take notes on a PDF version of this installment of inspireWIRE by selecting the download icon.

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BOXED WARNING

A Boxed Warning is used to highlight for prescribers one of the following situations:

  • There is an adverse reaction so serious in proportion to the potential benefit from the drug that it is essential to be considered in assessing the risks and benefits of the drug
  • There is a serious adverse reaction that can be prevented or reduced in frequency or severity by appropriate use of the drug
  • The FDA approved the drug with restrictions to ensure safe use because the FDA concluded that the drug can be safely used only if distribution or use is restricted

ARIKAYCE has a Boxed Warning regarding the risk of increased respiratory adverse reactions. ARIKAYCE has been associated with an increased risk of respiratory adverse reactions, including hypersensitivity pneumonitis, hemoptysis, bronchospasm, and exacerbation of underlying pulmonary disease, that have led to hospitalizations in some cases.

This information will be covered in greater detail in the article on Warnings and Precautions.

Select the PI icon to read the Boxed Warning for ARIKAYCE.

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SECTION 1: INDICATIONS AND USAGE

LIMITED POPULATION: ARIKAYCE is indicated in adults, who have limited or no alternative treatment options, for the treatment of Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial drug regimen in patients who do not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy.

As only limited clinical safety and effectiveness data for ARIKAYCE are currently available, reserve ARIKAYCE for use in adults who have limited or no alternative treatment options. This drug is indicated for use in a limited and specific population of patients.

This indication is approved under accelerated approval based on achieving sputum culture conversion (defined as 3 consecutive negative monthly sputum cultures) by Month 6. Clinical benefit has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

The ARIKAYCE label also includes a Limitation of Use: ARIKAYCE has only been studied in patients with refractory MAC lung disease defined as patients who did not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy. The use of ARIKAYCE is not recommended for patients with non-refractory MAC lung disease.

The Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) created a new pathway intended to encourage the development of antibacterial and antifungal drugs.

Select the topics for additional background information on LPAD.

What is LPAD?
What Does the FDA Consider a Serious or Life-Threatening Condition?
What is the Definition of Limited Population?
What is an Unmet Need?
How Should You Discuss LPAD With Healthcare Providers?

The Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) was created by the US FDA to encourage the development of antibacterial and antifungal drugs. Drugs approved under this pathway must be intended to treat a serious or life-threatening infection in a limited population of patients with unmet needs. The FDA requires that all drugs approved under the LPAD pathway include the statement “Limited Population” in all labeling, packaging, and advertising. Approval under this pathway means that the FDA has determined that the benefits of treatment outweigh the risks in the limited population identified. It does not alter FDA standards of evidence for approval.

An immediately life-threatening disease or condition means a stage of disease in which there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.

A serious disease or condition means a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible, provided it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.

A drug is intended to treat a serious or life-threatening disease or condition if:

  • The drug is intended to have an effect on a serious condition or a serious aspect of the serious or life-threatening condition, such as a direct effect on a serious manifestation or symptom of a condition or other intended effects.
  • This direct effect may include diagnosing, preventing, and/or treating a serious aspect of the condition.

To be eligible for approval via the LPAD pathway a drug must be intended for use in a limited population of patients, defined as a group of patients that is limited in such a way that is clinically relevant to healthcare providers. The labeling should define the limited population that the drug is intended to treat so that a healthcare provider would be able to identify the patients in the clinical setting, for whom FDA determined the benefits of the drug outweigh its risks.

A limited population may be defined as a subset of a broader population of patients for whom the drug could potentially be effective, and may be the only population of patients for whom the drug may be effective because of its narrow spectrum of activity.

To be eligible for approval via the LPAD pathway a drug must be intended for use in patients with unmet needs, which the FDA defines as a condition whose treatment or diagnosis is not addressed adequately by available therapy. It includes an immediate need for a defined population (for example, to treat a serious condition with no or limited treatment) or a longer-term need for society (for example, to address the development of resistance to antibacterial drugs).

Many physicians may not be familiar with the LPAD pathway, as it is relatively new. Some key points to convey include:

  • The LPAD pathway is a new pathway that was created as part of the 21st Century Cures Act to encourage development of antibacterial and antifungal drugs.
  • It is a guidance document describing the agency’s current thinking regarding the “decline in antibacterial drug research and development as serious antibacterial drug resistant infections increase.”
  • Drugs approved under the pathway must be intended to treat a serious or life-threatening infection in a limited population of patients with unmet needs.

When reviewing the application, the FDA can take into account rarity, severity, or lack of alternative treatment for a limited population.

The FDA has granted several additional designations to ARIKAYCE, suggesting high unmet need for the treatment of NTM lung disease caused by MAC.

Select the icon to learn about the designations ARIKAYCE has received during its development.

The FDA has granted several designations to ARIKAYCE, suggesting high unmet need in the treatment of NTM lung disease caused by MAC.
Orphan Drug Designation The Orphan Drug designation is granted to drugs that are intended for the safe and effective treatment of rare diseases or disorders that affect fewer than 200,000 people in the United States.
Breakthrough Therapy Designation Breakthrough Therapies are drugs that are intended to treat a serious or life-threatening disease or condition and that have preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over existing therapies.
Qualified Infectious Disease Product (QIDP) Designation This designation, which is given under the Generating Antibiotic Incentives Now (GAIN) program, creates incentives for the development of promising antibacterial drug products that treat serious or life-threatening infections.
Accelerated Approval Accelerated approval is granted to a product for a serious or life-threatening disease or condition based on clinical endpoints that suggests clinical benefit or an effect on morbidity and mortality, and taking into account the unmet need for new treatments for that disease or condition.
Priority Review In a priority review, the FDA takes action on applications for approval within 6 months (compared to 10 months under standard review).

Select the PI icon to read the Indications and Usage section of the PI.

SECTIONS 2 AND 3: DOSAGE AND ADMINISTRATION AND DOSAGE FORMS AND STRENGTHS

The Dosage and Administration section of the ARIKAYCE Prescribing Information provides guidance on the recommended dose and method of dosing.

Select the arrows in the slider to learn more about the Dosage and Administration of ARIKAYCE.

ARIKAYCE is for oral inhalation use only with the Lamira™ Nebulizer System.

The recommended dose of ARIKAYCE in adults is once daily inhalation of the contents of one 590 mg/8.4 mL ARIKAYCE vial (590 mg of amikacin) using the Lamira Nebulizer System.

Patients using a bronchodilator should be instructed to first use the bronchodilator following the bronchodilator leaflet for use information before using ARIKAYCE. Pretreatment with short-acting selective beta-2 agonists should be considered for patients with known hyperreactive airway disease, chronic obstructive pulmonary disease, asthma, or bronchospasm.

The medication should be at room temperature before use.

Prior to opening, the ARIKAYCE vial should be shaken well for at least 10 to 15 seconds until the contents appear uniform and well mixed.

The ARIKAYCE vial is opened by flipping up the plastic top of the vial, then pulling downward to loosen the metal ring. The rubber stopper and metal ring should be removed carefully.

The contents of the ARIKAYCE vial can then be poured into the medication reservoir of the nebulizer handset.

If a daily dose of ARIKAYCE is missed, the next dose should be administered the next day. DO NOT double the dose to make up for the missed dose.

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Section 3, Dosage Forms and Strengths, indicates that ARIKAYCE is supplied as a sterile, white, milky, aqueous liposome suspension for oral inhalation in a unit-dose glass vial containing amikacin 590 mg/8.4 mL (equivalent to amikacin sulfate 623 mg/8.4 mL).

Select the PI icon to read the Dosage and Administration section of the PI.

SECTIONS 4 AND 5: CONTRAINDICATIONS AND WARNINGS AND PRECAUTIONS

Contraindications

ARIKAYCE is contraindicated in patients with known hypersensitivity to any aminoglycoside.

Select the PI icon to read the Contraindications section of the PI.

Warnings and Precautions

ARIKAYCE has 8 Warnings and Precautions. Select each of the labels below to learn more.

Section 5.1: Hypersensitivity Pneumonitis

What it is: A form of pneumonia with wheezing, shortness of breath, and infiltrates into the lungs. Occurs after exposure to substances that cause allergic reactions.

What the PI Says: Hypersensitivity pneumonitis 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. If it occurs, ARIKAYCE should be discontinued and the patients managed as medically appropriate.

Further information about this Warning and Precaution can be found in Section 6.1

Section 5.2: Hemoptysis

What it is: Coughing up of blood derived from the lungs or bronchial tubes as a result of bleeding in the lungs or bronchi.

What the PI Says: Hemoptysis was reported at a higher frequency in patients treated with ARIKAYCE plus a background regimen (17.9%) compared to patients treated with a background regimen alone (12.5%). If it occurs, it should be managed as appropriate.

Further information about this Warning and Precaution can be found in Section 6.1

Section 5.3: Bronchospasm

What it is: Contraction of the smooth muscles in the walls of the bronchi and bronchioles, causing narrowing of the airways.

What the PI Says: 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%). If it occurs, it should be managed as appropriate.

Further information about this Warning and Precaution can be found in Section 6.1

Section 5.4: Exacerbations of Underlying Pulmonary Disease

What the PI Says: 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 (14.8%) compared to patients treated with background regimen alone (9.8%). If exacerbations of underlying pulmonary disease occurs during the use of ARIKAYCE, patients should be treated as medically appropriate.

Further information about this Warning and Precaution can be found in Section 6.1

Section 5.5: Ototoxicity

What it is: Toxicities affecting the inner ear.

What the PI Says: 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 (7.6% 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).

Patients with known or suspected auditory or vestibular dysfunction during treatment with ARIKAYCE should be monitored closely. If ototoxicity occurs, the patient should be managed as medically appropriate, including potentially discontinuing ARIKAYCE.

Further information about this Warning and Precaution can be found in Section 6.1

Section 5.6: Nephrotoxicity

What it is: Toxic side effects in the kidneys that occurs after exposure to a drug or toxin that causes damage to the kidneys.

What the PI Says: 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. Nephrotoxicity has been associated with the aminoglycosides. Close monitoring of patients with known or suspected renal dysfunction may be needed when prescribing ARIKAYCE.

Section 5.7: Neuromuscular Blockade

What the PI Says: Patients with neuromuscular disorders were not enrolled in ARIKAYCE clinical studies. Patients with known or suspected neuromuscular disorders such as myasthenia gravis should be monitored closely since aminoglycosides may aggravate muscle weakness by blocking the release of acetylcholine at neuromuscular junctions.

Section 5.8: Embryo-fetal Toxicity

What the PI Says: Aminoglycosides can cause fetal harm, including total, irreversible, bilateral congenital deafness in pediatric patients exposed in the womb. Patients who use ARIKAYCE during pregnancy, or become pregnant while taking ARIKAYCE should be apprised of the potential hazard to the fetus.

Further information about this Warning and Precaution can be found in Section 8.1

Select the PI icon to read the Warnings and Precautions section of the PI.

SECTION 6: ADVERSE REACTIONS

The Adverse Reactions section of the PI describes the overall adverse reactions to ARIKAYCE (including an overall analysis of all multiple-dose studies, including studies in cystic fibrosis) and adverse reactions seen in the pivotal clinical trial in NTM lung disease caused by MAC.

Select the Important Information icon to learn more about adverse reaction rates and clinical trials.

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.

Patient Population

A total of 388 patients with refractory NTM who were treated with ARIKAYCE 590 mg/day participated in 3 clinical trials. The median duration of exposure to ARIKAYCE in these trials was 169 days.

Select each of the trials to learn more.

Open-label, randomized (2:1) multicenter phase 3 trial in patients with refractory MAC lung disease. Patients were randomized to 8 months of therapy with:

  • ARIKAYCE plus a background regimen (n = 223)
  • Background regimen alone (n = 112)

Single-arm extension of Trial 1 for refractory MAC lung disease patients (N = 133) who 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

  • 74 patients were enrolled who were previously treated with the background regimen in Trial 1
  • 59 patients were previously treated with the ARIKAYCE plus background regimen in Trial 1

Double-blind, randomized, placebo-controlled phase 2 study in patients with refractory NTM lung disease caused by MAC and Mycobacterium abscessus. Patients were randomized to 84 days of therapy with:

  • ARIKAYCE plus background regimen
  • Inhaled diluted empty liposome placebo plus background regimen
Adverse Reactions Leading to Treatment Discontinuation

In all 3 NTM studies, the incidence of premature discontinuation was higher in patients who received ARIKAYCE. The table below summarizes discontinuations in these 3 trials.

Trial 1 Trial 2 Trial 3
ARIKAYCE + background regimen Background regimen only ARIKAYCE + background regimen ARIKAYCE + background regimen Empty liposome placebo
Premature discontinuation 33.5% 8% 20.3% 20.5% 0
Due to adverse reactions 17.4% 0.9% 14.9% — —
Withdrawal by subject 9.4% 5.4% — — —
Serious Adverse Reactions in Trials 1 and 3

In Trials 1 and 3, there were more serious adverse reactions (SARs) reported in the ARIKAYCE arm than in the control arm. 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.

Trial 1 Trial 3
ARIKAYCE + background regimen Background regimen only ARIKAYCE + background regimen Empty liposome placebo
Serious adverse reaction 20.2% 16.1% 18.2% 8.9%
Hospitalizations 18.4% 13.4% — —
Common Adverse Reactions

The incidence of adverse reactions in Trial 1 are displayed in Table 1 in the PI. 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

ARIKAYCE plus Background Regimen
(n = 223)
n (%)
Background Regimen Alone
(n = 112)
n (%)
Dysphoniaa 105 (47) 1 (1)
Coughb 87 (39) 19 (17)
Bronchospasmc 64 (29) 12 (11)
Hemoptysis 40 (18) 14 (13)
Ototoxicityd 38 (17) 11 (10)
Upper airway irritatione 37 (17) 2 (2)
Musculoskeletal painf 37 (17) 9 (8)
Fatigue and asthenia 36 (16) 11 (10)
Exacerbation of underlying pulmonary diseaseg 33 (15) 11 (10)
Diarrhea 28 (13) 5 (5)
Nausea 26 (12) 4 (4)
Pneumoniah 22 (10) 9 (8)
Headache 22 (10) 5 (5)
Pyrexia 16 (7) 5 (5)
Vomitingi 15 (7) 4 (4)
Rashj 14 (6) 2 (2)
Weight decreased 14 (6) 1 (1)
Change in sputumk 12 (5) 1 (1)
Chest discomfort 12 (5) 3 (3)
aIncludes aphonia and dysphonia
bIncludes cough, productive cough and upper airway cough syndrome
cIncludes asthma, bronchial hyperreactivity, bronchospasm, dyspnea, dyspnea exertional, prolonged expiration, throat tightness, wheezing
dIncludes deafness, deafness neurosensory, deafness unilateral, dizziness, hypoacusis, presyncope, tinnitus, vertigo
eIncludes oropharyngeal pain, oropharyngeal discomfort, throat irritation, pharyngeal erythema, upper airway inflammation, pharyngeal edema, vocal cord inflammation, laryngeal pain, laryngeal erythema, laryngitis
fIncludes back pain, arthralgia, myalgia, pain/body aches, muscle spasm and musculoskeletal
gIncludes COPD, infective exacerbation of COPD, infective exacerbation of bronchiectasis
hIncludes 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
iIncludes vomiting and post-tussive vomiting
jIncludes rash, rash maculo-papular, drug eruption and urticaria
kIncludes increased sputum, sputum purulent and sputum discolored

Selected adverse drug reactions that occurred in <5% of patients and at a higher frequency in ARIKAYCE-treated patients in Trial 1 are presented in Table 2 in the PI.

Table 2. Selected Adverse Reactions in <5% of ARIKAYCE-treated MAC Patients and More Frequent Than Background Regimen
Alone in Trial 1

ARIKAYCE plus Background Regimen
(n = 223)
n (%)
 Background Regimen Alone
(n = 112)
n (%)
Anxiety 10 (4.5) 0 (0)
Oral fungal infectiona 9 (4) 2 (1.8)
Bronchitis 8 (3.6) 3 (2.7)
Hypersensitivity pneumonitisb 8 (3.6) 0 (0)
Dysgeusia 7 (3.1) 0 (0)
Respiratory failurec 6 (2.7) 1 (0.9)
Epistaxis 6 (2.7) 1 (0.9)
Neuromuscular disorderd 5 (2.2) 0 (0)
Dry mouth 5 (2.2) 0 (0)
Pneumothoraxe 5 (2.2) 1 (0.9)
Exercise tolerance decreased 3 (1.3) 0 (0)
Balance disorder 3 (1.3) 0 (0)
aIncludes oral candidiasis and oral fungal infection
bIncludes allergic alveolitis, interstitial lung disease, and pneumonitis
cIncludes acute respiratory failure and respiratory failure
dIncludes muscle weakness, neuropathy peripheral, and balance disorder
eIncludes pneumothorax, pneumothorax spontaneous and pneumomediastinum

Select the PI icon to read the Adverse Reactions section of the PI.

SECTION 7: DRUG INTERACTIONS

Drugs With Neurotoxic, Nephrotoxic, or Ototoxic Potential

Concurrent use of ARIKAYCE with medications that are toxic to the nervous system, the kidney, or the ears should be avoided.

Ethacrynic Acid, Furosemide, Urea, or Mannitol

Some diuretics can enhance the toxicity of aminoglycosides by altering their concentration in the serum and tissue. Concomitant use of ARIKAYCE with ethacrynic acid, furosemide, urea, or intravenous mannitol should be avoided.

Select the PI icon to read the Drug Interactions section of the PI.

SECTIONS 8 and 10: USE IN SPECIFIC POPULATIONS AND OVERDOSAGE

Use in Specific Populations

As in all PIs, the ARIKAYCE PI includes a section that summarizes considerations in specific patient populations.

Select the buttons below to learn more about use in specific populations.

Pregnancy

There are no data on ARIKAYCE use in pregnant women to evaluate for any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Although systemic absorption of amikacin following oral inhalation is expected to be low, systemic exposure to aminoglycoside antibacterial drugs, including ARIKAYCE, may be associated with total, irreversible, bilateral congenital deafness when administered to pregnant women. Advise pregnant women of the potential risk to a fetus.

Animal reproductive toxicology studies have not been conducted with inhaled amikacin. Subcutaneous administration of amikacin to pregnant rats (up to 100 mg/kg/day) and mice (up to 400 mg/kg/day) during organogenesis was not associated with fetal malformations. Ototoxicity was not adequately evaluated in offspring in animal studies.

Subcutaneous administration to pregnant rats and mice did not result in birth defects, although high doses were excessively toxic in pregnant rats, precluding evaluation of offspring at the highest dose.
Lactation

There is no information regarding the presence of ARIKAYCE in human milk, effects on the breastfed infant, or effects on milk production after administration of ARIKAYCE by inhalation. Limited data suggest that amikacin delivered by other routes of administration is present in human milk; however, systemic absorption of ARIKAYCE is expected to be low.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ARIKAYCE and any potential adverse effects on the breastfed child from ARIKAYCE or from the underlying maternal condition.

Pediatric Use The safety and efficacy of ARIKAYCE in patients aged <18 years have not been established.
Geriatric use In NTM clinical trials, 50.5% of subjects were aged ≥65 years and 14.2% were aged ≥75 years. No overall differences in safety and effectiveness were observed between elderly subjects and younger subjects. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.
Patients with Hepatic Impairment ARIKAYCE has not been studied in patients with hepatic impairment. Because it is not metabolized by the liver, dose adjustments are not required based on liver function.
Patients with Renal Impairment ARIKAYCE has not been studied in patients with renal impairment. Given the low systemic exposure to amikacin following administration of ARIKAYCE, clinically relevant accumulation of amikacin is unlikely to occur in patients with renal impairment. However, renal function should be monitored in patients with known or suspected renal impairment, including elderly patients with potential age-related decreases in renal function.
Overdosage

Adverse reactions associated with ARIKAYCE overdose have not been identified. Acute toxicity should be treated with immediate withdrawal of ARIKAYCE and baseline tests of renal function should be conducted. Hemodialysis may be helpful in removing amikacin from the body.

Physicians should contact the Regional Poison Control Center for information about effective treatment. In the case of overdose, the possibility of drug interactions with alterations in drug disposition should be considered.

Select the PI icon to read the Use in Specific Populations and Overdosage sections of the PI.

SECTIONS 11, 12, AND 13: DESCRIPTION, CLINICAL PHARMACOLOGY, AND NONCLINICAL TOXICOLOGY

Description Amikacin

The active ingredient in ARIKAYCE is amikacin sulfate, an aminoglycoside antibacterial.

Amikacin has been used parenterally for decades in the treatment of NTM lung disease caused by MAC.

ARIKAYCE is supplied in a unit-dose, 10-mL clear glass vial containing amikacin 590 mg/8.4 mL (equivalent to amikacin sulfate 623 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. Inactive ingredients include cholesterol, dipalmitoylphosphatidylcholine (DPPC), sodium chloride, sodium hydroxide (for pH adjustment), and water for injection.

ARIKAYCE is administered only using a Lamira Nebulizer System. Under standardized testing conditions, the mean delivered dose of ARIKAYCE from the mouthpiece was approximately 312 mg of amikacin sulfate, or about 53% of the total dose.

Select the icon for background information on liposomal formulations of amikacin.

Why Amikacin? Why Liposomes?

Mycobacterium avium complex species are generally sensitive in vitro to aminoglycoside antibiotics, such as amikacin. However, amikacin and other aminoglycoside antibiotics accumulate poorly in cells, which can limit their effectiveness against intracellular infections.

Figure 2. Liposomes are microscopic membrane shells. In a liposome drug-delivery system, like ARIKAYCE, water-soluble drugs such as amikacin are located in the liposome’s water core.

One way to increase intracellular amikacin delivery is to package the antibiotic into liposomes, which are nanometer-sized vesicles composed of a phospholipid bilayer membrane surrounding an aqueous interior compartment (Figure 2). The physical characteristics of liposomes (small size and tissue/cell targeting) and their capability for delayed or triggered release of cargo molecules make them highly useful drug carriers.
Clinical Pharmacology

The clinical pharmacology section of the ARIKAYCE PI describes the mechanism of action of ARIKAYCE as well as its pharmacokinetic parameters.

Mechanism of Action

ARIKAYCE is an antibacterial drug. Further information on the mechanism of action of ARIKAYCE can be found in Microbiology (Section 12.4), discussed later in this module.

Pharmacodynamics

Pharmacodynamics is the study of what drugs do to the body. The relationship between ARIKAYCE exposure and clinical response, and the time course of clinical response, are unknown.

Pharmacokinetics

Pharmacokinetics is the study of what the body does to drugs. Pharmacokinetics is described by 4 key parameters: absorption, distribution, metabolism, and elimination (ADME). Additionally, this section describes the concentrations of ARIKAYCE in the sputum and serum and the results of drug interaction studies.

Select the buttons below to learn more about the key pharmacokinetic parameters for ARIKAYCE.

Sputum Concentrations Following once daily inhalation of the indicated dose of ARIKAYCE (590 mg) in patients with Mycobacterium avium complex (MAC), concentrations in the sputum at 1 to 4 hours after inhalation were 1720, 884, and 1300 micrograms/gram at 1, 3, and 6 months. There was high variability in amikacin concentrations. After 48 to 72 hours post-inhalation, amikacin sputum concentrations decreased to approximately 5% of those at 1 to 4 hours post-inhalation.
Serum Concentrations This section describes levels of ARIKAYCE in the blood. The maximum concentration and exposure to amikacin were lower than that observed for intravenous administration of amikacin for injection at its approved dosage of 15 mg/kg once daily in healthy adults.
Absorption The bioavailability of ARIKAYCE is expected to vary based on individual differences in nebulizer efficiency and airway pathology.
Distribution Amikacin is ≤10% bound to serum proteins.
Metabolism Amikacin does not undergo appreciable metabolism.
Elimination Amikacin is primarily eliminated by the kidney. On average, about 7.42% of the total dose is excreted unchanged in the urine, as compared to 94% following intravenous administration of amikacin sulfate. Unabsorbed amikacin, following ARIKAYCE inhalation, is probably eliminated by cellular turnover and by expectoration.
Drug Interactions No clinical drug interaction studies have been conducted with ARIKAYCE.
Microbiology
Mechanism of Action

ARIKAYCE is a polycationic (meaning positively charged), semisynthetic bactericidal aminoglycoside. It enters the bacterial cell by binding to the negatively charged components of the bacterial cell wall. In doing this, it disrupts the overall architecture of the cell wall. Its primary mechanism of action is the disruption and inhibition of protein synthesis in target bacteria by binding to the 30S subunit of the bacterial ribosome.

Select the Background icon to learn about the mechanism of action of amikacin.

How Do Aminoglycosides Work?

The primary mechanism of action of aminoglycosides (including amikacin) is shown in Figure 3. Aminoglycosides enter through the bacterial cell wall, disrupting its structure. Aminoglycosides bind to the smaller, 30S subunit of the ribosome—the cellular machinery that is responsible for decoding mRNA and generating protein. More specifically, they bind to a component of the 30S subunit known as the 16S ribosomal RNA (rRNA). This binding is thought to cause misreading of the mRNA and to inhibit production of proteins.

Figure 3. Aminoglycoside Primary Mechanism of Action

The mistranslation of mRNA produces abnormal proteins, including components of the cell wall. This further alters the structure, and the permeability, of the bacterial cell wall, allowing entry of more amikacin and ultimately causing death (Figure 4).

Figure 4. Aminoglycosides initiate a “vicious cycle” that ends with death of susceptible bacteria

Resistance

The primary mechanism of acquired resistance to amikacin in mycobacteria has been linked to mutations in a gene that codes for a component of ribosomal RNA, which is the key binding site in mycobacteria, including MAC. In clinical trials, MAC isolates developing an amikacin MIC of >64 mcg/mL after baseline were observed in a higher proportion of subjects treated with ARIKAYCE.

Select the Background icon to learn about the mechanism of resistance to amikacin.

What Is the Mechanism of Resistance to Amikacin?

Recall from above that aminoglycosides bind specifically to the 16S rRNA. Mutations in the 16S rRNA that disrupt binding result in resistance to aminoglycosides.

Interaction With Other Antimicrobials

Antagonism between amikacin and other antimicrobials has not been detected in in vitro studies. In some cases, some degree of synergy has been observed between amikacin and other agents, such as beta-lactams.

Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year inhalation carcinogenicity study, rats were exposed to ARIKAYCE at approximate inhaled doses of 5, 15, and 45 mg/kg/day. Squamous cell carcinoma was observed in the lungs of 2 of 120 rats administered the highest dose tested. Maximum serum AUC levels of amikacin in the rats were approximately 1.3, 2.8, and 7.6 mcg·hr/mL at the low, mid, and high doses, respectively, compared with 23.5 mcg·hr/mL (8.0 to 46.5 mcg·hr/mL) measured in humans. The squamous cell carcinomas may be the result of a high lung burden of particulates from ARIKAYCE in the rat lung. The relevance of the lung tumor findings with regards to humans receiving ARIKAYCE is unknown.

No evidence of mutagenicity or genotoxicity was observed in a battery of in vitro and in vivo genotoxicity studies with a liposomal formulation similar to ARIKAYCE (in vitro microbial mutagenesis test, in vitro mouse lymphoma mutation assay, in vitro chromosomal aberration study, and an in vivo micronucleus study in rats).

No fertility studies were conducted with ARIKAYCE. Intraperitoneal administration of amikacin to male and female rats at doses up to 200 mg/kg/day prior to mating through Day 7 of gestation was not associated with impairment of fertility or adverse effects on early embryonic development.

Animal Toxicology and/or Pharmacology

A 9-month inhalation toxicology study was conducted in dogs. Although there was an increase in foamy alveolar macrophages that was present at dose-related incidence and severity, there was no association with inflammation, overgrowth of tissue, or the presence of early changes associated with cancer.

Select the PI icon to read the Description, Clinical Pharmacology, and Nonclinical Toxicology sections of the PI.

SECTION 14: CLINICAL STUDIES

Trial 1
Design

The CONVERT study is referred to as Trial 1 in the ARIKAYCE PI. Trial 1 was an open-label, randomized multicenter trial.

Patients

The study was conducted in patients with refractory Mycobacterium avium complex (MAC) lung disease, as confirmed by ≥2 sputum culture results. Patients were considered to have refractory MAC lung disease if they did not achieve negative sputum cultures after a minimum duration of 6 consecutive months of a multidrug background therapy regimen that was either ongoing or stopped no more than 12 months before the screening visit.

Treatments

Patients were randomized to either:

  • ARIKAYCE plus background regimen (n = 224)
  • Background regimen alone (n = 112)
Surrogate Endpoint
  • The surrogate endpoint for assessing efficacy was based on achieving culture conversion, which was defined as 3 consecutive monthly negative sputum cultures by Month 6.
  • The date of conversion was defined as the date of the first of the 3 negative monthly cultures, which had to be achieved by Month 4 in order to meet the endpoint by Month 6.
Baseline Characteristics

A total of 336 patients were randomized. Baseline and treatment characteristics are summarized in the table below.

Baseline Characteristics and Treatments in Trial 1
N 336
ARIKAYCE 224
Background regimen alone 112
Patient and disease characteristics
Median age 64.7 years
Female 69.3%
Not current smoker 89.3%
Underlying bronchiectasis 62.5%
Treatment
On guideline-based regimen for NTM or off guideline-based
regimen for <3 months		 89.9%
Off treatment for 3 to 12 months prior to enrollment 10.1%
Most common components of background regimen
Macrolide 91.9%
Rifamycin 85.7%
Ethambutol 80.3%
Receiving a triple background regimen of a macrolide, rifamycin, ethambutol 54.9%
Efficacy Results

The proportion of subjects achieving culture conversion (3 consecutive monthly negative sputum cultures) by Month 6 was significantly (p<0.0001) greater for ARIKAYCE + background regimen (65/244; 29.0%) compared to background regimen alone (10/112; 8.9%).

In an analysis of sustained sputum culture conversion through Month 6, 3 subjects in each treatment arm who had initially achieved culture conversion did not have sustained culture conversion through Month 6. Thus, 27.7% (62/224) of ARIKAYCE plus background regimen patients and 6.3% (7/112) of background regimen alone patients had sustained sputum culture conversion through Month 6. "The proportion of subjects achieving culture conversion (3 consecutive monthly negative sputum cultures) by Month 6 was significantly (p<0.0001) greater for ARIKAYCE + background regimen (65/244; 29.0%) compared to background regimen alone (10/112; 8.9%)."

Recall that the primary endpoint of the study was the proportion of subjects achieving culture conversion, which was defined as 3 consecutive monthly negative sputum cultures by Month 6. In order to achieve this endpoint, the first negative sputum culture had to occur at Month 4 or earlier (Figure 5). Also note that 10 weeks elapsed between initial screening and the baseline timepoint shown in this graph; during this period, some patients converted, resulting in a small percentage of patients (4.9% in the ARIKAYCE plus background regimen and 5.4% in the background regimen alone groups) who were converters at baseline.

Figure 5. Cumulative Proportion of Subjects Achieving Culture Conversion Shown by the First Month of Conversion
( Intent-to-Treat Population)

In this study, 23/224 (10.3%) of patients had MAC isolates that developed MIC of >64 mcg/mL while receiving treatment with ARIKAYCE. In the background regimen alone arm, 4/112 (3.6%) of patients had MAC isolates that developed amikacin MIC of >64 mcg/mL.

Additional endpoints to assess the clinical benefit of ARIKAYCE, for example, change from baseline in six-minute walk test distance and the Saint George’s Respiratory Questionnaire, did not demonstrate clinical benefit by Month 6.

Select the PI icon to read the Clinical Studies section of the PI.

SECTION 16: HOW SUPPLIED/STORAGE AND HANDLING

ARIKAYCE has a number of requirements regarding storage and handling.

Select the arrows to review how ARIKAYCE is supplied and should be stored and handled.

How Supplied

ARIKAYCE 590 mg/8.4 mL is supplied in a sterile, unit-dose 10-mL glass vial. The product is dispensed as a 28-vial kit.

Each carton contains a 28-day supply of medication (28 vials). In addition to the ARIKAYCE vials in the carton, 1 Lamira Nebulizer Handset and 4 Lamira aerosol heads are provided.

The Lamira Nebulizer System contains a controller, a spare aerosol head, a spare handset, power cord, and accessories.

Storage

Prior to dispensing, ARIKAYCE vials must be stored at 2°C to 8°C (36°F to 46°F) until expiration date on the vial. Do not freeze. ARIKAYCE can be stored at room temperature up to 25°C (77°F) for up to 4 weeks. Once at room temperature, any unused drug must be discarded at the end of 4 weeks.

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Select the PI icon to read the How Supplied/Storage section of the PI.

SECTION 17: PATIENT COUNSELING INFORMATION

The Patient Counseling Information contains a list of topics that healthcare providers should discuss with patients prior to prescribing treatment.

  • The patient should be advised to read the FDA-approved patient labeling (Medication Guide and Patient Instructions for Use).
  • Important Instructions for Administration of ARIKAYCE: Patients should be instructed to read the Instructions for Use before starting ARIKAYCE. Patients should be instructed to only use the Lamira Nebulizer System to administer ARIKAYCE. The patient or caregiver should be instructed to not use the Lamira Nebulizer System with any other medicine.
  • Hypersensitivity Pneumonitis and Bronchospasm (Difficulty Breathing): Patients should be advised to inform their healthcare provider if they experience shortness of breath or wheezing after administration of ARIKAYCE. Patients with a history of reactive airway disease, asthma, or bronchospasm should be advised to administer ARIKAYCE after using a short-acting bronchodilator.
  • Hemoptysis or Cough: Patients should be advised to inform their healthcare provider if they cough up blood or experience episodic cough, either during or after ARIKAYCE administration, particularly in the first month after starting ARIKAYCE.
  • Exacerbation of Underlying Pulmonary Disease: Patients should be advised to inform their healthcare provider if they experience worsening of their lung disease after starting ARIKAYCE.
  • Dysphonia or Difficulty Speaking: Patients should be advised to inform their healthcare provider if they have difficulty speaking. Difficulty speaking or loss of ability to speak has been reported with ARIKAYCE.
  • Ototoxicity: Patients should be advised to inform their healthcare provider if they experience ringing in the ears, dizziness, or any changes in hearing because ARIKAYCE has been associated with hearing loss. Patients should be advised not to operate heavy machinery or do dangerous activities while inhaling ARIKAYCE through the Lamira Nebulizer System because ARIKAYCE can cause symptoms such as dizziness or respiratory symptoms.
  • Nephrotoxicity or Kidney Damage: Patients should be advised to inform their healthcare provider if they have kidney problems because kidney damage has been reported with aminoglycosides.
  • Neuromuscular Blockade: Patients should be advised to inform their healthcare provider if they have known neuromuscular disease, such as myasthenia gravis.
  • Embryo-fetal Toxicity: Pregnant women should be advised that aminoglycosides, including ARIKAYCE, may cause irreversible congenital deafness when administered during pregnancy.

Select the PI icon to read the Patient Counseling section of the PI.

Medication Guide

The ARIKAYCE Medication Guide includes a list of critical and frequently asked questions that patients have about ARIKAYCE and its use. Patients should read and understand this Medication Guide prior to initiating therapy with ARIKAYCE.

Select each of the key questions below to learn more about how these topics are presented to patients in the Medication Guide.

What is the most important information patients should know about ARIKAYCE?

ARIKAYCE can cause serious side effects including:

  • Allergic inflammation of the lungs that may be accompanied by fever, coughing, fast breathing, wheezing, or shortness of breath
  • Coughing up of blood (hemoptysis), a serious and common side effect of ARIKAYCE
  • Severe breathing problems, which may be symptoms of bronchospasm, a serious and common side effect of ARIKAYCE; bronchospasm symptoms include shortness of breath, wheezing, difficult or labored breathing, coughing or chest tightness

When using ARIKAYCE, these side effects may become serious enough that treatment in a hospital is needed.

Patients should call their healthcare provider or get medical help right away if any of these serious side effects occur; the healthcare provider may ask the patient to stop using ARIKAYCE for a short period of time or completely stop using ARIKAYCE.
What is ARIKAYCE?

ARIKAYCE is a prescription medicine used to treat adults with refractory (difficult to treat) Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial drug treatment plan.

It is not known if ARIKAYCE is safe and effective in children younger than 18 years of age.

This product was approved by FDA using the Limited Population pathway. This means FDA has approved this drug for a limited and specific patient population, and studies on the drug may have only answered focused questions about its safety and effectiveness.
When should ARIKAYCE not be used?

ARIKAYCE should not be used if the patient is allergic to any aminoglycoside or any of the ingredients in ARIKAYCE.
What conditions should the patient tell their physician about prior to initiating treatment?

Patients should tell their physician about all of their medical conditions, including if they:

  • Have asthma, chronic obstructive pulmonary disease (COPD), shortness of breath or wheezing (bronchospasm)
  • Have been told they have poor lung function
  • Have hearing problems such as ringing in the ears or hearing loss
  • Have dizziness or sense of the room spinning
  • Have kidney problems
  • Have neuromuscular disease such as myasthenia gravis
  • Are pregnant or plan to become pregnant. It is not known if ARIKAYCE can harm unborn babies. ARIKAYCE is in a class of medicines that may be connected with complete deafness in babies at birth. The deafness affects both ears and cannot be changed.
  • Are breastfeeding or plan to breastfeed. It is not known if the medicine in ARIKAYCE passes into breast milk and can harm the baby. The patient should talk to the healthcare provider about the best way to feed the baby during treatment with ARIKAYCE.

Patients should also tell their physician about all medications they take, including prescription medicines, vitamins, and herbal supplements.
How should ARIKAYCE be used?

Patients should read the step-by-step instructions for using ARIKAYCE at the end of the Medication Guide and the full Instructions for Use provided in the kit. The manufacturer’s Instructions for Use provides complete information about how to put together (assemble), prepare, use, clean, and disinfect the Lamira Nebulizer System.

  • Patients should not use ARIKAYCE unless they understand the directions provided. Questions should be directed to a healthcare provider or Arikares Support at 1-833-ARIKARE (1-833-274-5273).
  • ARIKAYCE must be used exactly as the healthcare provider tells the patient to use it. It should not be used more often than prescribed.
  • ARIKAYCE should only be used with the Lamira Nebulizer System.
  • Each daily dose of ARIKAYCE should be inhaled 1 time each day through the Lamira Nebulizer Handset. No more than 1 vial of ARIKAYCE should be used in a day.
  • ARIKAYCE should not be used after the expiration date on the vial. If the patient forgets to take the daily dose of ARIKAYCE, the next dose should be taken at the usual time the next day.
  • The dose should not be doubled to make up for the missed dose.
  • ARIKAYCE or other medicines to treat MAC lung disease should not be stopped unless the patient is told to do so by the healthcare provider.

If the patient uses too much ARIKAYCE, they should call their healthcare provider or go to the nearest emergency room right away.
What are the possible side effects of ARIKAYCE?

ARIKAYCE may cause serious side effects, including:

  • Hearing loss or ringing in the ears (ototoxicity). Ototoxicity is a serious and common side effect of ARIKAYCE. A healthcare provider should be told right away if the patient experiences hearing loss or if the patient hears noises in his or her ears such as ringing or hissing. The healthcare provider should be told if the patient starts having problems with balance or dizziness (vertigo).
  • Worsening kidney problems (nephrotoxicity). ARIKAYCE is in a class of medicines which may cause worsening kidney problems. The healthcare provider may do a blood test to check how well the kidneys are working during treatment with ARIKAYCE.
  • Worsening muscle weakness (neuromuscular blockade). ARIKAYCE is in a class of medicines which can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis).

The most common side effects of ARIKAYCE include:

  • Changes in voice and hoarseness (dysphonia)
  • Sore throat
  • Diarrhea
  • Muscle pain
  • Nausea
  • Tiredness (fatigue)
  • Headache
  • Rash
  • Cough during or after a dose of ARIKAYCE, especially in the first month after starting treatment
  • Fever
  • Decreased weight
  • Chest discomfort
  • Vomiting
  • Increased sputum

These are not all of the possible side effects of ARIKAYCE.

A doctor or pharmacist should be called for medical advice about side effects. Side effects may be reported to the FDA at 1-800-FDA-1088.
How should ARIKAYCE be stored?
  • Store ARIKAYCE vials refrigerated between 36°F to 46°F (2°C to 8°C) until the expiration date on the vial. Do not freeze.
  • After ARIKAYCE has been stored in the refrigerator, any unused medicine must be thrown away (disposed of) after the expiration date on the vial.
  • Store ARIKAYCE vials at room temperature between 68°F to 77°F (20°C to 25°C) for up to 4 weeks
  • After ARIKAYCE has been stored at room temperature any unused medicine must be thrown away (disposed of) at the end of 4 weeks.
  • Use an opened ARIKAYCE vial right away.
  • Throw away the ARIKAYCE vial right away after use.

Keep ARIKAYCE and all medicines out of the reach of children.
General information about safe and effective use of ARIKAYCE

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. ARIKAYCE should not be used for a condition for which it was not prescribed. ARIKAYCE should not be given to other people even if they have the same symptoms, as it may harm them.

Patients can ask their pharmacist or healthcare provider for information about ARIKAYCE that is written for health professionals.
What are the ingredients in ARIKAYCE?

Active ingredient: amikacin sulfate

Inactive ingredients: Dipalmitoylphosphatidylcholine (DPPC), cholesterol, sodium chloride, sodium hydroxide (for pH adjustment), and water for injection

Select the PI icon to read the Medication Guide.


Progress Check Questions

Answer the following Progress Check Questions to see how much you recall from the materials you reviewed. When you are finished, be sure to select the “Get Course Credit” button to receive credit.
  1. Q1
  2. Q2
  3. Q3
  4. Q4
  5. Q5
  6. Q6
  7. Q7
  8. Q8
  9. Q9

The Boxed Warning for ARIKAYCE focuses on:





Which of the following most closely represents the indication for ARIKAYCE?


antibacterial drug regimen in patients who do not achieve negative sputum cultures after a minimum of 6 months on a multidrug background regimen therapy


regimen in patients who do not achieve negative sputum cultures after a minimum of 6 months on a multidrug background regimen therapy


antibacterial drug regimen in patients who do not achieve negative sputum cultures after a minimum of 3 months on a multidrug background regimen therapy


achieve negative sputum cultures after a minimum of 6 months on a multidrug background regimen therapy

What is the recommended dose of ARIKAYCE?


Nebulizer System


Lamira Nebulizer System


Nebulizer System


Nebulizer System

Which of the following Warnings and Precautions are related to the Boxed Warning? (Select all that apply.)






The single most common adverse event associated with ARIKAYCE in clinical trials was:





In Trial 1, premature discontinuation of ARIKAYCE + background regimen occurred in _____% of patients, as compared to ____% of patients on the background regimen only.





Which of the following statements about use in geriatric patients is true?




younger subjects


True or false: Serum concentrations of amikacin are higher in patients who receive ARIKAYCE than in those who are administered amikacin intravenously.



The proportion of subjects achieving culture conversion by Month 6 was significantly (p<0.0001) greater for ARIKAYCE + background regimen (_____) compared to background regimen alone (____).





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