ARIKAYCE (amikacin liposome inhalation suspension)

ARIKAYCE (amikacin liposome inhalation suspension)

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ARIKAYCE (amikacin liposome inhalation suspension)

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-Dglucopyranosyl-(1→6)-O-[6-amino-6-deoxy-α-D-glucopyranosyl-(1→4)]-N1 -(4-amino-2-hydroxy-1- oxobutyl)-2-deoxy-, (S)-, sulfate (1:2) salt with a chemical formula of C22H43N5O13•2H2SO4 with a molecular weight of 781.76.

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 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 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.

Indications and usage

LIMITED POPULATION: ARIKAYCE is an aminoglycoside antibacterial 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.

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 nonrefractory MAC lung disease.

Mechanism of Action

Amikacin is a polycationic, semisynthetic, bactericidal aminoglycoside. Amikacin enters the bacterial cell by binding to negatively charged components of the bacterial cell wall disrupting the overall architecture of the cell wall. The primary mechanism of action is the disruption and inhibition of protein synthesis in the target bacteria by binding to the 30S ribosomal subunit.

Resistance

The mechanism of resistance to amikacin in mycobacteria has been linked to mutations in the rrs gene of the 16S rRNA. 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

Dosage and administration

  • For oral inhalation use only.
  • Use ARIKAYCE vials only with the Lamira Nebulizer System.
  • The recommended dosage in adults is once daily oral inhalation of the contents of one 590 mg/8.4 mL ARIKAYCE vial.
  • Pre-treatment with inhaled bronchodilator should be considered in patients with a history of hyperreactive airway disease.

Contraindications

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

Adverse reactions

Most common adverse reactions (incidence ≥10% and higher than control) in the patients with refractory MAC lung disease were: dysphonia, cough, bronchospasm, hemoptysis, ototoxicity, upper airway irritation, musculoskeletal pain, fatigue/asthenia and exacerbation of underlying pulmonary disease, diarrhea, and nausea

Warnings and precautions

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. If hypersensitivity pneumonitis occurs, discontinue ARIKAYCE and manage the patient as medically appropriate.

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 (17.9%) compared to patients treated with a background regimen alone (12.5%). If hemoptysis occurs, manage the patients as medically appropriate.

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%). If bronchospasm occurs during the use of ARIKAYCE treat the patients as medically appropriate.

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Exacerbation of Underlying Pulmonary Disease: Exacerbations of underlying pulmonary disease has 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 (14.8%) compared to patients treated with background regimen alone (9.8%). If exacerbations of underlying pulmonary disease occurs during the use of ARIKAYCE, treat the patients as medically appropriate.

Anaphylaxis and Hypersensitivity Reactions: Serious and potentially life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients taking ARIKAYCE. 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.

Ototoxicity: 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 (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).

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

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

Drug interactions

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

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.

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.

Lactation: There is no information regarding the presence of ARIKAYCE in human milk, the effects on the breastfed infant, or the effects on milk production after administration of ARIKAYCE by inhalation. Although limited published data on other routes of administration of amikacin indicate that amikacin is present in human milk, systemic absorption of ARIKAYCE following inhaled administration 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: Safety and effectiveness of ARIKAYCE in pediatric patients below 18 years of age have not been established.

Geriatric Use: In the NTM clinical trials, of the total number of patients receiving ARIKAYCE, 196 (50.5%) were ≥ 65 years and 55 (14.2%) were ≥ 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.

Hepatic Impairment: ARIKAYCE has not been studied in patients with hepatic impairment. No dose adjustments based on hepatic impairment are required since amikacin is not hepatically metabolized

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 specifically associated with overdose of ARIKAYCE have not been identified. Acute toxicity should be treated with immediate withdrawal of ARIKAYCE, and baseline tests of renal function should be undertaken.

Hemodialysis may be helpful in removing amikacin from the body.

In all cases of suspected overdosage, physicians should contact the Regional Poison Control Center for information about effective treatment. In the case of any overdosage, the possibility of drug interactions with alterations in drug disposition should be considered.

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