4.1. Therapeutic indications

ARIKAYCE liposomal is indicated for the treatment of non-tuberculous mycobacterial (NTM) lung infections caused by Mycobacterium avium Complex (MAC) in adults with limited treatment options who do not have cystic fibrosis (see sections 4.2, 4.4 and 5.1).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

ARIKAYCE liposomal should be used in conjunction with other antibacterial agents active against Mycobacterium avium Complex lung infections.

4.2. Posology and method of administration

ARIKAYCE liposomal treatment should be initiated and managed by physicians experienced in the treatment of non-tuberculous lung disease due to Mycobacterium avium Complex.

Posology

The recommended dose is one vial (590 mg) administered once daily, by oral inhalation.

Duration of treatment

Treatment with inhaled liposomal amikacin, as part of a combination antibacterial regimen, should be continued for 12 months after sputum culture conversion.

Treatment with inhaled liposomal amikacin should not continue beyond a maximum of 6 months if sputum culture conversion (SCC) has not been confirmed by then.

The maximum duration of treatment with inhaled liposomal amikacin should not exceed 18 months.

Missed doses

If a daily dose of amikacin is missed, the next dose should be administered the next day. A double dose should not be given to make up for the missed dose.

Elderly

No dose adjustment is required.

Hepatic impairment

Inhaled liposomal amikacin has not been studied in patients with hepatic impairment. No dose adjustments based on hepatic impairment are required since amikacin is not hepatically metabolised.

Renal impairment

Inhaled liposomal amikacin has not been studied in patients with renal impairment. Use is contraindicated in severe renal impairment (see sections 4.3 and 4.4).

Paediatric population

The safety and efficacy of inhaled liposomal amikacin in paediatric patients below 18 years of age have not been established. No data are available.

Method of administration

Inhalation use

Inhaled liposomal amikacin must only be used with the Lamira Nebuliser System (nebuliser handset, aerosol head and controller). For instructions for use, see section 6.6. It must not be administered by any other route or using any other type of inhalation delivery system.

The amount delivered to the lungs will depend upon patient factors. Under recommended in vitro testing with the adult breathing pattern (500 mL tidal volume, 15 breaths per minute, and inhalation: exhalation ration of 1:1), the mean delivered dose from the mouthpiece was approximately 312 mg of amikacin (approximately 53% of label claim) with an average drug delivery rate of 22.3 mg/min assuming the nebulisation time of 14 minutes. The average mass median aerodynamic diameter (MMAD) of the nebulised aerosol droplets is about 4.7 µm with D10 of 2.4 µm and D90 of 9.0 µm as determined using the next generation impactor method.

4.3. Contraindications

Hypersensitivity to the active substance, to any aminoglycoside antibacterial agent, or to any of the excipients listed in section 6.1.

Hypersensitivity to soya.

Co-administration with any aminoglycoside administered via any route of administration.

Severe renal impairment.

4.4. Special warnings and precautions for use

Anaphylaxis and hypersensitivity reactions

Serious and potentially life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients taking inhaled liposomal amikacin.

Before therapy with inhaled liposomal amikacin is instituted, an evaluation for previous hypersensitivity reactions to aminoglycosides should take place. If anaphylaxis or a hypersensitivity reaction occurs, inhaled liposomal amikacin should be discontinued and appropriate supportive measures should be instituted.

Allergic alveolitis

Allergic alveolitis and pneumonitis have been reported with the use of inhaled liposomal amikacin in clinical studies (see section 4.8).

If allergic alveolitis occurs, treatment with inhaled liposomal amikacin should be discontinued and patients should be treated as medically appropriate.

Bronchospasm

Bronchospasm has been reported with the use of inhaled liposomal amikacin in clinical studies. In patients with a history of reactive airway disease, asthma or bronchospasm, inhaled liposomal amikacin should be administered after using a short-acting bronchodilator. If there is evidence of bronchospasm due to inhaled liposomal amikacin inhalation, the patient may be pre-treated with bronchodilators (see section 4.8).

Exacerbation of underlying pulmonary disease

In clinical trials, exacerbation of underlying pulmonary disease (chronic obstructive pulmonary disease, infective exacerbation of chronic obstructive pulmonary disease, infective exacerbation of bronchiectasis) was reported with a higher frequency in patients treated with inhaled liposomal amikacin compared with patients not receiving inhaled liposomal amikacin. Caution should be exercised when initiating inhaled liposomal amikacin in patients presenting with these underlying conditions. Discontinuation of treatment with inhaled liposomal amikacin should be considered if signs of exacerbation are observed.

Ototoxicity

In clinical trials, ototoxicity, (including deafness, dizziness, presyncope, tinnitus, and vertigo) was reported with a higher frequency in patients treated with inhaled liposomal amikacin compared with patients not receiving inhaled liposomal amikacin. Tinnitus was the most commonly reported ototoxicity related adverse reaction.

Auditory and vestibular function should be monitored periodically in all patients and frequent monitoring is advised in patients with known or suspected auditory or vestibular dysfunction.

If ototoxicity occurs during treatment, consideration should be given to discontinuing inhaled liposomal amikacin.

There is an increased risk of ototoxicity in patients with mitochondrial DNA mutations (particularly the nucleotide 1555 A to G substitution in the 12S rRNA gene), even if aminoglycoside serum levels are within the recommended range during treatment. Alternative treatment options should be considered in such patients.

In patients with a maternal history of relevant mutations or aminoglycoside induced deafness, alternative treatments or genetic testing prior to administration should be considered.

Nephrotoxicity

Nephrotoxicity was reported in clinical trials in patients treated with inhaled liposomal amikacin. Renal function should be monitored periodically during treatment in all patients and frequent monitoring is advised in patients with pre-existing renal dysfunction.

Consideration should be given to stopping inhaled liposomal amikacin in patients who develop evidence of nephrotoxicity on treatment.

Use in patients with severe renal impairment is contraindicated (see section 4.3).

Neuromuscular blockade

In clinical trials, neuromuscular disorders (reported as muscle weakness, neuropathy peripheral and balance disorder) have been reported with inhaled liposomal amikacin. Aminoglycosides may aggravate muscle weakness because of a curare-like effect at the neuromuscular junction. Use of inhaled liposomal amikacin in patients with myasthenia gravis is not recommended. Patients with any known or suspected neuromuscular disorders should be closely monitored.

Co-administration with other medicinal products

Co-administration of inhaled liposomal amikacin with other aminoglycosides is contraindicated (see section 4.3).

Co-administration with any other medicinal product affecting auditory function, vestibular function or renal function (including diuretics) is not recommended.

4.5. Interaction with other medicinal products and other forms of interaction

No clinical drug interaction studies have been conducted with inhaled liposomal amikacin.

Pharmacodynamic interactions

Use of inhaled liposomal amikacin with any aminoglycoside administered by any route is contraindicated (see section 4.3).

Concurrent and/or sequential use of inhaled liposomal amikacin is not recommended with other medicinal products with neurotoxic, nephrotoxic or ototoxic potential that can enhance aminoglycoside toxicity (e.g. diuretic compounds such as ethacrynic acid, furosemide or intravenous mannitol) (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of inhaled liposomal amikacin in pregnant women. Systemic exposure to amikacin following inhalation of inhaled liposomal amikacin is expected to be low compared to parenteral administration of amikacin.

There are limited data from the use of aminoglycosides in pregnant women. Aminoglycosides can cause foetal harm. Aminoglycosides cross the placenta, and there have been reports of total, irreversible, bilateral congenital deafness in children, whose mothers received streptomycin during pregnancy. Although adverse reactions on the foetus or newborns have not been reported in pregnant women treated with other aminoglycosides, the potential for harm exists. Animal reproductive toxicity studies have not been conducted with inhaled amikacin. In reproductive toxicity studies in mice, rats and rabbits with amikacin administered parenterally, no foetal malformations were reported.

As a precautionary measure, it is preferable to avoid the use of inhaled liposomal amikacin during pregnancy.

Breast-feeding

There is no information regarding the presence of amikacin in human milk. However, systemic exposure to inhaled liposomal amikacin following inhalation is expected to be low compared to parenteral administration of amikacin.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from inhaled liposomal amikacin therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

No fertility studies were conducted with inhaled liposomal amikacin.

4.7. Effects on ability to drive and use machines

Amikacin has minor influence on the ability to drive and use machines. The administration of inhaled liposomal amikacin can cause dizziness and other vestibular disturbances (see section 4.8). Patients should be advised not to drive or operate machinery while using inhaled liposomal amikacin.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported respiratory adverse reactions were dysphonia (42.6%), cough (30.9%), dyspnoea (14.4%), haemoptysis (10.9%), oropharyngeal pain (9.2%), and bronchospasm (2.2%). Other commonly reported non-respiratory adverse reactions included fatigue (7.2%), diarrhoea (6.4%), infective exacerbation of bronchiectasis (6.2%), and nausea (5.9%).

Most common serious adverse reactions included Chronic Obstructive Pulmonary Disease (COPD) (1.5%), haemoptysis (1.2%), and infective exacerbation of bronchiectasis (1.0%).

Tabulated list of adverse reactions

Adverse drug reactions in Table 1 are listed according to system organ classes in MedDRA based on clinical trials and post marketing data. Within each system organ class, the following definitions apply to the frequency terminology used hereafter: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known: (cannot be estimated from the available data).

Table 1 – Summary of adverse reactions

System Organ Class

Adverse reactions

Frequency category

Infections and infestations

Infective exacerbation of bronchiectasis

Common

Laryngitis

Common

Oral candidiasis

Common

Immune system disorders

Anaphylactic reactions

Not known

Hypersensitivity reactions

Not known

Psychiatric disorders

Anxiety

Uncommon

Nervous system disorders

Headache

Common

Dizziness

Common

Dysgeusia

Common

Aphonia

Common

Balance disorder

Common

Ear and labyrinth disorders

Tinnitus

Common

Deafness

Common

Respiratory, thoracic and mediastinal disorders

Dysphonia

Very common

Dyspnoea

Very common

Cough

Very common

Haemoptysis

Very common

Oropharyngeal pain

Common

Allergic alveolitis

Common

Chronic Obstructive Pulmonary Disease

Common

Wheezing

Common

Productive cough

Common

Sputum increased

Common

Bronchospasm

Common

Pneumonitis

Common

Vocal cord inflammation

Common

Throat irritation

Common

Pharyngeal swelling

Not known

Nasal dryness

Not known

Epistaxis

Not known

Rhinorrhoea

Not known

Sneezing

Not known

Nasal Congestion

Not known

Gastrointestinal disorders

Diarrhoea

Common

Nausea

Common

Vomiting

Common

Dry mouth

Common

Decrease of appetite

Common

Dysphagia

Not known

Glossitis

Not known

Glossodynia

Not known

Salivary hypersecretion

Not known

Stomatitis

Not known

Abdominal pain

Not known

Abdominal pain upper

Not known

Abdominal discomfort

Not known

Abdominal distension

Not known

Skin and subcutaneous tissue disorders

Rash

Common

Pruritus

Common

Musculoskeletal and connective tissue disorders

Myalgia

Common

Arthralgia

Common

Renal and urinary disorders

Renal impairment

Common

General disorders and administration site conditions

Fatigue

Common

Pyrexia

Common

Chest discomfort

Common

Investigations

Weight decreased

Common

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Adverse reactions specifically associated with overdose of inhaled liposomal amikacin have not been identified in clinical trials. Overdose in subjects with pre-existing impaired renal function, deafness or vestibular disturbance, or impaired neuromuscular transmission may develop worsening of the pre-existing disorder.

In the event of an overdose inhaled liposomal amikacin should be stopped immediately. Where rapid removal of amikacin is indicated to prevent target organ damage, for example in subjects with renal impairment, peritoneal dialysis or haemodialysis will accelerate the extraction of amikacin from blood.