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To Breathe or Not To Breathe- That Is Not the Question: Access & Delivery of Inhaled CF Medications Kathleen Richards, RRT Primary Children’s Hospital Salt Lake City, UT

Presenter Disclosure Kathleen Richards, RRT The following relationship(s) exist(s) related to this presentation: Novartis Pharmaceuticals Corporation, Speaker Bureau

Factors that Influence Deposition Wasted Drug Ventilation Distribution Timing of therapies Adherence Patient age Inhalation Technique Device/ Equipment David E. Geller “Which Nebulizer For Which Drug” 2006 Cystic Fibrosis Foundation

Aerosol Drug Administration Nebulizers Unvented Nebulizer (T-piece) Sidestream Nebulizer Breath Enhanced Nebulizer Breath Actuated Nebulizer Ultrasonic Nebulizer Vibrating Perforated Membrane Technology Nebulizer

Unvented Nebulizer (T-piece) Has only one inlet, which is the driving flow for the nebulizer Has one outlet, which is either a T-piece and mouthpiece or a face mask for children too small to use a mouthpiece

Unvented Nebulizer (T-piece) Advantages: Output is independent of patients’ respiratory status Inexpensive Disadvantages: The aerosol is diluted as extra air is inhaled through back of T-piece Degradation of particle size distribution with repeated use (with unknown clinical implications) Plastic unable to withstand the proper cleaning and disinfecting guidelines from the CFF Decreased portability, requires a compressor needing AC outlet or batteries

Sidestream® Nebulizer Uses another method of shearing the liquid solution into an aerosol. Instead of shearing the liquid at a 90 degree angle, it takes place over the surface of the liquid. Air is drawn into the nebulizer all during nebulization.

Sidestream® Nebulizer Advantages: Output is independent of patients’ respiratory status Approved for use with Pulmozyme® and is a reasonable choice for Colistin Able to clean and disinfect following certain approved CFF guidelines (See manufacturers’ recommendations) Longer warranty than disposable nebulizers Disadvantages: More waste of medication during exhalation (fine for some drugs like bronchodilators, dornase alfa, or hypertonic saline, but it is not a good choice for dose-dependent drugs like antibiotics.) Decreased portability, requires a compressor needing AC outlet or batteries

Breath Enhanced Nebulizers Minimize drug loss during exhalation by entraining the inspiratory flow of the patient through the nebulizer. Particles are able to be swept into the airway because of the enhanced flow During expiration, increased rain-out occurs and the drug returns to the reservoir for re-nebulization.

Breath Enhanced Nebulizers Advantages: Delivers 2-4 times more drug to the lung than a T-piece or Sidestream® nebulizer Less waste of medication during exhalation The Pari LC Plus® is the nebulizer approved for use with TOBI® solution/ tobramycin solution, Bethkis ®, and Kitabis Pak ® Able to clean and disinfect following certain approved CFF guidelines. (See manufacturers’ recommendations) Longer warranty than disposable nebulizers Disadvantages: Decreased portability, requires a compressor needing AC outlet or batteries

Breath Actuated Nebulizers Medication is delivered during inspiration Conserves medication during exhalation Avoidance of emission of drug into environment

Breath Actuated Nebulizers Advantages: Increased fine particle mass compared with breath- enhanced nebulizer Capable of being used in continuous or breath actuated mode Able to clean and disinfect following certain approved CFF guidelines Longer warranty than disposable nebulizers Disadvantages: Compressor or air output can affect delivered drug dose. Dosing protocols may need to be adjusted Decreased portability, requires a compressor needing AC outlet or batteries

Compressors Jet nebulizers are powered by an electric compressor to make an aerosol. Standard compressor output pressure- 25 psi Particle size and output may vary when using different nebulizer/compressor systems More powerful compressors (i.e., Mobilaire) generate high pressures and airflow, resulting in smaller droplets and shorter treatment times, with more drug wasted during exhalation Battery operated compressors make travel more convenient, but not as powerful (i.e., PariTrek). Lower pressures, make larger droplets and may decrease deposition of drug into the lungs and result in longer treatment times

Vibrating Perforated Membrane Nebulizers The eFlow® class of nebulizers forces a liquid drug through a thin, vibrating steel mesh membrane The membrane rapidly vibrates forcing the liquid drug through the tiny laser-drilled holes creating an aerosol mist Three current versions: Trio®, Altera®, eRapid®

Vibrating Perforated Membrane Nebulizers Trio® Studies currently being performed, not approved for use with all drugs Due to its high efficiency and delivery of twice the predicted aerosol deposition, it is recommended that the dose of some drugs (e.g., antibiotics, bronchodilators, etc.) may need to be reduced to avoid side effects Altera® Similar to Trio® in function and handset components Vibrating mesh is unique to the Altera®, therefore only FDA approved for use with Cayston® Minimal medication left in medication reservoir eRapid® General use nebulizer designed to deliver same aerosol output and drug deposition as Pari LC® Plus nebulizer, but in half the time Approximately 1 mL of medication left in reservoir after treatment Currently felt any drug approved for use in Pari LC® Plus can be used in eRapid® (lacks FDA approval for use with TOBI®)

Vibrating Perforated Membrane Nebulizers Advantages: Increased portability (small size and has an option for battery power operation, doesn’t require a compressor) 2-4 times more efficient at creating small particles than current systems resulting in faster treatment times One-way valve in the aerosol chamber diverts exhaled air and minimizes waste during the expiratory phase The base controller unit is similar between the three devices and can be used with multiple handsets Disadvantages: Metal mesh membrane is delicate and must be handled carefully. It is not recommended that the membrane itself be touched, even with clean hands Drug suspensions containing larger particle size (e.g., Pulmicort Respules®) may clog the membrane. Additionally, increased use can result in longer treatment times Salt condensates may corrode the membrane (Rinsing immediately after use with hypertonic saline is recommended.) Each type of eFlow® nebulizer is specific to its own version of vibrating mesh membranes, aerosol chambers and medication reservoirs. Confusion may result if using more than one type of device for various inhaled medications

TOBI Podhaler® Tobramycin inhalation powder (TIP) comes in 4 capsules of 28 mg each (per dose= 112 mg total) to be taken twice a day Each treatment cycle is 28 days on drug, followed by 28 days off drug (unless otherwise prescribed by a physician) Each capsule contains the aminoglycoside tobramycin which is used in the treatment of Pseudomonas Aeruginosa

TOBI Podhaler® Advantages: Portable delivery device Medication does not need to be refrigerated Podhaler does not need to be sterilized. Wipe dry after each use. One new Podhaler device is provided for each week Dosing takes a few minutes compared to 20+ minutes to nebulize liquid solution Disadvantages: Not studied in children <6 years old Not studied in patients with an FEV1 <25% Side effects include: excessive coughing, shortness of breath, sore throat, etc.

DPI Advantages: Shorter treatment times Portable Breath actuated (easier to use for patients with poor MDI technique) Disadvantages: Oropharyngeal deposition Water soluble, so humidity may affect performance Throat irritation Minimum inspiratory flowrate required for full drug efficacy * Young children may not be able to generate this flowrate and may not be a candidate for this system

Special Considerations Do not mix medications in the same nebulizer unless proven to be compatible Use separate nebulizers for each medication needing to be administered Use a mouthpiece whenever possible (moving the mask just 2cm away from the face may reduce the delivery of nebulized drug by up to 85%; in addition, nasal deposition further reduces airway deposition) Be aware of, and advise patients, when a nebulizer should be replaced, e.g., manufacturer’s warranty, longer treatment times reported by patient- average treatment times 10-20 minutes Instruct patient in proper cleaning and disinfecting of equipment based on Infection Prevention and Control Guidelines and manufacturer’s recommendations Instruct patients on how each medication should be stored e.g., refrigerator (TOBI® solution, Cayston®), room temperature (TOBI Podhaler®), travel considerations and any special mixing concerns (Colistin) Be aware of possible adverse side effects for each medication, e.g., bronchospasm, hoarseness/voice changes, increased cough, sore throat, loss of taste or hearing M Everard Arch Dis Child 1992; 67: 586-591 Infection Prevention and Control Guidelines for Cystic Fibrosis: 2013 Update, Infection Control and Hospital Epidemiology August 2014, Vol.35,No. S1

Future Inhaled Antibiotics Aeroquin® Arikace ® AeroVanc ®