See the world in 3D - Kitabis · See the world in 3D Drug. Device. Delivered. 1 ... Nebulization time for the Tobramycin Inhalation Solution treatments should ... providing efficient

Please see important safety information on pages 2 and 5

See the world in 3DDrug. Device. Delivered.

1

Drug. Device. Delivered.

PARI introduces something different, something practical on behalf of patients, healthcare providers, and payors. Call it a “Paridigm” shift in thinking. Co-packaged nebulized Tobramycin Inhalation Solution with the PARI LC PLUS® Reusable Nebulizer, the only nebulizer handset used in the Tobramycin Inhalation Solution clinical trials to demonstrate safety and efficacy. Drug and device dispensed together. One prescription. One stop.*

Introducing Kitabis™ Pak Kitabis Pak (Ki TAH biss Pak) is indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older with P. aeruginosa. Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with FEV1 <25% or >75% predicted, or patients colonized with Burkholderia cepacia.

See the world in 3D

2

IMPORTANT SAFETY INFORMATION

Tobramycin Inhalation Solution is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Bronchospasm can occur with inhalation of Tobramycin Inhalation Solution. Bronchospasm should be treated as medically appropriate. Patients with known or suspected auditory or vestibular dysfunction should be closely monitored when taking Tobramycin Inhalation Solution. Monitoring might include obtaining audiometric evaluations and serum tobramycin levels. Avoid concurrent and/or sequential use of Tobramycin Inhalation Solution with other drugs with neurotoxic, nephrotoxic, or ototoxic potential.

Tobramycin Inhalation Solution should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. Aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function. Aminoglycosides can cause fetal harm when administered to a pregnant woman. Apprise women of the potential hazard to the fetus. The most common adverse reactions (>5%) occurring more frequently with Tobramycin Inhalation Solution were increased cough, pharyngitis, increased sputum, dyspnea, hemoptysis, and forced expiratory volume decrease.

To report SUSPECTED ADVERSE REACTIONS, contact PARI at 1-844 KITABIS (1-844-548-2247) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

PlEASE SEE AccOMPANYINg Full PREScRIbINg INFORMATION.

*Also requires use of compressor. compressor not included in KitAbis pAK. see pAcKAge insert for detAils.


Taking nebulized tobramycin requires the drug and a nebulizer system to deliver the drug. Kitabis Pak includes both the Tobramycin Inhalation Solution and a PARI LC PLUS Nebulizer – making it the first ever convenience kit with nebulized tobramycin. Simpler, smarter, and easier than ever for your patients to get the treatments they need.

Kitabis Pak is about patient convenience, patient access, and timing. Kitabis Pak is about removing the device from the equation. Peace of mind to know that all patients have access to the nebulizer handset used in clinical trials. The only nebulizer handset to demonstrate safety and efficacy with Tobramycin Inhalation Solution. No nebulizer device co-pay or out of pocket expense for the patient.

Drug. Device. Delivered.*

3

*Also requires use of compressor. compressor not included in KitAbis pAK. see pAcKAge insert for detAils.


Drug1:

Each drug carton contains 56 (non-branded single use ampules of Tobramycin Inhalation Solution (300 mg/5 mL per ampule) packaged 4 ampules per foil pouch. There are 14 (non-branded) foil pouches in a (non-branded) carton. Each carton constitutes a 28 day supply.

Device1:

The PARI LC PLUS Reusable Nebulizer is the only nebulizer to demonstrate safety and efficacy with Tobramycin Inhalation Solution in clinical trials and is the only approved nebulizer to deliver the Tobramycin Inhalation Solution in Kitabis Pak. Included is one complete reusable nebulizer with tubing and the PARI LC PLUS Instructions For Use.

Delivered1:

Tobramycin Inhalation Solution and the PARI LC PLUS Reusable Nebulizer are co-packaged into one convenient kit. One prescription is written for Kitabis Pak and our network of specialty distributors ensure fast delivery to the patient.

4

1Kitabis Pak [package insert]. Midlothian, VA: PARI Respiratory Equipment, Inc; 2014.

PLEASE SEE ACCOMPANyINg FULL PRESCRIBINg INFORMATION ANd PATIENT PROdUCT INFORMATION IN ThIS BROChURE.


■ Each dose of Tobramycin Inhalation Solution is administered by oral inhalation using only the co-packaged PARI LC PLUS Reusable Nebulizer (Model No. 022B81-T) included in KITABIS PAK, along with a DeVilbiss® Pulmo-Aide® air compressor (Model No. 5650D).1

■ One single-use ampule (300 mg/5 mL) of Tobramycin Inhalation Solution twice a day by oral inhalation in alternating periods of 28 days on drug, followed by 28 days off drug.1

■ The 300 mg/5mL dose of Tobramycin Inhalation Solution is the same for all patients regardless of age or weight.1

■ The doses should be taken as close to 12 hours apart as possible; they should not be taken less than 6 hours apart.1

■ Nebulization time for the Tobramycin Inhalation Solution treatments should take approximately 15 minutes.1

Dosing

5

IMPORTANT SAFETY INFORMATION

The safety and efficacy of Tobramycin Inhalation Solution have not been studied in pediatric patients under 6 years of age. Clinical studies of Tobramycin Inhalation Solution did not include patients aged 65 years and over. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.

Tobramycin Inhalation Solution is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Tobramycin Inhalation Solution should not be diluted or mixed with other drugs including dornase alfa (Pulmozyme®) in the nebulizer.

Tobramycin Inhalation Solution should not be used if it is cloudy, if there are particles in the solution, or if it has been stored at room temperature for more than 28 days. Tobramycin Inhalation Solution is not for subcutaneous, intravenous or intrathecal administration.

Instruct patients on multiple therapies to take their medications prior to inhaling the Tobramycin Inhalation Solution.

PlEASE SEE AccOMPANYINg Full PREScRIbINg INFORMATION.

It is not known if Kitabis Pak is safe and effective when used for more than 3 cycles.



Treatment schedule and dose1

using the FDA Approved Devices

In order for patients to receive the benefits of the Tobramycin Inhalation Solution included in Kitabis Pak, it is important to use only the equipment approved for delivery of Tobramycin Inhalation Solution. The PARI LC PLUS Nebulizer and the devilbiss® Pulmo-Aide® (Pulmo-Aide®) compressor are the only FdA approved devices to deliver Tobramycin Inhalation Solution. Patients should read and understand the Instructions For Use for the PARI LC PLUS contained in Kitabis Pak and read and understand the Instructions For Use included with the Pulmo-Aide®.

Instructions For Use are available at:

www.Kitabis.com (PARI lc PluS) & www.DeVilbissHealthcare.com (Pulmo-Aide®)

2xdaily mins

15

2 times a day Approximately 15 minute nebulization time

28 days on, then 28 days off

on

off

28 days

28 days

6



7 PLEASE SEE ACCOMPANyINg FULL PRESCRIBINg INFORMATION ANd PATIENT PROdUCT INFORMATION IN ThIS BROChURE.


Formulation Comparison

• 56 vials of tobramycin inhalation solution.

• One PARI LC PLUS® Reusable Nebulizer with tubing & instructions.

Management of cystic fibrosis patients with Pseudomonas aeruginosa.

Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with FEV1 <25% or >75% predicted, or patients colonized with Burkholderia cepacia.

5 mL

300 mg

Approximately 15 minutes

One single-use ampule (300 mg / 5 mL) of tobramycin inhalation solution twice a day by oral inhalation in repeated cycles of 28 days on drug followed by 28 days off drug.

60 mg / mL

PARI LC PLUS® Reusable Nebulizer with a DeVilbiss® Pulmo-Aide® air compressor.

NO

Under refrigeration at 36°- 46°F / 2°- 8°C. May be stored at room temperature for up to 28 days.




4 mL

300 mg



75 mg / mL

PARI LC PLUS® Reusable Nebulizer with a PARI Vios® air compressor.

YES





5 mL

300 mg



60 mg / mL

PARI LC PLUS® Reusable Nebulizer with a DeVilbiss® Pulmo-Aide® air compressor.

YES


Contents

Indication

Volume

Dosage

Nebulization Time

Dosing

Concentration

Nebulizer/Compressor

Nebulizer Device Co-Pay, Co-Insurance, or Deductible

Storage

Tobramycin Inhalation Solution Tobramycin Inhalation Solution Tobramycin Inhalation SolutionKitabis™ Pak1 Bethkis®2 Tobi®3

8

*Trademarks are the property of their respective companies.

1Kitabis Pak [package insert]. Midlothian, VA: PARI Respiratory Equipment, Inc; 2014.2BETHKIS [package insert]. Cary, NC: Cornerstone Therapeutics Inc; 2013.

3TOBI [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.


9 PLEASE SEE ACCOMPANyINg FULL PRESCRIBINg INFORMATION ANd PATIENT PROdUCT INFORMATION IN ThIS BROChURE.


PARI PROVIDE is a patient access program that removes the compressor device burden from the treatment equation for the patient. Providing the approved compressor enables proper administration of the Tobramycin Inhalation Solution together with the PARI LC PLUS

contained in Kitabis Pak.

PARI PROVIDE

pAri proVide offers compressor Access: Many patients with CF already own a compressor to use with

their PARI LC PLUS Nebulizer to deliver Tobramycin Inhalation

Solution. In cases where they don’t, PARI will ensure access

to the only FdA approved compressor to deliver Tobramycin

Inhalation Solution included in Kitabis Pak (deVilbiss® Pulmo-

Aide® model 5650d). We coordinate this program through

our network of specialty distributors.

pAri proVide includes: Referrals to our specialty distributors that offer

Kitabis Pak.

pAri proVide continues: To look for additional ways to support patients

with CF.

Visit www.Kitabis.com/PARIProvide for additional information.

10


About PARI

There aren’t many companies like PARI. Over 100 years in existence, 50 years selling nebulizers worldwide, and 20 years formulating nebulized medications.

PARI products are designed with our patients in mind, providing efficient aerosol therapy (drug + device) in order to improve the lives of nebulizer patients and their families. PARI’s identity includes a strong clinical track record earned through years of clinical research, and through proven safety and efficacy with well-known nebulized medications for patients with asthma, COPD and cystic fibrosis.

Distributed by:PARI Respiratory Equipment, Inc.Midlothian, VA 23112

© 2014 PARI Respiratory Equipment, Inc. 044D5602 Rev B 1/15

For more information, call 1-844-Kitabis (548-2247)

See the world in 3DDrug. Device. Delivered.

Reference ID: 3666579

HIGHLIGHTSOFPRESCRIBINGINFORMATIONThesehighlightsdonotincludealltheinformationneededtouseKITABISTMPAKsafelyandeffectively.SeefullprescribinginformationforKITABISPAK.KITABISPAK(tobramycininhalationsolution),fororalinhalationuseInitialU.S.Approval:1975‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐INDICATIONSANDUSAGE‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐KITABISPAKcontainstobramycin,anaminoglycosideantibacterialdrugindicatedforthemanagementofcysticfibrosisinadultsandpediatricpatients6yearsofageandolderwithPseudomonasaeruginosa(1).‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐DOSAGEANDADMINISTRATION‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ KITABISPAKisaco‐packagingoftobramycininhalationsolution

withaPARILCPLUS®ReusableNebulizer(2.1). Administertobramycininhalationsolutionasonesingle–useampule

(300mg/5mL)twiceadaybyoralinhalationinalternatingperiodsof28daysondrug,followedby28daysoffdrug(2.1).

Dosageisnotadjustedbyweight(2.1). Takedosesascloseto12hoursapartaspossible;butnotlessthan6

hoursapart(2.1). Administereach300mgdoseusingthePARILCPLUSReusable

NebulizerandDeVilbiss®Pulmo‐Aide®compressor(2.2).‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐DOSAGEFORMSANDSTRENGTHS‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ Inhalationsolution:300mginasingle‐use5mLampule(3).

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐CONTRAINDICATIONS‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ Knownhypersensitivitytoanyaminoglycoside(4).

FULLPRESCRIBINGINFORMATION:CONTENTS*1INDICATIONSANDUSAGE2DOSAGEANDADMINISTRATION2.1DosingInformation2.2AdministrationofTobramycinInhalationSolution3DOSAGEFORMSANDSTRENGTHS4CONTRAINDICATIONS5WARNINGSANDPRECAUTIONS5.1Bronchospasm5.2Ototoxicity5.3Nephrotoxicity5.4NeuromuscularDisorders5.5Embryo‐FetalToxicity5.6ConcomitantUseofSystemicAminoglycosides6ADVERSEREACTIONS

6.1ClinicalTrialsExperience6.2PostmarketingExperience

7DRUGINTERACTIONS7.1DrugswithNeurotoxic,NephrotoxicorOtotoxicPotential7.2Diuretics

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐WARNINGSANDPRECAUTIONS‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Bronchospasm:Canoccurwithinhalationoftobramycininhalationsolution.Treatasmedicallyappropriate,ifitoccurs(5.1).

Ototoxicity:Tinnitusandhearinglosshavebeenreportedinpatientsreceivingtobramycininhalationsolution.Ifnoted,manageasmedicallyappropriate,includingpotentiallydiscontinuingtobramycininhalationsolution(5.2).

Nephrotoxicity:Hasbeenassociatedwithaminoglycosidesasaclass.Ifnephrotoxicitydevelops,managethepatientasmedicallyappropriate,includingpotentiallydiscontinuingtobramycininhalationsolution(5.3).

NeuromuscularDisorders:Aminoglycosidesmayaggravatemuscleweaknessbecauseofapotentialcurare‐likeeffectonneuromuscularfunction.Ifneuromuscularblockadeoccurs,itmaybereversedbytheadministrationofcalciumsaltsbutmechanicalassistancemaybenecessary(5.4).

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ADVERSEREACTIONS‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐Themostcommonadversereactions(>5%)inpatientstreatedwithtobramycininhalationsolutionwerecough,pharyngitis,andincreasedsputum(6.1).ToreportSUSPECTEDADVERSEREACTIONS,contactPARIat1‐844KITABIS(1‐844‐548‐2247)orFDAat1‐800‐FDA‐1088orwww.fda.gov/medwatch‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐DRUGINTERACTIONS‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ Concurrentand/orsequentialusewithotherdrugswithneurotoxic,

nephrotoxicorototoxicpotentialshouldbeavoided(7.1). Concomitantadministrationwithethacrynicacid,furosemide,urea,

orintravenousmannitolisnotrecommendedduetopossibleenhancementofaminoglycosidetoxicity(7.2).

See17forPATIENTCOUNSELINGINFORMATIONandFDA‐approvedpatientlabeling

Revised:11/2014

8USEINSPECIFICPOPULATIONS8.1Pregnancy8.3NursingMothers8.4PediatricUse8.5GeriatricUse10OVERDOSAGE11DESCRIPTION12CLINICALPHARMACOLOGY12.1MechanismofAction12.3Pharmacokinetics12.4Microbiology13NONCLINICALTOXICOLOGY13.1Carcinogenesis,Mutagenesis,ImpairmentofFertility14CLINICALSTUDIES15REFERENCES16HOWSUPPLIED/STORAGEANDHANDLING16.1HowSupplied16.2Storage17PATIENTCOUNSELINGINFORMATION*Sectionsorsubsectionsomittedfromthefullprescribinginformationarenotlisted


FULLPRESCRIBINGINFORMATION1.INDICATIONSANDUSAGEKITABISPAK(co‐packagingoftobramycininhalationsolutionandPARILCPLUSReusableNebulizer)isindicatedforthemanagementofcysticfibrosisinadultsandpediatricpatients6yearsofageandolderwithP.aeruginosa.Safetyandefficacyhavenotbeendemonstratedinpatientsundertheageof6years,patientswithFEV1<25%or>75%predicted,orpatientscolonizedwithBurkholderiacepacia[seeClinicalStudies(14)].2.DOSAGEANDADMINISTRATION2.1DosingInformation KITABISPAKisaco‐packagingoftobramycininhalationsolutionampuleswithaPARILCPLUS

ReusableNebulizer.Administerasfollows:Onesingle‐useampule(300mg/5mL)oftobramycininhalationsolutiontwiceadaybyoralinhalationinalternatingperiodsof28daysondrug,followedby28daysoffdrug.

The300mg/5mLdoseoftobramycininhalationsolutionisthesameforallpatientsregardlessofageorweight.

Thedosesshouldbetakenascloseto12hoursapartaspossible;theyshouldnotbetakenlessthan

6hoursapart.

2.2AdministrationofSolutionEachdoseoftobramycininhalationsolutionisadministeredbyoralinhalationusingonlytheco‐packagedPARILCPLUSReusableNebulizer(ModelNo.022B81‐T)includedintheKITABISPAK,alongwithaDeVilbissPulmo‐Aideaircompressor(ModelNo.5650D).Tobramycininhalationsolutionisnotforsubcutaneous,intravenousorintrathecaladministration.Priortoadministration,readthePatientInformation/InstructionsforUseforKITABISPAKfordetailedinformationonhowtouseKITABISPAKandfollowthemanufacturer’sinstructionsforuseandcareoftheDeVilbissPulmo‐Aideaircompressor.Theentiretobramycininhalationsolutiontreatmentshouldtakeapproximately15minutestocomplete.Continuetreatmentuntilallthetobramycininhalationsolutionhasbeendelivered,andthereisnolongeranymistbeingproduced.Tobramycininhalationsolutionshouldnotbedilutedormixedwithotherdrugsincludingdornasealfainthenebulizer.Instructpatientsonmultipletherapiestotaketheirmedicationspriortoinhalingthetobramycininhalationsolution,orasdirectedbytheirphysician.Tobramycininhalationsolutionshouldnotbeusedifitiscloudy,ifthereareparticlesinthesolution,orifithasbeenstoredatroomtemperatureformorethan28days.


3.DOSAGEFORMSANDSTRENGTHInhalationsolution:300mg/5mLinasingle‐useampule4.CONTRAINDICATIONSTobramycininhalationsolutioniscontraindicatedinpatientswithaknownhypersensitivitytoanyaminoglycoside.5.WARNINGSANDPRECAUTIONS5.1 BronchospasmBronchospasmcanoccurwithinhalationoftobramycininhalationsolution.Inclinicalstudieswithtobramycininhalationsolution,changesinFEV1measuredaftertheinhaleddoseweresimilarintobramycininhalationsolutionandplacebogroups.Bronchospasmthatoccursduringtheuseoftobramycininhalationsolutionshouldbetreatedasmedicallyappropriate.

5.2OtotoxicityTransienttinnitusoccurredineighttobramycininhalationsolutiontreatedpatientsversusnoplacebopatientsintheclinicalstudies.Tinnitusmaybeasentinelsymptomofototoxicity,andthereforetheonsetofthissymptomwarrantsfurtherclinicalinvestigation.Inpostmarketingexperience,patientsreceivingtobramycininhalationsolutionhavereportedhearingloss.Ototoxicity,manifestedasbothauditoryandvestibulartoxicity,hasbeenreportedwithparenteralaminoglycosides.Vestibulartoxicitymaybemanifestedbyvertigo,ataxiaordizziness.Patientswithknownorsuspectedauditoryorvestibulardysfunctionshouldbecloselymonitoredwhentakingtobramycininhalationsolution.Monitoringmightincludeobtainingaudiometricevaluationsandserumtobramycinlevels.Ifototoxicityisnoted,thepatientshouldbemanagedasmedicallyappropriate,includingpotentiallydiscontinuingtobramycininhalationsolution[seeAdverseReactions(6.2)].5.3NephrotoxicityNephrotoxicitywasnotseenduringclinicalstudieswithtobramycininhalationsolutionbuthasbeenassociatedwithaminoglycosidesasaclass.Patientswithknownorsuspectedrenaldysfunctionortakingconcomitantnephrotoxicdrugsalongwithtobramycininhalationsolutionshouldhaveserumconcentrationsoftobramycinandlaboratorymeasurementsofrenalfunctionobtainedatthediscretionofthetreatingphysician.Ifnephrotoxicitydevelops,thepatientshouldbemanagedasmedicallyappropriate,includingpotentiallydiscontinuingtobramycininhalationsolution.5.4NeuromuscularDisordersAminoglycosides,includingtobramycin,mayaggravatemuscleweaknessbecauseofapotentialcurare‐likeeffectonneuromuscularfunction.Neuromuscularblockade,respiratoryfailure,andprolongedrespiratoryparalysismayoccurmorecommonlyinpatientswithunderlyingneuromusculardisorders,suchasmyastheniagravisorParkinson’sdisease.Prolongedrespiratoryparalysismayalsooccurinpatientsreceivingneuromuscularblockingagents.Ifneuromuscularblockadeoccurs,itmaybereversedbytheadministrationofcalciumsaltsbutmechanicalassistancemaybenecessary.5.5Embryo‐FetalToxicityAminoglycosidescancausefetalharmwhenadministeredtoapregnantwoman.Aminoglycosidescrosstheplacenta,andstreptomycinhasbeenassociatedwithseveralreportsoftotal,irreversible,bilateralcongenitaldeafnessinpediatricpatientsexposedinutero.Theriskwithinhaledtobramycinislesswellcharacterized.Patientswhousetobramycininhalationsolutionduringpregnancy,orbecomepregnantwhiletakingtobramycininhalationsolutionshouldbeapprisedofthepotentialhazardtothefetus.


5.6ConcomitantUseofSystemicAminoglycosidesPatientsreceivingconcomitanttobramycininhalationsolutionandparenteralaminoglycosidetherapyshouldbemonitoredasclinicallyappropriatefortoxicitiesassociatedwithaminoglycosidesasaclass.Serumtobramycinlevelsshouldbemonitored.6.ADVERSEREACTIONSThefollowingseriousadversereactionsaredescribedbelowandelsewhereinthelabeling:

Bronchospasm[seeWarningsandPrecautions(5.1)] Ototoxicity[seeWarningsandPrecautions(5.2)]

6.1ClinicalTrialsExperienceBecauseclinicaltrialsareconductedunderwidelyvaryingconditions,adversereactionratesobservedintheclinicaltrialsofadrugcannotbedirectlycomparedtoratesintheclinicaltrialsofanotherdrugandmaynotreflecttheratesobservedinpractice.Tobramycininhalationsolutionwasstudiedintwoclinicalstudiesin258cysticfibrosispatientsranginginagefrom6to48years.Patientsreceivedtobramycininhalationsolutioninalternatingperiodsof28daysonand28daysoffdruginadditiontotheirstandardcysticfibrosistherapyforatotalof24weeks.Adversereactionsreportedinthesestudiesaredescribedbelow: Themostfrequentadversereactionsinthetobramycininhalationarmwerecough,pharyngitis,and

increasedsputum(seeTable1). Thirty‐threepatients(13%)treatedwithtobramycininhalationsolutioncomplainedofvoice

alterationcomparedto17(7%)placebopatients.Voicealterationwasmorecommonintheon‐drugperiods.

Eightpatientsfromthetobramycininhalationsolutiongroup(3%)reportedtinnituscomparedtonoplacebopatients.Allepisodesweretransient,resolvedwithoutdiscontinuationofthetobramycininhalationsolutiontreatmentregimen,andwerenotassociatedwithlossofhearinginaudiograms.

Table1liststhepercentofpatientswithselectedadversereactionsthatoccurredin>5%oftobramycininhalationsolutionpatientsduringthetwoPhaseIIIstudies.Table1:PercentofPatientsWithSelectedAdverseReactionsOccurringin>5%ofTobramycinInhalationSolutionPatientsAdverseReaction Tobramycin

InhalationSolution(n=258)%

Placebo(n=262)%

CoughIncreased 46.1 47.3Pharyngitis 38.0 39.3SputumIncreased 37.6 39.7Dyspnea 33.7 38.5Hemoptysis 19.4 23.7LungFunctionDecreased1 16.3 15.3VoiceAlteration 12.8 6.5TastePerversion 6.6 6.9Rash 5.4 6.1

1Includesreporteddecreasesinpulmonaryfunctiontestsordecreasedlungvolumeonchestradiographassociatedwithintercurrentillnessorstudydrugadministration.


Selectedadversereactionsthatoccurredinlessthanorequalto5%ofpatientstreatedwithtobramycininhalationsolution

EarandlabyrinthdisordersTinnitus

MusculoskeletalandconnectivetissuedisordersMyalgia

InfectionsandinfestationsLaryngitis6.2PostmarketingExperience

Thefollowingadversereactionshavebeenidentifiedduringpostapprovaluseoftobramycininhalationsolution.Becausethesereactionsarereportedvoluntarilyfromapopulationofuncertainsize,itisnotalwayspossibletoreliablyestimatetheirfrequencyorestablishacausalrelationshiptodrugexposure.

Earandlabyrinthdisorders

Hearingloss:Someofthesereportsoccurredinpatientswithpreviousorconcomitanttreatmentwithsystemicaminoglycosides.Patientswithhearinglossfrequentlyreportedtinnitus.[seeWARNINGSandPrecautions(5.2)]SkinandsubcutaneoustissuedisordersHypersensitivity,pruritus,urticaria,rash

NervoussystemdisordersAphonia,dysgeusia

Respiratory,thoracic,andmediastinaldisordersBronchospasm[seeWarningsandPrecautions(5.1)],oropharyngealpain

7.DRUGINTERACTIONS

7.1DrugswithNeurotoxic,NephrotoxicorOtotoxicPotentialConcurrentand/orsequentialuseoftobramycininhalationsolutionwithotherdrugswithneurotoxic,nephrotoxic,orototoxicpotentialshouldbeavoidedifpossible.7.2DiureticsSomediureticscanenhanceaminoglycosidetoxicitybyalteringaminoglycosideconcentrationsinserumandtissue.Tobramycininhalationsolutionshouldnotbeadministeredconcomitantlywithethacrynicacid,furosemide,urea,orintravenousmannitol.8.USEINSPECIFICPOPULATIONS8.1PregnancyPregnancyCategoryD[SeeWarningsandPrecautions(5.5)]Aminoglycosidescancausefetalharm(e.g.,congenitaldeafness)whenadministeredtoapregnantwoman.Noadequateandwell‐controlledstudiesoftobramycininhalationsolutionhavebeenconductedinpregnantwomen.Iftobramycininhalationsolutionisusedduringpregnancy,orifthepatientbecomespregnantwhiletakingtobramycininhalationsolution,thepatientshouldbeapprisedofthepotentialhazardtothefetus.


Noreproductiontoxicologystudieshavebeenconductedwithtobramycininhalationsolution.However,subcutaneousadministrationoftobramycinatdosesof100or20mg/kg/dayduringorganogenesiswasnotteratogenicinratsorrabbits,respectively.Dosesoftobramycin≥40mg/kg/daywereseverelymaternallytoxictorabbitsandprecludedtheevaluationofteratogenicity.Ototoxicitywasnotevaluatedinoffspringduringnonclinicalreproductiontoxicitystudieswithtobramycin.8.3NursingMothersItisnotknowniftobramycininhalationsolutionwillreachsufficientconcentrationsafteradministrationbyinhalationtobeexcretedinhumanbreastmilk.Becauseofthepotentialforototoxicityandnephrotoxicityinnursinginfantsfromtobramycininhalationsolution,adecisionshouldbemadewhethertodiscontinuenursingortodiscontinuethedrug,takingintoaccounttheimportanceofthedrugtothemother.8.4PediatricUseThesafetyandefficacyoftobramycininhalationsolutionhavenotbeenstudiedinpediatricpatientsunder6yearsofage.8.5GeriatricUseClinicalstudiesoftobramycininhalationsolutiondidnotincludepatientsaged65yearsandover.Tobramycinisknowntobesubstantiallyexcretedbythekidney,andtheriskofadversereactionstothisdrugmaybegreaterinpatientswithimpairedrenalfunction.Becauseelderlypatientsaremorelikelytohavedecreasedrenalfunction,itmaybeusefultomonitorrenalfunction[seeWarningsandPrecautions(5.3)].10.OVERDOSAGE

SignsandsymptomsofacutetoxicityfromoverdosageofIVtobramycinmightincludedizziness,tinnitus,vertigo,lossofhigh‐tonehearingacuity,respiratoryfailure,andneuromuscularblockade.Administrationbyinhalationresultsinlowsystemicbioavailabilityoftobramycin.Tobramycinisnotsignificantlyabsorbedfollowingoraladministration.Tobramycinserumconcentrationsmaybehelpfulinmonitoringoverdosage.11.DESCRIPTIONKITABISPAKcontainstobramycininhalationsolution,USPandthePARILCPLUSReusableNebulizer(PARILCPLUS).Tobramycininhalationsolutionisasterile,clear,slightlyyellow,non‐pyrogenic,aqueoussolutionwiththepHandsalinityadjustedspecificallyforadministrationbyacompressedairdrivenPARILCPLUS®ReusableNebulizer.ThechemicalformulafortobramycinisC18H37N5O9andthemolecularweightis467.52.TobramycinisO‐3‐amino‐3‐deoxy‐α‐D‐glucopyranosyl‐(1→4)‐O‐[2,6‐diamino‐2,3,6‐trideoxy‐α‐D‐ribo‐hexopyranosyl‐(1→6)]‐2‐deoxy‐L‐streptamine.Thestructuralformulafortobramycinis:


Eachsingle‐use5mLampulecontains300mgtobramycinand11.25mgsodiumchlorideinsterilewaterforinjection.SulfuricacidandsodiumhydroxideareaddedtoadjustthepHto6.0.Nitrogenisusedforsparging.Theformulationcontainsnopreservatives.Theinhalationsolutionhasanosmolalityintherange135to200mOsmol/kg.ThePARILCPLUSReusableNebulizerhasthefollowingperformancecharacteristicswithtobramycininhalationsolution[measuredusingNextGenerationImpactor(NGI)at15L/mincontinuousflow,standardconditions(50%RH,23ºC)]:(1)DeliveredDose:174mg;(2)FineParticleDose(<5µm):97mg;(3)NebulizationTime:13min.;(4)MassMedianAerodynamicDiameter:4.3µm;(5)GeometricStandardDeviation(GSD):2.2µm.12.CLINICALPHARMACOLOGY12.1MechanismofActionTobramycinisanantibacterialdrug[seeClinicalPharmacology(12.4)].12.3PharmacokineticsTobramycininhalationsolutioncontainstobramycin,acationicpolarmoleculethatdoesnotreadilycrossepithelialmembranes.Thebioavailabilityoftobramycininhalationsolutionmayvarybecauseofindividualdifferencesinnebulizerperformanceandairwaypathology.Followingadministrationoftobramycininhalationsolution,tobramycinremainsconcentratedprimarilyintheairways.SputumConcentrations:Tenminutesafterinhalationofthefirst300‐mgdoseoftobramycininhalationsolution,theaverageconcentrationoftobramycinwas1237mcg/g(rangingfrom35to7414mcg/g)insputum.Tobramycindoesnotaccumulateinsputum;after20weeksoftherapywiththetobramycininhalationsolutionregimen,theaverageconcentrationoftobramycinattenminutesafterinhalationwas1154mcg/g(rangingfrom39to8085mcg/g)insputum.Highvariabilityoftobramycinconcentrationinsputumwasobserved.Twohoursafterinhalation,sputumconcentrationsdeclinedtoapproximately14%oftobramycinlevelsattenminutesafterinhalation.SerumConcentrations:Theaverageserumconcentrationoftobramycinonehourafterinhalationofasingle300mgdoseoftobramycininhalationsolutionbycysticfibrosispatientswas0.95mcg/mL.After20weeksoftherapyonthetobramycininhalationsolutionregimen,theaverageserumtobramycinconcentrationonehourafterdosingwas1.05mcg/mL.Elimination:Theeliminationhalf‐lifeoftobramycinfromserumisapproximately2hoursafterintravenous(IV)administration.AssumingtobramycinabsorbedfollowinginhalationbehavessimilarlytotobramycinfollowingIVadministration,systemicallyabsorbedtobramyciniseliminatedprincipallybyglomerularfiltration.Unabsorbedtobramycin,followingtobramycininhalationsolutionadministration,islikelyeliminatedprimarilyinexpectoratedsputum.12.4MicrobiologyMechanismofActionTobramycinisanaminoglycosideantibacterialproducedbyStreptomycestenebrarius.Itactsprimarilybydisruptingproteinsynthesis,leadingtoalteredcellmembranepermeability,progressivedisruptionofthecellenvelope,andeventualcelldeath.TobramycinhasinvitroactivityagainstGram‐negativebacteriaincludingP.aeruginosa.Itisbactericidalinvitroatpeakconcentrationsequaltoorslightlygreaterthantheminimuminhibitoryconcentration.


SusceptibilityTestingInterpretivecriteriaforinhaledantibacterialproductsarenotdefined.InvitroantimicrobialsusceptibilitytestmethodsusedtodeterminethesusceptibilityforparenteraltobramycintherapycanbeusedtomonitorthesusceptibilityofP.aeruginosaisolatedfromcysticfibrosispatients.(1,2,3)Therelationshipbetweeninvitrosusceptibilitytestresultsandclinicaloutcomewithtobramycininhalationsolutiontherapyisnotclear.AsinglesputumsamplefromacysticfibrosispatientmaycontainmultiplemorphotypesofP.aeruginosaandeachmorphotypemayrequireadifferentconcentrationoftobramycintoinhibititsgrowthinvitro.Patientsshouldbemonitoredforchangesintobramycinsusceptibility.13.NONCLINICALTOXICOLOGY13.1Carcinogenesis,Mutagenesis,ImpairmentofFertilityAtwo‐yearratinhalationtoxicologystudytoassesscarcinogenicpotentialoftobramycininhalationsolutionhasbeencompleted.Ratswereexposedtotobramycininhalationsolutionforupto1.5hoursperdayfor95weeks.Theclinicalformulationofthedrugwasusedforthiscarcinogenicitystudy.Serumlevelsoftobramycinofupto35mcg/mLweremeasuredinrats,incontrasttotheaverage1mcg/mLlevelsobservedincysticfibrosispatientsinclinicaltrials.Therewasnodrug‐relatedincreaseintheincidenceofanyvarietyoftumor.Additionally,tobramycinhasbeenevaluatedforgenotoxicityinabatteryofinvitroandinvivotests.TheAmesbacterialreversiontest,conductedwith5testerstrains,failedtoshowasignificantincreaseinrevertantswithorwithoutmetabolicactivationinallstrains.Tobramycinwasnegativeinthemouselymphomaforwardmutationassay,didnotinducechromosomalaberrationsinChinesehamsterovarycells,andwasnegativeinthemousemicronucleustest.Subcutaneousadministrationofupto100mg/kgoftobramycindidnotaffectmatingbehaviororcauseimpairmentoffertilityinmaleorfemalerats.14.CLINICALSTUDIESTwoidenticallydesigned,double‐blind,randomized,placebo‐controlled,parallelgroup,24‐weekclinicalstudies(Study1andStudy2)atatotalof69cysticfibrosiscentersintheUnitedStateswereconductedincysticfibrosispatientswithP.aeruginosawithtobramycininhalationsolution.Subjectswhowerelessthan6yearsofage,hadabaselinecreatinineof>2mg/dL,orhadB.cepaciaisolatedfromsputumwereexcluded.AllsubjectshadbaselineFEV1%predictedbetween25%and75%.Intheseclinicalstudies,258patientsreceivedtobramycininhalationsolutiontherapyonanoutpatientbasis(seeTable2)usingaPARILCPLUSnebulizeralongwithaDeVilbissPulmo‐Aidecompressor.Table2:DosingRegimensinClinicalStudies

Cycle1 Cycle2 Cycle3 28days28days

28days28days 28days28days

TOBRAMYCINInhalationSolutionregimenn=258

TOBRAMYCINNodrugInhalationSolution300mgBID



Placeboregimenn=262

PlaceboBID

PlaceboBID

PlaceboBID


Allpatientsreceivedeithertobramycininhalationsolutionorplacebo(salinewith1.25mgquinineforflavoring)inadditiontostandardtreatmentrecommendedforcysticfibrosispatients,whichincludedoralandparenteralanti‐pseudomonaltherapy,Beta2‐agonists,cromolyn,inhaledsteroids,andairwayclearancetechniques.Inaddition,approximately77%ofpatientswereconcurrentlytreatedwithdornasealfa.Ineachstudy,tobramycininhalationsolution‐treatedpatientsexperiencedsignificantimprovementinpulmonaryfunction.ImprovementwasdemonstratedinthetobramycininhalationsolutiongroupinStudy1byanaverageincreaseinFEV1%predictedofabout11%relativetobaseline(Week0)during24weekscomparedtonoaveragechangeinplacebopatients.InStudy2,tobramycininhalationsolution‐treatedpatientshadanaverageincreaseofabout7%comparedtoanaveragedecreaseofabout1%inplacebopatients.Figure1showstheaveragerelativechangeinFEV1%predictedover24weeksforbothstudies.Figure1:RelativeChangeFromBaselineinFEV1%Predicted

Ineachstudy,tobramycininhalationsolutiontherapyresultedinasignificantreductioninthenumberofP.aeruginosacolonyformingunits(CFUs)insputumduringtheon‐drugperiods.Sputumbacterialdensityreturnedtobaselineduringtheoff‐drugperiods.Reductionsinsputumbacterialdensityweresmallerineachsuccessivecycle.(seeFigure2).Figure2:AbsoluteChangeFromBaselineinLog10CFUs


Patientstreatedwithtobramycininhalationsolutionwerehospitalizedforanaverageof5.1dayscomparedto8.1daysforplacebopatients.Patientstreatedwithtobramycininhalationsolutionrequiredanaverageof9.6daysofparenteralanti‐pseudomonalantibiotictreatmentcomparedto14.1daysforplacebopatients.Duringthe6monthsoftreatment,40%oftobramycininhalationsolutionpatientsand53%ofplacebopatientsweretreatedwithparenteralanti‐pseudomonalantibiotics.Therelationshipbetweenin‐vitrosusceptibilitytestresultsandclinicaloutcomewithtobramycininhalationsolutiontherapyisnotclear.However,4tobramycininhalationsolutionpatientswhobegantheclinicaltrialwithP.aeruginosaisolateshavingMICvalues≥128µg/mLdidnotexperienceanimprovementinFEV1oradecreaseinsputumbacterialdensity.15.REFERENCES1.ClinicalandLaboratoryStandardsInstitute(CLSI).MethodsforDilutionAntimicrobialSusceptibilityTestsforBacteriathatGrowAerobically;ApprovedStandard‐NinthEdition.CLSIdocumentM07‐A9,ClinicalandLaboratoryStandardsInstitute,950WestValleyRoad,Suite2500,Wayne,Pennsylvania19087,USA,2012.2.ClinicalandLaboratoryStandardsInstitute(CLSI).PerformanceStandardsforAntimicrobialDiskDiffusionSusceptibilityTests;ApprovedStandard–EleventhEdition.CLSIdocumentM02‐A11,ClinicalandLaboratoryStandardsInstitute,950WestValleyRoad,Suite2500,Wayne,Pennsylvania19087,USA,2012.3.ClinicalandLaboratoryStandardsInstitute(CLSI).PerformanceStandardsforAntimicrobialSusceptibilityTesting;Twenty‐fourthInformationalSupplement,CLSIdocumentM100‐S24,ClinicalandLaboratoryStandardsInstitute,950WestValleyRoad,Suite2500,Wayne,Pennsylvania19087,USA,2014.16.HOWSUPPLIED/STORAGEANDHANDLING16.1HowSuppliedKITABISPAKco‐packagedkit(NDC24492‐850‐56)isavailableincartonscontainingonereusablePARILCPlusnebulizer(ModelNo.:022B81‐T)and14tobramycininhalationsolutionpouches.Eachpouchcontainsfour300mg/5mlampulesoftobramycininhalationsolutionforatotalof56ampulesineachcarton.Eachcartonconstitutesa28daysupply.16.2Storage Tobramycininhalationsolutionshouldbestoredunderrefrigerationat2‐8ºC/36‐46ºF.Upon

removalfromtherefrigerator,orifrefrigerationisunavailable,tobramycininhalationsolutionpouches(openedorunopened)maybestoredatroomtemperature(upto25ºC/77ºF)forupto28days.Tobramycininhalationsolutionshouldnotbeusedbeyondtheexpirationdatestampedontheampulewhenstoredunderrefrigeration(2‐8ºC/36‐46ºF)orbeyond28dayswhenstoredatroomtemperature(25ºC/77ºF).

Tobramycininhalationsolutionampulesshouldnotbeexposedtointenselight.Thesolutionintheampuleisslightlyyellow,butmaydarkenwithageifnotstoredintherefrigerator;however,thecolorchangedoesnotindicateanychangeinthequalityoftheproductaslongasitisstoredwithintherecommendedstorageconditions.

17.PATIENTCOUNSELINGINFORMATIONAdvisethepatienttoreadtheFDA‐approvedpatientlabeling(PatientInformationandInstructionsforUse).


InstructionsforAdministrationInstructpatientstoreadtheInstructionsforUsebeforestartingKITABISPAK.InstructpatientstousethetobramycininhalationsolutioninKITABISPAKonlywiththePARILCPlus®ReusableNebulizerincludedintheKITABISPAK.DifficultyBreathingAdvisepatientstoinformtheirphysiciansiftheyexperienceshortnessofbreathorwheezingafteradministrationoftobramycininhalationsolution.Tobramycininhalationsolutioncancauseanarrowingoftheairway[seeWarningsandPrecautions(5.1)].HearingLossAdvisepatientstoinformtheirphysicianiftheyexperienceringingintheears,dizziness,oranychangesinhearingbecausetobramycininhalationsolutionhasbeenassociatedwithhearingloss[seeWarningsandPrecautions(5.2)].KidneyDamageAdvisepatientstoinformtheirphysicianiftheyhaveanyhistoryofkidneyproblemsbecausetobramycininhalationsolutionisinaclassofdrugsthathavecausedkidneydamage[seeWarningsandPrecautions(5.3)].PregnancyAdvisepatientstotalkwiththeirphysicianiftheywanttobecomepregnantwhileontobramycininhalationsolutionbecausetobramycininhalationsolutionisinaclassofantibacterialdrugsthathavecausedharmtothefetus[seeWarningsandPrecautions(5.5)].NursingMothersAdvisepatientstotalkwiththeirphysicianbeforeusingtobramycininhalationsolutionwhilenursingababy[seeUseinSpecificPopulations(8.3)].AdditionalInformationPARILCPLUS®ReusableNebulizer:1‐800‐327‐8632Devilbiss®Pulmo‐Aide®aircompressor:1‐800‐338‐1988KITABISPAK:1‐844‐KITABIS(548‐2247)Manufacturedby:CatalentPharmaSolutions,LLCWoodstock,IL60098Distributedby:

PARIRespiratoryEquipment,Inc.2412PARIWay,Midlothian,VA23112850D5601RevB11/2014©2013‐2014PulmoFlow,Inc.Allrightsreserved.

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