Inhalation Tobramycin for the Management of Cystic Fibrosis

PICHON RIVIERE, A.; AUGUSTOVSKI, F.; GARCIA MARTI, S.; GLUJOVSKY, D.; LOPEZ, A.; REY-ARES, L.; ALCARAZ, A.; BARDACH, A.; CIAPONI, A; SPIRA, C

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2013 p. 1 - 30

1668-2793

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by a mutation in the CFTRgene (Cystic Fibrosis Transmembrane Conductance Regulator) affecting 80,000 individualsworldwide. This genetic disorder results in dysfunction of the exocrine glands causing an intenseinflammatory response of the airways, abnormal mucous, airway obstruction and tissue damagefavoring pathogen bacteria growth. Pseudomona Aeruginosa (Pa) is one of the main colonizationpathogens since this bacterium is the main cause of morbidity and mortality of this disease.Eradication of this microorganism colonization is essential to improve prognosis.TechnologyTobramycin is a broad spectrum aminoglycoside antibiotic used for the treatment of PA chroniclung infection in patients with CF. Inhaled tobramycin has proven to be an alternative and effectiveroute of administration.PurposeTo assess the available evidence on the efficacy, safety and comparative coverage relatedaspects among different inhalation tobramycin formulations in patients with cystic fibrosis.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internetgeneral search engines, in health technology evaluation agencies and health sponsors. Prioritywas given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs);health technology assessments and economic evaluations; clinical practice guidelines andcoverage policies of other health systems.Additionally, the documents issued by the Argentine National Administration of Drugs, Food andMedical Technology (ANMAT) were reviewed as well as the Sciences and Technologies for yourPharmacy Magazine (Revista de Ciencias y Tecnologías para su farmacia) Kairos andAlphaBeta.net.ResultsOne multicenter RCT, one coverage policy and five clinical practice guidelines were selected.In our setting, two types of inhalation tobramycin are available: Tobramycin inhalation solution(TIS) marketed as twelve products that do not differ in its administration or excipients but theydiffer in costs and Tobramycin inhalation powder (TIP) marketed as only one product. No studiescomparing both types of solutions are found.The multicenter RCT published in 2011, compared the safety, efficacy and convenience of twodifferent inhaled tobramycin formulations, TIS and TIP, in 517 patients, children over 6 years oldand adults, with CF and forced expiratory volume in one second (FEV1) of 25% to 75% ofpredicted value and culture of sputum and throat positive for PA: TIS or TIP. The follow up periodwas 24 weeks where the patients completed three cycles of therapy; a 28 days on-treatmentfollowed by 28 days off-treatment. No significant differences were found in the clinically relevantresults such as incidence of serious adverse events, hematological determinations, hearing loss,increased FEV1 predicted in relation to baseline at day 28 of the third cycle; decrease in the Pasputum density, increase in the tobramycin minimum inhibitory concentration against Pa; drugserum concentration and hospitalizations due to respiratory related events.TIP was associated to higher satisfaction (76.2 vs. 71.0; p=0.0018; 0 to 100 score scale), andshorter administration time (5.6 minutes vs. 19.7 minutes; p<0.0001). However, it required anincreased use of other antibiotics and presented a higher number of adverse events (90.3% vs.84.2%; p< 0.05), being cough the most common one.Clinical Practice GuidelinesIn a preliminary document, the United Kingdom Institute for Clinical Excellence and Health (NICE)recommends inhaled tobramycin as a second-line therapeutic option for the treatment of PArespiratory infections in patients with CF endorsing the powder presentation only if certainconditions related to its cost are met.In 2007, both the Ministry of Chile and the United States Cystic Fibrosis Foundation recommendedTIS as treatment for Pa infection. But none of the agencies mention powder tobramycin as atherapeutic option.Coverage policiesThe Scottish National System approves the use of TIP for the suppressive treatment of PA chroniclung infection.CostsThe cost of tobramycin solution ranges according to the different laboratories between $40,501 -59,731 (Argentine pesos, 2013) for 56 ampoules equivalent to approximately U$S 7,776 - 11,468(American dollars, 2013). Tobramycin powder is $64,916 (Argentine pesos, 2013), equivalent toU$S12,463 (American dollars) for 224 hard capsules plus five inhalers. Both costs are for a 28-daytreatment.ConclusionsNo studies comparing the differences between both TIS presentations have been found. Highquality evidence provided by one single comparative study of the two inhaled formulations did notfind significant differences in clinically relevant results. It was found that TIP has advantages interms of administration and higher satisfaction for the patients although its use is associated to anincreased use of other antibiotics and more side effects such as cough. In Argentina, the cost ofthe treatment implemented in this study is somewhat higher with TIP than with TIS.