A 2-year post-authorization safety study of high-strength pancreatic enzyme replacement therapy (pancreatin 40,000) in cystic fibrosis.

OBJECTIVE: At the request of the Medicines and Healthcare Regulatory Agency and in agreement with the appropriate authorities, an observational, multi-center, non-interventional, post-authorization safety study of high-strength pancreatic enzymes was conducted. RESEARCH DESIGN AND METHODS: Patients with exocrine pancreatic insufficiency due to cystic fibrosis (CF) who had previously taken high doses of pancreatic enzymes received pancreatin 40,000 capsules (Creon 40,000 Minimicrospheres, Abbott GmbH, Hanover, Germany) as part of their normal treatment for up to 2 years. Initial doses were calculated to match previous established doses in lipase units, with adjustment if required. MAIN OUTCOME MEASURES: Safety focused on serious suspected adverse drug reactions. Maldigestion symptoms and body weight were also monitored. Patients were managed according to general guidelines common to all major CF units in the UK, although minor variations were expected. The coefficient of fat absorption was not assessed as this was a safety rather than an efficacy study. RESULTS: Sixty-four patients were enrolled at nine UK centers. Two deaths occurred during the study, which were considered unrelated to therapy by investigators. There were no further serious suspected adverse drug reactions related to pancreatin 40,000 and no cases of fibrosing colonopathy. Daily lipase doses were reduced by 11% after switching to pancreatin 40,000. Maldigestion symptoms improved and mean body weight increased from baseline to last observation (mean + 6.1 kg in patients < 18 years old). CONCLUSIONS: No safety concerns were identified with pancreatin 40,000 therapy for up to 2 years. Daily lipase doses were not increased when switching to pancreatin 40,000.

Diagnosis and treatment of intestinal malabsorption in cystic fibrosis.

Intestinal malabsorption is severe and of early onset in virtually all people who have cystic fibrosis. The main cause is deficiency of pancreatic enzymes. Bicarbonate deficiency, abnormal bile salts, mucosal transport problems, motility differences, and anatomical structural changes are other contributory factors. Effective treatment should allow a normal to high-fat diet to be taken, control symptoms, correct malabsorption, and achieve a normal nutritional state and growth. Appropriate pancreatic enzyme replacement therapy will achieve normal or near-normal absorption in most people with cystic fibrosis. Early identification and treatment of intestinal malabsorption is critical to achieving optimal nutritional status. The occurrence of fibrosing colonopathy in a few patients on very high doses of those enzymes which have the copolymer Eudragit L30 D55 in their covering resulted in guidelines in the UK to avoid doses equivalent to more than 10,000 IU lipase per kg per day, and also to avoid preparations containing this copolymer in children and adolescents. For patients not responding to 10,000 IU lipase per kg per day review of adherence to treatment, change of enzyme preparation, variation in time of administration, and reduction in gastric acid may improve absorption. The importance of early investigation to exclude other gastrointestinal disorders as a cause of the patient's symptoms, rather than merely increasing the dose of enzymes, is stressed. With modern pancreatic enzymes in doses up to or only slightly in excess of 10,000 IU lipase per kg per day, adequate control of gastrointestinal symptoms and absorption can be achieved, and a normal nutritional state and growth rate maintained in most people with cystic fibrosis.

Reduction in prevalence of chronic Pseudomonas aeruginosa infection at a regional pediatric cystic fibrosis center.

Various management strategies were introduced at the Leeds Regional Cystic Fibrosis (CF) Unit in an attempt to reduce the prevalence of chronic Pseudomonas aeruginosa respiratory infection, previously thought to be inevitable in most children with CF. These included neonatal screening (1975), regular microbiological monitoring (1975), early antibiotic treatment of first isolations of P. aeruginosa (1985), intensive intravenous antibiotic treatment where nebulized antibiotics failed to eradicate P. aeruginosa (1988), and separate clinics for patients chronically infected with P. aeruginosa and uninfected patients (1991). The aim of this study was to assess the impact of these interventions. All 232 patients receiving full-time care at the Leeds Paediatric CF Centre during the period January 1990-December 2000 were categorized into four groups: never grown P. aeruginosa; free of P. aeruginosa for at least 1 year; intermittent grower of P. aeruginosa with 50% of months with samples positive for P. aeruginosa over the previous 12 months. The yearly prevalence of patients having chronic P. aeruginosa infection fell significantly during the study, from 24.5% in 1990 to 18.1% in 2000 (P < 0.05), despite an increase in mean age of patients from 7.73 to 9.42 years. The number of patients aged less than 11 years who had chronic P. aeruginosa infection fell from 23.8% in January 1990 to only 4.3% by December 2000. The annual incidence and mean age of first acquisition of P. aeruginosa did not alter significantly. In conclusion, antipseudomonal management strategies were associated with both reduced prevalence, and an increase in the mean age of onset of chronic P. aeruginosa infection.

Newborn screening programmes for cystic fibrosis.

We review the current situation with respect to newborn cystic fibrosis screening (NCFS) across the world. The challenges of establishing an NCFS programme are reflected in the diversity of those programmes identified. All employ an initial immunoreactive trypsinogen (IRT) measurement during the first week of life. If this is positive, a second IRT analysis at 4 weeks of age improves the specificity of the test; most programmes have, however, moved to DNA analysis at this point, which improves their sensitivity. Incorporating DNA analysis results in the identification of carriers, which may have implications for families but is generally considered positive. Some programmes have incorporated a second IRT test as well as DNA analysis, either to increase the sensitivity of the test in an area with a low DeltaF508 frequency or to reduce the number of infants requiring a sweat test. Whichever algorithm is selected, the implementation of a successful programme relies on clear pathways and good information for parents.

Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients.

BACKGROUND: Patients were defined each successive month as either 'chronic' when more than 50% of the preceding 12 months were PA culture positive, 'intermittent' when < or =50% of the preceding 12 months were PA culture positive, 'free of PA', with no growth of PA for the previous 12 months, having previously been PA culture positive, or 'never infected', when PA had never been cultured. METHODS: Cross-sectional analysis of 146 children attending the Leeds Regional Cystic Fibrosis Centre was performed to assess relationship between the new definition and clinical scores and investigations. The response variable was regressed on age and sex and the residuals analysed using the Kruskal-Wallis test. RESULTS: The 'chronic' group (18% of patients) had significantly worse Shwachman-Kulczycki (SK) and Northern chest X-ray scores, and % predicted FEV(1) values than the 'free' (28%) or 'never' (20%) categories (P<0.004). The 'intermittent' group (34%) had a significantly higher SK score than the 'chronic' group (P<0.0001), and a significantly lower % predicted FEV(1) value than the 'free' or 'never' groups (P<0.0003). 'Chronic' patients were significantly associated with a positive, and 'never' patients with a negative, PA antibody result (P<0.001). CONCLUSIONS: The validity and importance of identifying these four subgroups is demonstrated. Previous definitions may over-estimate the prevalence of chronic infection.