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December 2015 PharmacyTimes.org 103 30 years in the United States and other countries. 14 Doses of 75 to 150 mg 2 times a day have been used either as chronic continuous therapy or every- other-month therapy for patients who do not respond to approved agents. More inhaled antibiotics are in clinical test- ing, and more should be available in the coming years (ie, levofloxacin and vancomycin). 30 These aerosol preparations require appropriate drug delivery. 35 The types of nebulizers available have grown sig- nificantly since some of these aerosol preparations were released; hence, it is important to check which nebulizer can be used with which product. For example, the Altera nebulizer is only approved for aerosol delivery of aztreo- nam lysine, which uses a piezoelectric vibrating mesh for generation of particle for inhalation. 36 These newer nebulizers tend to give better and more predictable delivery in less time. Dry powder inha- lation is now available as well, which requires a simple plastic delivery device for a few seconds with inhalation. A more detailed review of inhaled antibiot- ics can be found in Table 2. 37 Management of Gastrointestinal Pathologies Nearly 85% of patients with CF have pancreatic insufficiency or the inability to adequately digest fat and protein. 14 As the pancreas fibroses, minimal amounts of pancreatic enzymes are secreted and transported to the duodenum to digest fat and protein. Most patients take pan- creatic enzymes (derived from animal sources) to facilitate digestion, as out- lined in Table 3. 30 Malabsorption of protein and particu- larly fat leads to poor weight gain and malnutrition. Coupled with increased metabolic needs, many patients with CF have a difficult time gaining weight and maintaining a good nutritional status. In addition to pancreatic enzymes, some patients require a proton pump inhibitor or H 2 antagonist to help increase the pH of the duodenum to increase the efficacy of the pancreatic enzymes supplemented. In addition, patients require fat-soluble vitamins at approximately twice the rec- ommended daily allowance for their age- matched counterparts; most also require a substantial increase in calories second- ary to their increased metabolism and a lower bioavailability of fat. Nutritional supplementation, including gastrostomy tube placement, as well as nocturnal feedings of nutritional supplements, may be necessary. For increased liver function test and cholestasis, patients are administered ursodiol to help prevent or reverse this condition. 38 Supplementation may be required until liver function enzymes decrease to 2 to 3 times normal. Most patients tolerate this well, and improve- ment is usually observed within 1 to 2 months. For the management of CF-related dia- betes, insulin is the drug of choice. 39 Patients with CF typically develop post- prandial hyperglycemia initially and then fasting hyperglycemia. Most patients can be managed with daily long-acting insulin in combination with meal-time coverage. What new therapies can help cor- rect or improve the basic defect in patients with CF? Are any now available for patients? Disease-Modifying Therapies The drug therapies that have been described above are aimed at manag- ing the symptoms of CF. Understanding the basic defect of CF has proven to be a target for drug therapy advances. 25,40 Mutation-specific pharmacotherapeutic options that modulate the CFTR func- tion are now available or in development, and are categorized into the following classes: potentiators, correctors, and acti- vators. 13,27,28,41,42 Ivacaftor Ivacaftor (Kalydeco), a potentiator, was the first available therapy that direct- ly targeted the underlying defect in CF. 13,28,42 Ivacaftor augments the CFTR gating in response to cAMP signaling, increasing the time in which the CFTR channel remains open at the cell sur- face in Class III mutations. G551D is the more common mutation within this class, occurring in approximately 4% to 5% of individuals with CF; there are, however, a host of additional gating mutations. 29,34,43,44 In a dose-finding phase 2 study, 39 adults with CF and at least 1 copy of G551D received ivacaftor. At day 28, the subjects who received a dose of 150 mg every 12 hours had a median change from baseline of predicted FEV 1 of 8.7%. 45 Following this, a phase 3 study random- ized 161 subjects to receive placebo or ivacaftor 150 mg every 12 hours. Eighty- three subjects received ivacaftor therapy, and the results showed improvements in lung function at 24 weeks, which were sustained through week 48 at an ivacaftor dose of 150 mg every 12 hours in patients 12 years and older. 43 Ramsey et al found that subjects had a change in baseline of predicted FEV 1 of more than 10.6%. 43 Other end points indicated that subjects maintained on ivacaftor were 55% less likely to have a pulmonary exacerbation, had improvements in their quality-of-life score as measured by the Cystic Fibrosis Questionnaire-revised, and gained an average of 2.7 kg. Sweat chloride concen- trations were evaluated to assess CFTR activity. In this study, ivacaftor decreased sweat chloride concentrations by 47.9 mmol/L. Similar results were found in patients 6 to 11 years of age with 1 copy of the mutation G551D. 46 Ivacaftor was also studied in other gat- ing mutations that account for approxi- mately 1% of patients with CF. 44 These gating mutations studied include G178R, S549N, S549R, G551S, G1244E, STAR TABLE 2: INHALED ANTIBIOTIC THERAPY FOR CHRONIC SUPPRESSIVE THERAPY 37 Antibiotic Dose Frequency Tobramycin inhalation solution 300 mg Every 12 hr Tobramycin inhalation powder 112 mg (4 × 28-mg capsule) Every 12 hr Aztreonam 75 mg Every 8 hr Colistimethate a 75 to 150 mg Every 12 hr Vancomycin a 250 mg Every 12 hr a Not FDA approved.