Slide Lecture with Audio
This activity is based on a 45-minute slide lecture presented by Dr. M. James Lopez and Dr. Robert J. Kuhn. This program is available as read only and with accompanying audio.
*Scroll to read lecture and/or follow along with audio.
Slide 1: Dr. Kuhn: Welcome to “Evidence-Based Management of Pancreatic Exocrine Insufficiency in Cystic Fibrosis.”
This activity is sponsored by Princeton CME and is supported by an educational grant from Solvay Pharmaceuticals.
I’m Robert Kuhn, Professor of Pharmacy Practice and Pediatrics for the Colleges of Pharmacy and Medicine at the University of Kentucky here in Lexington, Kentucky.
I’ll be your presenter along with Dr. M. James Lopez, who is Associate Professor and Medical Director of the Pediatric Liver Disease and Transplantation Department for the Department of Pediatrics and Communicable Diseases at the University of Michigan, in Ann Arbor.
Please note that all faculty disclosures for this activity are included in the front of your activity book. Please remember that to receive continuing education credit following the conclusion of this activity, each participant must complete the post-test and evaluation form located in the back of the activity booklet.
These forms can be easily completed online for immediate receipt of credit at www.princetoncme.com. Thank you again for joining us.
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Slide 4: Now, to begin with our case, DD is a 17-day-old, 3.08 kg white male, who was referred to the cystic fibrosis center after a positive neonatal screen for CF. The diagnosis is confirmed by an elevated sweat chloride of 109mEq/L and the final genotyping is pending.
The patient is seen in clinic today, the patient has a history of weight loss, is 100g under their birth rate, and Mom gives a history of a very different kind of stool than she’s used to in her other children and diarrhea. Nutritional input was adequate by history at over 120kcal/kg/day of formula.
Slide 5: In evaluating a patient like this, I think it’s important to note that aggressive nutritional therapy is required and part of that is that pancreatic enzyme replacement therapy – PERT, as it’s referred to – is instituted as soon as possible. Perhaps the patients will also need an increased caloric requirement and utilizing a high fat diet and instituting vitamin replacement therapy to help for nutritional overall health.
Now, there is a direct correlation in CF patients between good nutrition and preservation of lung function, so the adage “as goes to weight, so goes the lung,” and this concept will be discussed in great detail by Dr. Lopez.
Slide 6: In dealing with vitamin replacement therapy, the recommendations from the Cystic Fibrosis Foundation and others are to start at two times the recommended daily allowances both fat and water soluble vitamins.
In regards to pancreatic enzyme replacement therapy, the starting dose in a patient like this would be about 5,000 units of lipase per feeding, which fits into the dosage range of 2-4,000 units per four ounces of formula or with each feeding from the breast. The dosage form, typically, would be a micro-encapsulated capsule administered with either a little baby food, or perhaps the contents of the capsule is placed on the child’s tongue, and then the child is able to nurse or to suck from the bottle. The release of these polymers that typically surround these pancreatic enzymes have various pH’s and they’re noted in this slide, but they do vary.
Slide 7: In monitoring the pancreatic enzyme replacement therapy, it’s important to watch the consistency of the stool and evidence of improved steatorrhea. And frequent, perhaps even weekly weight checks need to be instituted using the same scale and the same conditions for the child, perhaps with a clean diaper on and very little clothing, so that we can get good, accurate weights to see how weight gain is improving. You can actually increase the dose if no significant weight gain is seen, or decreased symptoms, in about two to three weeks.
And in a patient like this, we could actually increase the dose to 5,000 units per feeding to really push the dose up there, or about 10,000 units of lipase. Some would consider the use of an H2 antagonist or a PPI to supplement the ability for the nutrition to be maximized. And it’s also important to monitor for complications of PERT therapy; for instance, intestinal allergic reactions or colonic strictures, and Dr. Lopez will talk more about that in detail.
Slide 8: There are several questions to consider when administrating pancreatic enzyme replacement therapy, -- the actual formulation of the drug, is it an uncoated or coated tablet, or a bead or powder -- to determine the appropriate and safe dose of that in regards to lipase, but remember that these enzymes contain amylases and proteases as well. There are also different amounts of enzymes in various formulations and their dissolution rates are different as well.
So in evaluating the clinical response, it’s important to have guidelines for adjusting therapy if necessary, as we mentioned above. And also, when considering changing formulations, careful consideration needs to be done. As you listen now to the main presentation, think about what therapies should be considered for cystic fibrosis patients experiencing pancreatic exocrine insufficiency.
Slide 9: I would now like to welcome and introduce you to Dr. Lopez for his presentation on pancreatic exocrine insufficiency in cystic fibrosis.
Dr. Lopez: Thank you, Dr. Kuhn. This is an important topic for managed market physicians and pharmacists, because of the changing environment for the availability of pancreatic enzyme products and the need to carefully monitor these products for efficacy and side effects.
Slide 10: On the first slide, I’m going to start with a brief discussion of cystic fibrosis, to give enough background to make sense of the studies related to efficacy and safety.
Cystic fibrosis is the most common life-limiting genetic disease among whites in the United States. Approximately 30,000 individuals are affected in the United States, with the incidence in the Caucasian population at one in 3,200. Other incidences for other ethnic groups are listed on this slide.
Slide 11: The CF gene is localized to chromosome 7. This is a regulated chloride channel and a regulatory protein for other conductances, with over 1,500 mutations now described.
Slide 12: The initial features at time of presentation for those identified with cystic fibrosis are highly variable. There are two points to take away from this particular slide. That is, that a high percentage of individuals are still identified late at the time of presentation with acute or persistent respiratory symptoms, but a growing number are now identified through neonatal screening. And this population will undoubtedly grow, as more states adopt this method of identifying those early with cystic fibrosis.
Slide 13: Cystic fibrosis can be established, if there are several features – either typical phenotypic features of cystic fibrosis, a sibling with a known diagnosis of cystic fibrosis, or a positive newborn screening test that then is validated by evidence that there is CFTR functional abnormalities or mutations.
These are listed as elevated sweat chlorides on at least two occasions done in a cystic fibrosis center, two identified CFTR mutations, or a less commonly used test, an abnormal nasal potential difference, as this test requires very specialized technical ability and knowledge.
Slide 14: The median predicted survival has risen markedly since 1985, with the latest information suggesting that the median survival was now close to 37 years.
Slide 15: If you look at the survival based on birth cohort, you will notice on this slide that those born in 1995-2004 have very few deaths prior to the adolescent years, reflecting both earlier diagnosis and improved care.
Slide 16: Cystic fibrosis affects primarily four major systems; the pulmonary system, the intestinal system, the hepatobiliary system and the pancreatic system. The lung disease is the primary determinant of morbidity and mortality, and nutrition directly impacts on this.
Slide 17: Pancreatic manifestations are the most important for our discussions. And on the next slide, we summarize the primary manifestations of cystic fibrosis.
Pancreatic insufficiency is present in 85-90% of individuals with cystic fibrosis. 10-15% will have either partial or normal function and are termed pancreatic sufficient.
In those who are pancreatic sufficient, pancreatitis can also occur. This would represent about 20% of those with pancreatic sufficiency, or one percent of the total group with a diagnosis of cystic fibrosis. As survival has improved, a new problem has arisen. And that is namely abnormal glucose tolerance or cystic fibrosis-related diabetes, now with a prevalence of 14.3%.
Slide 18: Pancreatic insufficiency is defined as a loss of greater than 90% of pancreatic function, and functionally is defined as the loss of amylase, lipase and protease activities, as well as bicarbonate secretion.
Slide 19: Lipases are the primary enzymes the hydrolyze fat. Fat is exceedingly important in infants and young children as the primary source of energy, and thus, of growth.
There are multiple types of lipases present in the human. The most important for our discussions today are the human gastric lipase produced by the chief cells of the fundus of the stomach and human pancreatic lipase.
Slide 20: Human gastric lipase accounts for lipolysis of up to 40% of ingested lipids and approximately 7.5% of the duodenal lipolysis of ingested fat.
It is of greater importance in cystic fibrosis, as there is absence of the pancreatic lipase, and in studies in individuals with cystic fibrosis has been said to account for around 36 percent of lipolysis. Importantly, it’s much more active in the acidic pH of the duodenum, making it more resistant to inactivation. Human pancreatic lipase, on the other hand, requires cofactor co-lipase to prevent inhibition by bile and phospholipids, and requires that the pH in the duodenum be greater than 6.0 for effective lipolysis to occur.
Slide 21: CF is characterized by fat and protein malabsorption, but with relatively minimal carbohydrate malabsorption. The pH in the duodenum of those with cystic fibrosis is often acidic, because of a lack of bicarbonate secretion, such that children with cystic fibrosis will have prolonged periods of pH’s less than 4.0 in the duodenum.
Slide 22: Fat malabsorption in cystic fibrosis at the time of diagnosis is very variable, with malabsorption of up to 80% of fat intake in some individuals. Even after the implementation of pancreatic enzyme replacement with self or provider-optimized dosing, malabsorption remains quite variable, with individuals still documented as having greater than 50% fat malabsorption on what are considered to be optimal doses of enzymes.
Slide 23: It is best to confirm formally the presence of pancreatic insufficiency, even if there are clinical symptoms that may be suggestive of malabsorption. These symptoms would include abdominal distension; abdominal discomfort; abnormal stools that are loose, oily, pale and foul-smelling; or malnourishment.
The best available clinical tests to document pancreatic insufficiency are either a 72-hour fecal fat collection, for which there is poor compliance outside the inpatient setting, or fecal elastase, which simply requires a spot collection of stool. Those who have confirmed pancreatic insufficiency should receive replacement enzymes.
Slide 24: There are two basic types of pancreatic enzyme products – a non-enteric coated powder derived from desiccated porcine pancreatic extracts that is now used only in special circumstances, and the more standard enteric coated, standard strength microspheres or mini microspheres. These products are dosed based on the lipase units being delivered.
Slide 25: The Cystic Fibrosis Foundation has established dosing guidelines, in part related to side effects that were reported with very high doses of enzymes. The recommendations are to maintain lipase doses of less than or equal to 2,500 U/kg/meal, or a total of 10,000
U/kg/day. An alternate way of dosing is to give lipase at a dose of 4,000 U/g fat consumed, using that as your maximum dose.
Infants tend to ingest higher amounts of fat than older children or adults, and will often consume up to 5g fat/kg, versus 1-2g fat/kg in older children. This leads to a high total dose, but if evaluated on either the basis of fat consumed or on a per kilogram basis, is generally in the recommended range. The starting doses are recommended to start at 1,000 U/kg/meal in those under four years of age, and at 500 U/kg/meal in those greater than four years of age.
Slide 26: If, despite being on what are considered to be adequate doses based on the previously stated recommendations, there remain abdominal symptoms that are suggestive of malabsorption, then a careful review needs to be made of all the factors that might influence the adequacy of dosing or the efficacy of dosing.
It should start with a review of the actual enzyme dosing being taken by the individual, the method that they are using to take them and the timing of administration. It would be important to consider confirming if there is persistent fat malabsorption with a 72-hour fat collection and a careful dietary review to determine if there is either non-adherence, such as skipping doses with meals or snacks, or there is higher fat intake than expected.
Slide 27: It also in some cases is useful to consider changing to using grams of fat intake as the basis for dosing, rather than weight alone.
In some cases, changing to alternate forms of enzymes, if there is variability between products, also results in improved response – at least as reported by patients – and in some cases, also with 72-hour fecal fat collections.
Finally, we should consider adding acid-reducing agents to increase the duodenal pH, as this is often a factor in individuals if there is a very prolonged acidic pH, which is inactivating the lipases or below the optimum for maximal activity.
Slide 28: Particularly in the case of persistent abdominal pain, other causes should be considered. On this slide, there is a list of a variety of alternate diagnoses that have been established in individuals with a primary diagnosis of cystic fibrosis.
But with persistence, increasing enzymes is not necessarily the correct answer, but rather, keeping an open mind, having a broad differential, and looking for other reasons why there might be enzyme failure in terms of that particular symptom.
Slide 29: At this time, there are at least 23 manufacturers and 26 repackers of pancreatic enzyme products, with 38 formulations available.
Slide 30: On the next two slides, we list the primary ones that have been used actively.
Slide 31: Most individuals would use Creon, Pancrease, Pancrecarb, Ultrase or Viokase as the primary forms that are used in most CF centers.
Slide 32: Pancreatic enzymes were first used prior to the 1938 Food, Drug and Cosmetic Act. Thus, they’ve never been subjected to the usual dose ranging, efficacy and safety studies of other medications.
Side effects are characterized by published articles in the literature, but never have been subjected to the careful analysis in controlled trials, and are not reported on a routine basis. But, there may be side effects that have never been documented carefully.
Slide 33: Enzyme products are highly variable, as they are crude extracts of porcine pancreas. There can be impurities; other proteins contaminating the extract. There is variability from batch to batch. And there can be loss of activity, because of a variety of factors such as time, sunlight, heat and humidity.
Slide 34: Lipases are irreversibly inactivated at pH less than 4.0. Maximal activity is at a pH between 7.0 and 8.0. The pH must be greater than 4.0 for over 90 minutes to maximize its enzyme activity, and preferably above 6.0 in the duodenum. Bacterial lipases may offer a solution, in that they have greater stability at low pH’s, and are more protease-resistant, as well.
Slide 35: The next slide simply lists a variety of factors to be considered – again, in the situation where you are concerned that there may be inappropriate or ineffective activity of pancreatic enzyme replacement therapy. These involve the enzyme product itself, gastric function, intestinal function, pancreatic function and hepatobiliary system – all of which can be abnormal in the setting of cystic fibrosis.
Slide 36: The enzymes themselves fall into, again, two categories – the conventional non-enteric coated powders, Viokase being the primary form used in this country. These are used under special circumstances only. Generally, this is when there is a gastrostomy-dependent patient that cannot ingest these enzymes orally. These need to be used in conjunction with an acid reducing agent, such as a proton pump inhibitor or bicarbonate.
Slide 37: Enteric coated enzymes are the primary form used by most individuals with cystic fibrosis. There are two formulations – a standard-strength microsphere, and minispheres – usually with lipase concentrations well under 20,000 units per capsule. They are acid-resistant, because of their enteric coatings, and are the first choice for infants and others with initial presentation with pancreatic insufficiency. Earlier there were high-strength formulations, some of which are available outside this country, but after side effects were reported, were withdrawn from the United States market.
Slide 38: The enteric coating of these products requires an alkaline pH for dissolution. There is a wide variability in the release of these enzymes between pH’s 5.5 and 6.5, although all are acid-resistant.
In addition, the size of the microspheres in each product affects both mixing and emptying. Smaller spheres empty first, but there’s high variability even when using the same meal and the same enzyme product among individuals in the timing of gastric emptying of both the food and the enzymes. It is difficult always to sort out simply on size alone. There are other individual patient factors that affect these issues.
Slide 39: The enzyme content of these products varies. And when compared to the stated values, protease, lipase and amylase potencies often exceed the stated value – in the case of lipases, evaluated up to 155% of the stated amount in the particular product.
The ratio of enzymes may also be important in each product. Pancreatic lipases are readily denatured by proteases, and so, most of the products have a higher lipase-to-protease ratio to try to reduce the denaturation of the lipase by the protease.
Slide 40: Additionally, it’s important to consider in the setting of a gastrostomy tube how to administer these. The powder enzyme preparations are the primary ones used. They would be mixed with fluid and usually dosed in the amount of around 2,000 U/g fat, administered with a bolus feeding, given every three to four hours in the case of a continuous feeding. An acid-reducing agent needs to be used in this setting, as these are much more susceptible to acid inactivation.
There is only one product that is a microsphere – Pancrecarb MS-4 – that is small enough to use with a gastrostomy tube, but it must be a 14French or larger tube in order not to clog and stop off the tube.
Slide 41: In 1994, five children were described who developed colonic strictures on very high doses of pancreatic enzymes. These findings were confirmed in a case-controlled study from the U.K. in 1995, and an independent study from North America in 1997.
Each case was associated with high doses of enzymes with lipase doses of greater than 6,000 U/kg/meal. The entity was called fibrosing colonopathy. This called attention to problems with enzyme preparations and usage in a very dramatic form.
Slide 42: However, as early as 1991, the FDA had become aware of longstanding problems with these preparations and the inadequacy of both monitoring, and of consistency from product to product in terms of the preparation.
Slide 43: When they reviewed the products, they noted that there was a wide range of enzyme activity, a wide variety of dosage forms and uneven quality of even the enteric coatings among the pancreatic extract products.
In 2001, the Cystic Fibrosis Foundation also reported failures when individuals were switched to generic versions of the drug products rather than brand name, suggesting again that there were even more problems than were apparent by general review
Slide 44: In 2004, the FDA determined that all pancreatic enzyme products would need to be subject to new drug applications, all under FDA scrutiny, and need to present data that indicated there was adequate efficacy and safety for each of these products.
Slide 45: As of 2004, when this announcement was made, only one product, Cotazym, had received approval from a new drug application by the FDA. The FDA, however, was careful to state that this did not equate to general recognition of safety and effectiveness or pancreatic enzymes as a class. And this relates back to the concerns that bioactivity was very variable from product to product, because there was no good standardization, and that there was limited safety and efficacy data for these products. This is again stated on the next slide.
Slide 46: When the application was made for Creon, they received an approval letter from the FDA that stated that the manufacturer would have to provide additional clinical data, chemistry, manufacturing and control information prior to approval.
Slide 47: The question that then arises is, what data are available to assess both the efficacy and safety of pancreatic enzyme products? Thus, these concerns were raised by the FDA as early as 1991, and the Cystic Fibrosis Foundation. And particularly, more information is available since the identification of fibrosing colonopathy as a serious side effect from presumed overdosing of these enzymes.
I will focus on studies since 2000 that contain information about efficacy and/or safety to set the stage for understanding what products are available, what we know about their safety and, therefore, to help us in making decisions on what should be on our formularies.
There are four products that are already in use widely in CF centers – the Creon, Cotazym, Ultrase and Pancrecarb – that are mentioned in these studies, and a new product that is from a bacterial-derived lipase.
Most of these studies suffer from being limited by size.
Slide 48: In this next slide, I will begin a discussion of six studies published between 2000-2006.
In the first column, a study by Stern is summarized. This study had two groups, both adults and children. There were not significant differences in the response in either of these groups, so I will focus only on the pediatric portion of the study.
This was a randomized placebo-controlled study with an open label running phase of Creon 20 mini microspheres. The subjects were initially stabilized in an open label phase on a high-fat diet, in which they were asked to consume 100 g/fat/day, and then adjusted their pancreatic enzyme doses to this fat intake.
The subjects determined when they had achieved the correct dose and needed to be on this for a minimum of two days before they were entered in the study.
The 72-hour fecal fat collection was done, and then only subjects who had a >80% absorption of their fat were allowed to enroll in the study. So, this does not truly represent the normal CF population. These subjects were then randomized to either placebo or treatment.
After a minimum of three days on their blinded treatment, they then were admitted to the clinic to begin a 72-hour fecal fat collection. The total duration of this study for the subjects was 5-7 days.
The coefficient of fat absorption data are shown on the bottom of that column, with placebo compared to the treatment. You’ll note that there was a significant improvement in fat absorption while on the enzyme product.
The doses of the lipase that were used in this study were all within the ranges recommended between 500-4,000 lipase U/g fat/day.
The side effects were minimal in the pediatric group. 70% of the placebo group subjects complained about abdominal complaints, such as flatulence and abdominal pain, versus 61% in the treated group.
The second study by Patchell was summarized in the second column. In this study, the primary outcome was patient preference for the product. It does not report on side effects, but rather focuses on efficacy and preference.
This compared Creon 10 mini microspheres with Creon 8 microspheres. It’s important to note that the Creon 8 capsules are larger than the Creon 10.
54 subjects completed the study. Enzyme doses were somewhat similar, though lower in the Creon 8. The study was an open, randomized crossover design with their subjects receiving both products, and each product was administered for a total of 28 days.
Those on the Creon 8 averaged 6,000 U/kg/day, which was equivalent to an average of 26 capsules per day. The Creon 10 averaged 8,500 U/kg/day, but equivalent to 23.4 capsules per day.
There is no statistical difference between the coefficients of fat absorption, as noted on the bottom of the column. There were also no differences reported in symptoms such as stool frequency, stool consistency, flatulence, or abdominal pain.
Subjects noted a preference for the Creon 10 capsules, which the authors felt related to the size of the capsule, but may also have related to the reduction in the number of capsules, as well.
This raises the important point that, in considering products that we place on formulary, adherence may be impacted by both the size of a particular product and the difficulty in swallowing that, as well as the number of capsules that would need to be consumed to achieve an equivalent dose.
The third study on this slide, in the third column, by Kalnins, was a double-blind, randomized crossover trial evaluating differences between a buffered enzyme product, Pancrecarb 8 with bicarbonate, versus Cotazym 8, a conventional enteric-coated formulation.
21 subjects were enrolled. 18 of these had a pre-study fecal fat collection done while on their usual doses of enzymes.
This fecal fat showed there was a wide range of fat malabsorption, with up to 50% of the fat malabsorbed in some individuals. Nine of the 18 had severe fat malabsorption of greater than 25% of the ingested fat. No subjects were excluded based on these criteria, however, so this is a better representation of the entire cystic fibrosis population.
There were no obvious differences between the two groups. The coefficients of fat absorption are listed on the bottom of the slide in the third column. The conclusion was that there was no difference between these products. They were equally efficacious, and there was no apparent advantage offered by the buffered product.
There was no documentation of side effects in this particular publication.
Slide 49: On the next slide in the first column, a study by Konstan was a double-blind, placebo-controlled, randomized crossover design comparing Ultrase MT-12 to placebo and Ultrase MT-20 to placebo.
Four days prior to the inpatient portion, subjects were place on a high-fat diet of at least two grams of fat per kilogram per day. They remained on this diet throughout the study. Enzyme optimization was done by the subject, but not allowed to exceed 2,500 IU/kg/meal of lipase.
Symptoms were recorded before, during, and after treatment, and each subject was on a treatment arm for a minimum of 6 days before crossover.
There was clear improvement in the coefficient of fat absorptions documented on the bottom portion of the slide in placebo to treatment, with the best improvement on the MT-20 treatment arm.
There were no significant differences between the enzyme and placebo groups with regard to symptoms or side effects that were reported. Usually those reported included increased reports of abdominal pain and flatulence, and were slightly higher in the placebo group than in the treatment group.
This study is one of the better structured to document both efficacy and safety, and would suggest that these two products are both efficacious and safe, though again is limited by sample size.
The second column on this slide summarizes a phase two study of a new bacterial-derived lipase. This study was a double-blind parallel study of three doses. They were not adjusted for weight or fat intake, but rather limited to either 5,000, 25,000 or 100,000 units of lipase per meal.
In addition, this product is unusual in that the ratio of lipase to protease is one-to-one, as the bacterial lipase is more resistant to protease inactivation.
The coefficient of fat absorption levels were measured off-treatment, and then remeasured after 14 days on the product. No subjects were excluded because of severe malabsorption. We also note that this included more patients, or more subjects, than any other study.
The baseline fat absorption was 50-55%. There was significant improvement over baseline in the 50,000 and 100,000 unit treatment groups, with 100,000 unit at approximately 70% – similar to that reported in other studies which did not exclude anyone with fat malabsorption.
This product did not appear to have significant side effects in this particular study. It is now under phase three evaluation, which will determine whether or not it is an effective and safe new product that will come on the market for use in cystic fibrosis.
Finally, in the third column, Brady and colleagues studied a non-buffered and a buffered enzyme product. 18 subjects completed this study. The buffered product was again Pancrecarb 8 with bicarbonate, versus the subjects’ usual enzyme products, so it was variable, and there was not one consistent comparison.
The diet was controlled during the 4 days of each treatment, but subjects were reduced to 50% of their usual enzyme dose, because it was believed by these authors that this would increase the probability of detecting differences in efficacy.
They did note that on the buffered product there was a slight improvement in fat absorption, seen on the bottom of this column on this slide, with the buffered percent at 81.8% versus the non-buffered products at 75.1%. This was statistically significant, but hard to interpret in terms of clinical significance, based on the small size and the variable enzymes used for comparison to the one buffered product.
Slide 50: At present, there are 3 active trials listed on the Cystic Fibrosis Foundation Web site. More importantly are those listed in the clinical trials at NIH, which include a total of 5 products.
Slide 51: On this slide, Pancrease MT-20 is under phase three evaluation, enrolling eight patients; a new product, EUR-1008, also in phase three trials, enrolling 30 individuals; Pancrecarb MS-16 in phase three trials, enrolling 20; and the ALTU-135 bacterial-derived lipase just discussed on the last slide in phase three trials, enrolling 200 individuals.
Slide 52: There’s also a delayed release pancreatic enzyme product that is in phase 3 trials, enrolling 24 individuals.
Slide 53: In terms of discussing the impact of the new FDA regulations on pancreatic insufficiency management, it is likely there will be fewer products available after 2008. This will mean there will be fewer choices for patients and providers, and fewer other options as alternatives, if it does not appear that the pancreatic enzyme supplementation is effective.
It is also possible that no powder forms will be available, as none of these are under study at this time. It is unknown whether the Pancrecarb MS-4s will still be available, but it is possible, as they do not specifically have to be studied for this indication for use in gastrostomy tubes.
And then we have on the horizon the potential of a new bacterially-derived lipase that may be better in this circumstance when maximized in terms of grams of fat consumed or by body weight, because of the better activity at low pH’s and characteristic of the duodenum of those with CF, as well as more resistance to protease inactivation.
The final important impact of this is that there will be better reporting of adverse effects and better monitoring required for the use of these products.
Slide 54: In conclusion, pancreatic insufficiency in individuals with cystic fibrosis requires the use of pancreatic enzyme replacement therapy. The use of these enzymes should be monitored carefully for both benefits and side effects.
Dosing should be based on either body weight or grams of fat intake. Maximum doses should not exceed either 2,500 IU/kg/meal, or 10,000 IU/kg/day.
Pancreatic systems can persist despite what are felt to be adequate enzyme doses. And if they do, require careful investigation, including the possibility of other diagnostic diseases such as Celiac disease, inflammatory bowel disease and the list that we had on the previous slide.
The new regulations by the FDA require careful review of the efficacy, dosing and side effects of pancreatic enzymes, which will improve overall, I think, both the benefit and the safety of these medications for us.
Approval based on such data is required by April 2008, to allow the enzyme preparations to be prescribed and continue to be used. This may limit our choices and our forms available.
The enzyme preparations on formulary and prescribed by physicians should have at a minimum phase three data to validate their use in cystic fibrosis. The type of information that is available in some of the studies cited helps make better decisions about efficacy, though the size limits our knowledge of side effects. We will now turn back to Dr. Kuhn for a discussion of the case study presented at the beginning of this activity.
Slide 55: Dr. Kuhn: Thank you, Dr. Lopez. Let’s revisit the case. DD is now four months old and goes to the clinic for a follow-up appointment, his third, and his weight now is 5,880 grams. He’s just under the 50th percentile. He’s still taking good, adequate PO nutrition from formula, and some rice cereal, which is used to administer his enzymes. His stool appears much more normal as per history, and there’s little or no diarrhea reported by Mom. Currently, he is on pancrelipase, 5,000 units of lipase per capsule; two capsules with feedings, that was increased due to his increase in weight; and he’s currently tolerating his liquid fat soluble vitamins quite well.
Slide 56: So in looking back at some of the questions we brought up earlier and in discussion with Dr. Lopez, the selection of administration form or the dosage form is important, because we know the acid destruction of enzymes by the pH of the stomach, that uncoated tablets are really not appropriate, especially in this patient. And then the contents of the capsule can be administered to patients, especially if we use very small particles, and some of the preparations have very, very small particles which make it much easier for the child to actually take.
We need to determine the appropriate and safe dose of drug – in this case, lipase – as well as their response to protease and amylase. Although the lipase is labeled in each on these preparations, they’re different, and the protease to lipase ratios and the different ratios of enzymes are different. And we now know and had a review of the FDA initiatives on how we can get a better understanding of the ramifications of various formulations of these drugs. And we note, truly, there are different amounts in enzymes in various formulations.
Slide 57: And the rate at which they dissolve and the pH in which they dissolve is different, so that could affect overall dosing and success.
And finally, the evaluation of clinical response and the guidelines for adjusting therapy are extremely important for a good follow-up, good weight gain, good pulmonary function.
That needs to be clear for everybody, so how we monitor patients. And even the considerations when changing formulations, we need good follow-up, and we need careful follow-up, to make sure that decision was the right one and the patient’s overall goals have been better met.
