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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
November 11, 2017

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Branded vs. Compounded Progesterone for Preventing Preterm Birth: Not Getting More
   for the Money
Are Type 1 Diabetes and Celiac Disease Linked?
Acetaminophen or NSAIDs for Extremity Trauma?
Does Acetaminophen Exposure In Utero Increase Risk for ADHD?
Extending Prenatal Care to All Women Residing in the U.S.
Biomarkers of Ovarian Reserve Are Not Always Effective for Predicting Conception
IV Antibiotics for Urinary Tract Infection in Infants: Is Less More?
The Hospital Readmissions Reduction Program: Searching for a Better Measure
Meta-Analysis of Strategies to Prevent Injurious Falls in Older Adults
The FDA announces the next Pharmacy Compounding Advisory Committee (PCAC)
   meeting for November 20-21, 2017.

JAMA Intern Med 2017 Oct 2
Branded vs. Compounded Progesterone for Preventing Preterm Birth: Not Getting More for the Money
Branded progesterone costs vastly more than the compounded product but is not associated with better birth outcomes.
Weekly intramuscular injection of 17-alpha hydroxyprogesterone caproate (17-OHP) during pregnancy in women with prior histories of preterm birth has been associated with reduced risk for preterm birth and is endorsed by relevant professional societies. KV Pharmaceutical's successful FDA application for manufacturing rights came with a large increase in per-dose price that many criticized (NEJM JW Womens Health Jul 2011 and Obstet Gynecol 2011; 117:1408). Following a public-health catastrophe involving fungal infections arising from (nonobstetric) use of compounded medications, prescription and coverage of compounded 17-OHP has been curtailed in many states. Now, investigators queried commercial insurance claims to determine relative prevalence, cost, and efficacy of branded versus compounded 17-OHP from 2008 through 2015.
During the period studied, 535 women received branded 17-OHP and 3350 received a compounded version. Mean per-pregnancy cost was $10,917 for the branded product versus $206 for the compounded drug. Rates of preterm birth were 24% (branded) and 25% (compounded).
COMMENT; As the cost of U.S. healthcare skyrockets, we as clinicians often feel that this problem is out of our control. But in our institutions and at the state level, we must be empowered to demand high value (i.e., outcomes per unit cost) from the interventions we provide. Armed with efficacy and safety data for medications that may cost 50 times less than brand-name alternatives, those of us with unimpeded access should prescribe the lower-cost products, and those of us who face legislative or coverage barriers must advocate for better value for our patients.
CITATION(S): Fried I et al. Utilization, cost, and outcome of branded vs compounded 17-alpha hydroxyprogesterone caproate in prevention of preterm birth. JAMA Intern Med 2017 Oct 2; [e-pub].
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Pediatrics 2017 Nov; 140:e20171305
Are Type 1 Diabetes and Celiac Disease Linked?
The co-occurrence of type 1 diabetes autoimmunity and celiac disease autoimmunity is higher than would be expected in the general population.
There has been a global rise in the incidence of type 1 diabetes (T1D) and celiac disease (CD), which often present in childhood. Up to 8% of people with T1D develop CD — a higher co-occurrence than expected in the general population.
Researchers followed a prospective birth cohort of 5891 infants (all of whom were known to be genetically at risk for developing T1D) for a median of 66 months. The infants were monitored periodically for the development of islet autoantibodies and T1D and tissue transglutaminase autoantibodies and CD.
Of the 457 children who screened positive for islet autoantibodies, 130 (28.5%) developed T1D; in children screening negative, only 8 of 5434 (0.15%) developed T1D. Similarly, of the 898 children who screened positive for tissue transglutaminase autoantibodies, 321 (36%) developed CD, compared with 2 of 4993 (0.04%) among those screening negative. The number of children with both types of autoantibody was 1.3 times higher than expected for the general population.
COMMENT: This study supports the notion that one autoimmunity (e.g., against the pancreas in T1D) could trigger another (e.g., against the intestines in CD). Understanding the epigenetics better might lead to therapies that could prevent more than one autoimmune disease. Understanding the linkage between T1D and CD is important for following patients with either condition.
CITATION(S): Hagopian W et al. Co-occurrence of type 1 diabetes and celiac disease autoimmunity. Pediatrics 2017 Nov; 140:e20171305.
Ferrara CT and Gitelman SE.Type 1 diabetes and celiac disease: Causal association or true, true, unrelated? Pediatrics 2017 Nov; 140:e20172424.
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Ann Emerg Med 2017 Oct 13
Acetaminophen or NSAIDs for Extremity Trauma?
Acetaminophen was noninferior to diclofenac alone or to diclofenac plus acetaminophen in reducing acute minor musculoskeletal pain.
Treating pain with nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious renal, gastrointestinal, and cardiovascular adverse effects. To determine whether acetaminophen is noninferior to NSAIDs in reducing pain, investigators in the Netherlands conducted a multicenter, randomized, double-blind trial in which 547 adults with acute minor extremity trauma received acetaminophen (4000 mg/day), the NSAID diclofenac (150 mg/day), or both for 3 days. All patients received omeprazole (20 mg/day) for 3 days.
The main outcome was decrease in pain measured on a numeric rating scale 90 minutes after the first dose. Also assessed were adverse events and patient satisfaction.
Acetaminophen was noninferior to the other regimens across all outcome measures, with a difference in pain score of zero.
COMMENT: Simple on its face, this paper rewards closer reading and is a model for clinical trial design. The authors conservatively recommend that any of the three strategies be used for management of pain due to minor musculoskeletal trauma, based on the finding of equivalence. I would take that a step farther and say out loud what their paper implies: These patients should use acetaminophen (or the European equivalent, paracetamol), not NSAIDs.
CITATION(S): Ridderikhof ML et al. Acetaminophen or nonsteroidal anti-inflammatory drugs in acute musculoskeletal trauma: A multicenter, double-blind, randomized, clinical trial. Ann Emerg Med 2017 Oct 13; [e-pub].
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Pediatrics 2017 Nov; 140:e20163840.
Does Acetaminophen Exposure In Utero Increase Risk for ADHD?
A large dataset analysis adjusted for multiple confounders indicates that acetaminophen use for ≥29 days during in pregnancy doubles the risk for ADHD in offspring.
Because anti-inflammatory medications are known to be harmful to the developing fetus, many pregnant women use acetaminophen for fever and pain relief. Recent research has also shown an increase in the risk for attention-deficit/hyperactivity disorder (ADHD) in offspring from prenatal acetaminophen exposure. But it is unclear whether indications for acetaminophen use or parental ADHD explain these findings.
To determine whether acetaminophen use during pregnancy is associated with ADHD in offspring after adjusting for potential confounders, researchers compared data from a Norwegian registry of nearly 113,000 children born between 1999 and 2009 (including 2246 with ADHD) with data on maternal and paternal ADHD symptoms, prepregnancy acetaminophen use, and conditions for acetaminophen use.
Results were as follows:

COMMENT: These results suggest that women should limit, but not completely eliminate acetaminophen use during pregnancy. For mothers with ADHD or other mental health conditions that make it difficult to tolerate pain, approaches such as mindfulness or yoga should be offered, which would also be helpful for tolerating the stress of parenting. For pediatric providers, it is important to reassure mothers who feel guilty about their prenatal acetaminophen use that ADHD is primarily determined by genetic factors and also to empower mothers by explaining that ADHD symptoms can be improved by behavioral treatment and positive parenting.
CITATION(S): Ystrom E et al. Prenatal exposure to acetaminophen and risk of ADHD. Pediatrics 2017 Nov; 140:e20163840.
Wolraich ML.An association between prenatal acetaminophen use and ADHD: The benefits of large data sets. Pediatrics 2017 Nov; 140:e20172703.
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Obstet Gynecol 2017 Nov; 130:938
Extending Prenatal Care to All Women Residing in the U.S.
A state government program supporting prenatal healthcare for recent and unauthorized immigrant women improved neonatal outcomes.
To assess the effects of offering government-supported prenatal care to pregnant, noncitizen women living in the U.S., investigators studied the outcomes of the Oregon Citizen/Alien Waived Emergent Medical Care program, which added prenatal care to standard Emergency Medicaid. Rollout of the program occurred between 2008 and 2013.
Medical claims data from 2003 through 2015 in Oregon showed that the addition of prenatal care to standard Emergency Medicaid services increased the mean number of prenatal visits per pregnancy from <1.0 to 8.5; increased maternal Rh immunization, glucose testing, and tetanus, diphtheria, and pertussis vaccination; lessened the likelihood of extremely low birth weight from 1.8 to 0.7 per 1000 births; and lowered death rates in the first year from 1.1 to 0.3 per 1000 children — all statistically significant differences.
COMMENT: The United Nations reported that, in 2015, the largest numbers of people who were born outside their current country of residence lived in the U.S. (46.6 million), Germany (12.0 million), Russia (11.6 million), Saudi Arabia (9.0 million), and the U.K. (8.5 million). Many immigrants of reproductive age living in the U.S. are not citizens and, in some states, are ineligible to access prenatal care through government-supported programs. However, the newborns of these women are U.S. citizens and thus are generally covered by government-supported health programs. This study shows that expanding prenatal healthcare coverage to noncitizens can greatly increase such care while also reducing infant mortality.
CITATION(S): Swartz JJ et al. Expanding prenatal care to unauthorized immigrant women and the effects on infant health. Obstet Gynecol 2017 Nov; 130:938.
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JAMA 2017 Oct 10; 318:1333
Biomarkers of Ovarian Reserve Are Not Always Effective for
Predicting Conception

Low AMH and high FSH levels may be of little use for estimating reproductive potential in non-infertile women who delay pregnancy.
Serum levels of antimüllerian hormone (AMH) and early-follicular-phase follicle-stimulating hormone (FSH) are used routinely to help predict the response to controlled ovarian hyperstimulation prior to in vitro fertilization. Increasingly, these biomarkers are being utilized to estimate fertility potential in women who delay pregnancy until later in reproductive life; but is this strategy effective? In a time-to-pregnancy cohort study involving 750 women (mean age, 33) who had been attempting to conceive for ≤3 months, investigators evaluated the associations between biomarkers of ovarian reserve and reproductive potential as defined by a positive pregnancy test.
After adjusting for variables such as age, race, body-mass index, smoking, and recent hormonal contraceptive use, women with low AMH values (<0.7 ng/mL), those with high serum FSH values (>10 mIU/mL), and those with high urinary FSH values (>11.5 mIU/mg creatinine) did not have significantly different predicted probabilities of conceiving within 6 or 12 cycles compared with women who had normal values. In addition, inhibin B levels were not associated with probability of conceiving in a given cycle.
COMMENT: These data suggest that biomarkers of ovarian reserve are of little or no use for evaluating the likelihood of pregnancy in noninfertile women as they age. As an editorialist notes, these biomarkers provide an estimate of oocyte quantity but not quality. Moreover, the study participants were carefully selected to exclude any fertility problems, and pregnancy outcomes were not assessed. Still, the data raise questions about relying on these biomarkers to encourage women who are delaying pregnancy to cryopreserve some of their oocytes by suggesting they are nearing the end of their reproductive life.
CITATION(S): Steiner AZ et al. Association between biomarkers of ovarian reserve and infertility among older women of reproductive age. JAMA 2017 Oct 10; 318:1367.
Santoro N.Using antimüllerian hormone to predict fertility. JAMA 2017 Oct 10; 318:1333.
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Pediatrics 2017 Nov 2; e20171021
IV Antibiotics for Urinary Tract Infection in Infants: Is Less More?
Shorter IV antibiotic courses are not associated with increased morbidity.
For children older than 2 months of age, guidelines do not dictate a preference for intravenous (IV) over oral antibiotics as initial therapy for urinary tract infection (UTI). Children younger than 60 days with UTI are frequently admitted to the hospital and treated with IV antibiotics, but the optimal duration of treatment is not known.
Using an administrative and billing database of 46 children's hospitals from 2005 to 2015, investigators reviewed trends in IV antibiotic treatment of otherwise healthy infants <60 days of age with a primary diagnosis of UTI. The primary outcome was hospital readmission within 30 days.
Among nearly 4000 hospitalizations reviewed, 69% of infants received short-term (≤3 days) IV antibiotic therapy and 31% received long-term (≥4 days) therapy. The percentage of patients receiving long-term IV antibiotics decreased from 50% at the start of the study to 19% at the end, although the change over time varied widely across hospitals. The 30-day readmission rate for UTI also varied across hospitals, but was not correlated with IV antibiotic duration. In multivariate analyses, the adjusted readmission rate was similar for infants who received short- or long-term IV antibiotics (1.6% and 1.5%), was higher in girls than boys, and was higher in infants <15 days of age than in those aged 45–60 days (2.5% vs. 1.2%).
COMMENT: Because the investigators excluded patients with central line placement, they may have underestimated the number of patients receiving longer term IV antibiotic therapy. Despite this, the study shows a significant trend over time toward decreased duration of hospitalization and IV antibiotic treatment for UTI in very young infants, without increased risk for readmission for failed therapy. Shorter IV antibiotic courses allow for earlier discharge, which promotes infant bonding and reduces the risk for complications, including nosocomial infection.
CITATION(S): Lewis-de Los Angeles WW et al. Trends in intravenous antibiotic duration for urinary tract infections in young infants. Pediatrics 2017 Nov 2; e20171021; [e-pub].
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N Engl J Med 2017 Oct 19; 377:1551
The Hospital Readmissions Reduction Program: Searching for a Better Measure
A hospital-wide readmission measure would increase penalties substantially for safety-net hospitals.
The Hospital Readmissions Reduction Program (HRRP; part of the Affordable Care Act) penalizes hospitals that have higher-than-expected 30-day readmissions for patients with five specific conditions (heart failure, myocardial infarction, pneumonia, hip or knee replacement, and chronic obstructive pulmonary disease). These current readmissions measures are not applicable to hospitals with smaller condition-specific volumes (fewer than 25 admissions during 3 years for each condition), and they disproportionately penalize large-volume safety-net hospitals. Would a hospital-wide readmission measure (reflecting all readmissions, not just readmissions for patients with the 5 specific conditions) be more effective and equitable?
Researchers used Medicare hospital claims from 2011 to 2013 to compare average penalties for eligible hospitals (those that met current condition-specific volumes) with penalties that would have been assessed under a proposed hospital-wide measure (for hospitals that had ≥25 index admissions during 1 year). Readmission rates were 15% to 20% in both condition-specific and hospital-wide analyses. Using a hospital-wide measure instead of condition-specific measures would have resulted in 76 additional hospitals (2.3%) receiving penalties, an increase in penalties from 0.42% to 0.89% of base diagnosis–related group (DRG) payments and an increase in disparity between safety-net hospitals and other hospitals.
COMMENT: Potential advantages of hospital-wide measures include broadening hospital eligibility, incentivizing improvement across more clinical conditions, and reducing time between performance measurement and penalty assessment because more hospitals would meet admission volume thresholds in a single year. However, this study suggests that such a change would negatively affect safety-net hospitals.
Dr. Helgerson is an Associate Professor of Medicine and the Hospital Medicine Section Head at the University of Virginia in Charlottesville.
CITATION(S): Zuckerman RB et al. Effect of a hospital-wide measure on the readmissions reduction program. N Engl J Med 2017 Oct 19; 377:1551.
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JAMA 2017 Nov 7; 318:1687
Meta-Analysis of Strategies to Prevent Injurious Falls in Older Adults
Exercise alone or as part of a multicomponent intervention was effective.
Studies of approaches to prevent falls that result in serious injury in older adults (age, ≥65) have focused mostly on comparing single interventions, as have subsequent meta-analyses. Now, investigators have conducted complex pairwise and network meta-analyses of data from 283 randomized, controlled trials with 160,000 participants (mean age, 78; 74% women) to explore the effects of both single and multicomponent fall-prevention interventions.
The following four single and combined interventions were associated with lower risk for injurious falls, compared with usual care:

COMMENT: The solution to the expensive and clinically serious problem of injurious falls lies in combining home-based and clinic-based interventions. This analysis is a good example of how improving population health requires not only moving out of typical emergency and hospital settings but also making a coordinated commitment of resources by health care systems beyond the level of individual clinicians.
CITATION(S): Tricco AC et al. Comparisons of interventions for preventing falls in older adults: A systematic review and meta-analysis. JAMA 2017 Nov 7; 318:1687.
Larson EB.Evidence supports action to prevent injurious falls in older adults. JAMA 2017 Nov 7; 318:1659.
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The FDA announces the next Pharmacy Compounding Advisory Committee (PCAC) meeting for November 20-21, 2017.
The vast majority of pharmacists are not aware of what all goes on at a PCAC meeting. You are strongly encouraged to go to the following website and look at the meeting materials that will be discussed and voted on during the PCAC meeting.

The Table of Contents of this document is as follows:             Table of Contents



I. Introduction


A. Bulk Drug Substances That Can Be Used by Compounders under Section 503A


B. Drug Products and Categories of Drug Products that Present Demonstrable Difficulties for Compounding



II. Substances Nominated for Inclusion on the 503A Bulks List
(in order of discussion at the meeting)



III. Drug Products and Categories of Drug Products That Present Demonstrable Difficulties for Compounding


A. Liposome Drug Products (Tab 7)


B. Drug Products Produced Using Hot Melt Extrusion (Tab 8)



IV. Draft Points to Consider


Last week, we provided the list of drugs to be discussed. The FDA presentations are contained in the above document, which is 338 pages long. Generally, not all committee members read and study in detail the complete document but depend somewhat on the FDA summaries presented at the meeting. These are usually in-depth presentations by the FDA (generally on why the drug should not be approved for the Bulk Drug Substance list) and time for short rebuttals provided by those that have petitioned for the drug to be included on the Bulk Drug Substance list.

The FDA is recommending to PCAC that the following drugs NOT be allowed:

The FDA is recommending to PCAC the following drug BE allowed:

Regarding the Difficult to Compound subject, these are often presentations by the pharmaceutical firms that have requested that the products be added to the Difficult to Compound list, oftentimes because they tend to be protecting their own turf and not always being fully educated on the importance of many of these products in individualizing patient care. These presentations also include a lot of negative aspects that are not always related to compounding and make the issue "seem" more difficult than it really is. Regarding the two types of products for discussion:
Liposome Drug Products
This might include ALL products where liposomes are used, topical, oral, injectable, etc. How important are Liposomes in compounding pharmacy today? EXTREMELY IMPORTANT! Think about all the PLO-type products that are compounded.
Please note that the FDA discussion involves "injectable liposomes" but the phrase "liposome drug products" is used throughout, which also includes topical, oral, etc. This is an unfair presentation and does not delineate the different dosage forms where liposomes can be used…
Hot Melt Extrusion Products
This is similar to the cold compression method of making suppositories that has been around for over 150 years. It does use heat, and there are many advantages for individualizing patient therapy using hot melt extrusion. It is a technology that has a great future in compounding and is currently being utilized. Also, it is somewhat related to 3D printing that is up and coming and very useful in the future of compounding. It must be available for pharmacists. The International Journal of Pharmaceutical Compounding has published articles on all these topics and their utilization and application for individualized patient care.
In both cases above, these topics have been combined with "nanotechnology," which, by itself, is a separate topic and is not necessarily applicable to both liposomes and extrusion. This is misrepresentation, and liposomes and hot melt extrusion must be considered on their own merits.
What happens is up to you! You can wait and see the minutes of the meeting and see how your profession has been changed, OR you can let your representatives/organizations know how you feel and maybe have an impact on the decisions! Please keep in mind that the FDA and the committee have limited experience/information with which to work and are not aware of all the different aspects of compounding specific medications for individual patient care throughout the entire U.S.
Loyd V. Allen, Jr., PhD, RPh 
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy Twenty-second edition

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