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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
May 13, 2017

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Study Says EpiPens Work Up to 4 Years Past Expiration
Pediatric Adverse Events from Over-the-Counter Cough and Cold Medications
Can Oats Be Included in a Gluten-Free Diet for Celiac Disease?
Silymarin Associated with Improved Fibrosis in Nonalcoholic Steatohepatitis
Colonoscopy for Women with History of Breast Cancer: How Often?
Losing a Sibling During Childhood Linked to Increased Mortality
Does Maternal Stress During Pregnancy Affect Longevity of Offspring?
The High Cost of Surgery for Benign Colon Polyps
Why Wait? Place That Contraceptive Implant Now
What Accounts for the Reported Association Between Prenatal Antidepressant
   Exposure and Autism Spectrum Disorder?

Study Says EpiPens Work Up to 4 Years Past Expiration
A just-released study reports that for more than four years past their stamped expiration dates, the EpiPen injectors retained sufficient epinephrine to, in all likelihood, prevent potentially fatal allergic reactions.
Pharmacist F. Lee Cantrell, Director of the California Poison Control System in San Diego, analyzed 40 expired EpiPens and EpiPen Juniors. He found that the auto-injectors did lose potency over time but even 50 months past expiration, the EpiPens retained 84 percent of epinephrine concentrations—enough to prevent anaphylactic shock. In a phone interview, he stated, "In every pen we tested there was enough to give what would be considered a therapeutic dose," said Cantrell, lead author of a letter published in the Annals of Internal Medicine.
Mylan has filed an application with the FDA for a new EpiPen formulation, which would extend the product's shelf life. EpiPens currently have an 18-month expiration date; pharmacists have told Cantrell that they do not receive the devices until six months after they were manufactured, putting the injectors into patients' hands with less than one year left until they need to be replaced. 
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Pediatrics 2017 Jun; 139:e20163070
Pediatric Adverse Events from Over-the-Counter Cough and Cold Medications
Adverse events were most commonly reported in children <4 years of age, and most often involved accidental unsupervised ingestions in the home.
To assess the rate of pediatric adverse events associated with over-the-counter (OTC) cough and cold medications in the U.S., investigators analyzed data from the Pediatric Cough and Cold Safety Surveillance System for patients <12 years of age reported to have at least one adverse event associated with any of the following pharmaceuticals: brompheniramine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, pseudoephedrine, and phenylephrine.
Of 3251 adverse events reported from 2009 to 2014, 60% occurred in children <4 years of age. The most common exposures were accidental unsupervised ingestions (67%) and medication dosing errors (13%). Almost all accidental unsupervised ingestions were self-administered, with 90% occurring at home. Diphenhydramine was the most common medication involved in accidental unsupervised ingestions (63%), while most medication errors involved dextromethorphan (60%).
The most common adverse events were tachycardia, somnolence, hallucinations, ataxia, mydriasis, and agitation. There were 20 fatal cases (0.6%), most in children <2 years of age and most involving diphenhydramine or dextromethorphan. Fatalities involved accidental unsupervised exposures (2), medication errors (2), and other exposures (6 homicides, 1 use as a sleep aid, 2 nontherapeutic indications); 7 were unknown. Six fatalities involved a prescription opioid-containing medication. No death was determined to be the result of a therapeutic dose. The reported adverse event rate was 1 case per 1.75 million units sold.
COMMENT: We must weigh the risks and benefits of any therapeutic intervention, including over-the-counter medications. Since we lack data demonstrating efficacy of over-the-counter cough and cold medications for children, it's a stretch to justify the risk. The common cold in children is generally a self-limited illness that requires nothing more than hydration, rest, and sometimes antipyretics.
CITATION(S): Green JL et al. Safety profile of cough and cold medication use in pediatrics. Pediatrics 2017 Jun; 139:e20163070.
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Gastroenterology 2017 Apr 18
Can Oats Be Included in a Gluten-Free Diet for Celiac Disease?
A meta-analysis indicates that oats are safe but is limited by low-quality data.
A gluten-free diet (GFD), one without wheat, barley, and rye, is important in the treatment of celiac disease. The safety of including oats in the diet to increase its nutritional value is debated.
In a systematic review, investigators identified 28 studies of the effect of oats on symptoms, serologic markers, or histology in celiac disease (defined broadly) and/or dermatitis herpetiformis. They conducted a meta-analysis of eight controlled trials (six randomized) comprising 661 patients.
Including oats in a GFD for 12 months did not affect symptoms, histology, intraepithelial lymphocyte counts, or serologic markers. Results were similar for adults and children. The authors conclude that inclusion of uncontaminated oats in a GFD for up to 12 months is well tolerated in both adults and children but that further randomized, controlled trials are needed.
COMMENT: The data on oats in celiac disease are very confusing and weak. As the authors note, studies are low in quality and vary in methodology. Furthermore, the degree of contamination of oats with gluten is variable between countries, and information on source of oats was unclear in several uncontrolled studies reviewed. Finally, assessment of outcomes beyond 12 months is limited.
Although it appears that the inclusion of oats without gluten contamination in a GFD does not affect subjective or objective measures of disease activity, if oats are included in a GFD, the patient should be followed for serologic evidence of increased disease activity, which if present should prompt a duodenal biopsy, as recommended by the North American Society for the Study of Celiac Disease.
CITATION(S): Pinto-Sánchez MI et al. Safety of adding oats to a gluten-free diet for patients with celiac disease: Systematic review and meta-analysis of clinical and observational studies. Gastroenterology 2017 Apr 18; [e-pub].
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Clin Gastroenterol Hepatol 2017 Apr 15
Silymarin Associated with Improved Fibrosis in Nonalcoholic Steatohepatitis
However, it was not superior to placebo in achieving histologic improvement.
Silymarin, a derivative of the milk thistle plant shown to have antioxidant, anti-inflammatory, and antifibrotic effects, was shown ineffective in clearing chronic hepatitis C virus but might be effective in improving nonalcoholic fatty liver disease (NAFLD).
To assess its safety and efficacy in this setting, researchers performed a double-blind trial involving 99 consecutive patients receiving care for biopsy-proven nonalcoholic steatohepatitis (NASH) at a single tertiary care center in Malaysia. Patients with a NAFLD histologic activity score ≥4 were randomized to receive silymarin 700 mg or placebo three times daily for 48 weeks. Liver biopsy was repeated after treatment ended.
The primary efficacy outcome, a decrease in NAFLD histologic activity score ≥30% from baseline, was similar between silymarin and placebo groups (33% and 26%, respectively). However, improvement in fibrosis (≥1-point reduction) occurred significantly more frequently in patients taking silymarin (22% vs. 6%). Serious adverse events occurred in three patients in the silymarin group and two in the placebo group. No adverse event was related to the study drug.
COMMENT: This small but well-designed and well-executed randomized study demonstrated that 48 weeks of silymarin therapy was not more effective in achieving global histologic improvement in NASH compared with placebo. However, significant fibrosis improvement was noted in the silymarin group, possibly reflecting the antifibrotic effect of silymarin. As degree of fibrosis has been shown to be the key driver of morbidity and mortality among NASH patients, further studies of silymarin alone or in combination with other candidate NASH drugs are warranted, especially as silymarin appears to be safe and well tolerated.
Note to readers: At the time NEJM Journal Watch reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.
CITATION(S):Chan W-K et al. A randomized trial of silymarin for the treatment of non-alcoholic steatohepatitis. Clin Gastroenterol Hepatol 2017 Apr 15; [e-pub].
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Gastrointest Endosc 2017 Apr 20
Colonoscopy for Women with History of Breast Cancer: How Often?
A meta-analysis indicates there's no need to decrease the interval between colonoscopies or other forms of screening.
Women with a history of breast cancer are often concerned about developing second malignancies. Numerous studies have addressed the risk for colorectal cancer (CRC) in breast cancer patients, and no current guidelines recommend that they receive earlier or more frequent CRC screening.
To determine the prevalence of CRC in women with breast cancer, investigators performed a meta-analysis and systematic review of 37 retrospective cohort studies and 8 case-control studies involving more than 1 million women with breast cancer, of whom more than 9000 had incident CRC.
A random-effects model showed that the pooled event rate for CRC in the retrospective studies was significantly lower for women with breast cancer (0.7%). In the case-control studies, breast cancer patients have nonsignificantly higher risks for CRC (odds ratio, 1.2) and advanced adenomas (OR, 1.5). The only increased CRC risk was in patients diagnosed with breast cancer before age 45 or 50 (OR for both, 2.5).
COMMENT: The authors suggest that these data indicate no need to decrease the interval between colonoscopies or other forms of screening in women with a history of breast cancer. They also suggest that screening begin at age 45 in women diagnosed with breast cancer before age 45, though they admit that the available data do not indicate the age at which young women with breast cancer developed CRC. My own approach for women age 50 and older with a history of breast cancer is to perform colonoscopy, but to reassure them that standard intervals, including 10-year intervals for screening, are appropriate. For women diagnosed before age 50 with breast cancer, it may be best to perform colonoscopy or other screening for those who request it, but to reassure them that available data do not support shortening screening intervals.
CITATION(S): Lai JH et al. Association between breast cancer and the risk of colorectal cancer: Systematic review and meta-analysis. Gastrointest Endosc 2017 Apr 20; [e-pub].
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JAMA Pediatr 2017 Apr 24
Losing a Sibling During Childhood Linked to Increased Mortality
Children who experienced a sibling death had a 71% higher risk for all-cause mortality into adulthood.
Increased risk for mortality has been found in adults who experience the death of a family member, but whether losing a sibling while in childhood is associated with mortality is unknown.
Researchers retrospectively analyzed national health data for over 5 million children from Denmark and Sweden born between 1973 and 2006, comparing all-cause, cause-specific, and type-specific (due to diseases vs. external causes) mortality between approximately 56,000 children who lost a sibling (of any age) between ages 6 months and 18 years and nearly 5 million who did not. Adjusted models estimating the mortality rate ratios (MRRs) included covariates such as maternal age, social status, parity, and smoking, as well as prematurity, birth weight, and age of child at sibling death.
Children exposed to sibling death had higher risk for all-cause mortality (MRR, 1.71), cause-specific mortality (e.g., endocrine, nutritional, and metabolic: MRR, 5.15; nervous system: MRR, 2.62; suicide and other self-harm: MRR, 1.57), and type-specific mortality (due to diseases: MRR, 1.94; external causes: MRR, 1.55) throughout the follow-up period (range, 2–37 years). Risks were higher within the first year after sibling death, when siblings were closer in age or the same sex, and when cause or type of death was the same as the sibling's.
COMMENT: Clinicians will be aware of the psychosocial stress a child feels on losing a sibling, but the increased mortality described here may be surprising. The results suggest that something more than simple genetics is at work. The growing field of traumatic stress offers insight into how genetics, physiology, and social context could interact to make a child vulnerable to disease and death after a sibling dies. In the clinic setting, principles of trauma-informed care should be used to address a child's and family's needs in the wake of such a stressful event.
CITATION(S): Yu Y et al. Association of mortality with the death of a sibling in childhood. JAMA Pediatr 2017 Apr 24; [e-pub].
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Proc Natl Acad Sci U S A 2017 Apr 18; 114:4201
Does Maternal Stress During Pregnancy Affect Longevity of Offspring?
Adult lifespan was shortened in offspring of women whose husbands died during (but not after) the mother's pregnancy.
Considerable evidence indicates that stressors to a pregnant woman or her very young offspring can affect the child's subsequent health. French investigators studied the adult longevity of 5671 children born from August 1914 through December 1916 (i.e., during World War I), a time when 350 French women lost their husbands each day to combat. In analysis matched for date of birth, sex, and mother's age, adult mortality of children who had lost their fathers (either before or after their birth) was compared with lifespans of those whose fathers were not killed.
Individuals who did not lose their fathers lived longer than those whose fathers died in the war. However, this shortened lifespan was seen only in those who lost their fathers when they still were in utero: Such individuals lived 2.4 years less than their matched controls who did not lose their fathers. Individuals who lost their fathers within the first year or two after their birth had normal lifespans.
COMMENT: Consistent with other animal and human research, this study shows that maternal stress during pregnancy can negatively affect the health of the offspring decades later — specifically, by shortening lifespan. Animal studies suggest a mother's stress during pregnancy can alter the expression of her offspring's genes, particularly those involved in the stress response.
CITATION(S): Todd N et al. Prenatal loss of father during World War One is predictive of a reduced lifespan in adulthood. Proc Natl Acad Sci U S A 2017 Apr 18; 114:4201.

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Gastrointest Endosc 2017 Apr 10
The High Cost of Surgery for Benign Colon Polyps
The decision to refer patients with benign polyps to surgery should be taken seriously.
Using prospectively collected data from a U.S. surgical outcomes database, researchers assessed morbidity and mortality in 12,732 patients undergoing elective surgery for benign colon polyps, primarily in academic centers. Results were as follows:

COMMENT:These findings support those from a series of recent studies showing that the risk for surgical resection for benign colon polyps is quite substantial and suggesting that the decision to refer a patient for a benign colon polyp should be taken very seriously. In my opinion, a surgeon performing colonoscopy should never be allowed to self-refer a patient with a benign polyp that they have identified at colonoscopy for segmental resection without review of the photographs by an expert endoscopist. Among the recent studies, comparisons of complications from surgery and endoscopic resection have shown that endoscopic resection has much lower cost and risk. Gastroenterologists should also consistently consult experts in endoscopic resection when they encounter benign colon polyps that they feel are too technically challenging or too risky to remove themselves.
Note to readers: At the time NEJM Journal Watch reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.
CITATION(S): Peery AF et al. Morbidity and mortality after surgery for nonmalignant colorectal polyps. Gastrointest Endosc 2017 Apr 10; [e-pub].
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Contraception 2017 Apr; 95:364
Why Wait? Place That Contraceptive Implant Now
Young women had extremely low pregnancy rates whether their implants were placed in accord with package guidelines or on the day of their clinic visit.
Contraceptive implant labeling advises placement within 5 days of menstrual cycle day 1 or within 7 days of discontinuing hormonal contraception, both after a negative pregnancy test. Women who request implants outside these guidelines are often advised to return at the “proper time,” but can unintentionally become pregnant if they don't return. The CDC endorses implant placement at any time if the clinician is reasonably certain the patient is not pregnant (see: https://www.cdc.gov/reproductivehealth/unintendedpregnancy/
). However, concern that women in luteal phase may harbor a fertilized ovum or undetectable early pregnancy prevents some clinicians from implementing this approach. Researchers used electronic medical record data to identify women at a cost-free Colorado reproductive health clinic who received implants after a negative pregnancy test and, if appropriate, levonorgestrel emergency contraception. For placements outside guidelines, patients were instructed to use a back-up method for 7 days, take a pregnancy test in 2 to 4 weeks, and return to the clinic if they suspected they were pregnant.
Among 3180 implant placements (median age of recipients, 19.7; ethnically diverse; 66.6% nulliparous), pregnancy data were available for 1726 patients. Of these, 660 (50.3%) received implants within product guidelines and 1066 (57.0%) outside guidelines. Luteal phase pregnancies (LPP) occurred in 2 women within guidelines and 10 outside guidelines; LPP rates were 0.30% (95% confidence interval, 0.0–1.1%) and 0.94% (95% CI, 0.5–1.7%).
COMMENT: Same-day initiation of highly effective, long-acting contraceptive methods has the potential to lower the chances of unintended pregnancy in adolescents (who have the highest unintended pregnancy rate). The very low pregnancy rates in this study should reassure clinicians that implant placement outside manufacturer guidelines, with follow-up pregnancy testing in 2 to 4 weeks, is appropriate. Implants are not known to adversely affect existing pregnancies.
CITATION(S): Richards M et al. Risk of luteal phase pregnancy with any-cycle-day initiation of subdermal contraceptive implants. Contraception 2017 Apr; 95:364.
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JAMA Pediatr 2017 Apr 17
What Accounts for the Reported Association Between Prenatal Antidepressant Exposure and Autism Spectrum Disorder?
It's unlikely that in utero exposure to antidepressant medications directly causes ASD.
Evidence linking in utero antidepressant exposure to subsequent adverse neurodevelopmental outcomes remains inconsistent. For example, a meta-analysis of 6 case-control studies including 117,737 patients reported a significant association between prenatal exposure to an antidepressant medication and childhood autism spectrum disorder (ASD; odds ratio, 1.81; 95% confidence interval, 1.49–2.20). However, a meta-analysis of 2 cohort studies involving 772,331 patients reported no significant association between prenatal exposure to antidepressant medication and childhood ASD (hazard ratio, 1.26; 95% CI, 0.91–1.74).
To further explore this issue, Swedish investigators studied 1,580,629 children born to 943,776 mothers. A total of 22,544 children were exposed to antidepressant medication during the first trimester. Models comparing outcomes in exposed and unexposed siblings showed no association between maternal use of antidepressants and risk for ASD (HR, 0.83; 95% CI, 0.62–1.13) or attention-deficit hyperactivity disorder (HR, 0.99). In addition, a Canadian study of 35,906 children showed that risk for diagnosis of ASD did not significantly differ among siblings prenatally exposed or unexposed to antidepressants (HR, 1.60; 95% CI, 0.69–3.74).
COMMENT: The authors of these Swedish and Canadian cohort studies conclude that the association between prenatal exposure to antidepressant medication and childhood ASD suggested in prior studies could be due to confounding factors, including parental genetics and mental health, family environment, and socioeconomic factors. The lack of a direct causal link between maternal antidepressant use and ASD should reassure parents and clinicians.

  1. Mezzacappa A et al. Risk for autism spectrum disorders according to period of prenatal antidepressant exposure: A systematic review and meta-analysis. JAMA Pediatr 2017 Apr 17; [e-pub].
  1. Sujan AC et al. Associations of maternal antidepressant use during the first trimester of pregnancy with preterm birth, small for gestational age, autism spectrum disorder, and attention-deficit/hyperactivity disorder in offspring. JAMA 2017 Apr 18; 317:1553.
  1. Brown HK et al. Association between serotonergic antidepressant use during pregnancy and autism spectrum disorder in children. JAMA 2017 Apr 18; 317:1544.
  1. Oberlander TF and Zwaigenbaum L.Disentangling maternal depression and antidepressant use during pregnancy as risks for autism in children. JAMA 2017 Apr 18; 317:1533.

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