Which Proton Pump Inhibitor is the Most Potent?

A recent study (DY Graham, A Tansel. Clin Gastroenterol Hepatol 2018; 16: 800-808) analyzed 56 randomized trials to determine relative potency of proton pump inhibitors (PPIs) based on time in which intragastric pH was 4 or less (pH4time).

Key findings:

  • Pantoprazole 20 mg was equivalent to 4.5 mg of omeprazole
  • Lansoprazole 15 mg was equivalent to 13.5 mg of omeprazole
  • Esomeprazole 20 mg was equivalent to 32 mg of omeprazole
  • Rabeprazole 20 mg was equivalent to 36 mg of omeprazole

The authors note that peak effectiveness for PPIs was at ‘approximately 70 mg of omeprazole equivalents’.  In addition, they state that twice a day dosing was more effective than increasing once a day dosing; however, three times a day dosing was not more effective than twice a day. “Dexlansoprazole, a quasi-twice-a-day formulation produced similar acid suppression to the lowest twice-daily PPI regimen and 20 mg vonoprazan once daily provided similar efficacy aas high-dose twice-daily PPI.” The authors also compare costs; generics of pantoprazole, omeprazole, and esomeprazole cost as little as $0.02-0.04 per omeprazole equivalent.  Thus, 20 mg of omeprazole would be as little as 40 cents.

My take: Using the lowest effective dose of a PPI is recommended.  In patients needing higher dosing or with suboptimal response to acid suppression, this data can be very helpful.

 

Proctor Creek Trail

Bad Combination? Lansoprazole and Ceftriaxone

From Gastroenterology & Endoscopy News Nov 2016: Giving PPIs and Antibiotics Together May Disrupt Heart Rhythm

An excerpt:

Taking two common drugs—an over-the-counter proton pump inhibitor (PPI) and an antibiotic—together was associated with an increased risk for life-threatening arrhythmia (J Am Coll Cardiol 2016 Oct 10. [Epub ahead of print]).

New York researchers scanned data from two independent databases to investigate possible QT interval–prolonging drug–drug interactions: 1.8 million adverse event reports from the FDA’s Adverse Event Reporting System and 1.6 million ECGs from 382,221 patients treated at NewYork-Presbyterian Hospital/Columbia University Medical Center, in New York City, between 1996 and 2014…

In the study, patients taking ceftriaxone, a cephalosporin antibiotic, and the PPI lansoprazole were 40% more likely to have a QT interval above 500 milliseconds, the current FDA-stated threshold of clinical concern. Among men taking the two drugs, QT intervals were 12 milliseconds longer than men who took either drug alone…

The interaction identified in the data analysis was specific to lansoprazole and ceftriaxone, but not other cephalosporins.

My take: The magnitude of this risk is very low for a single individual but is important when one considers how many patients could be taking this combination of medications.

‘Little’ Knowledge Exists Regarding Medicines for Neonates

Despite federal legislation encouraging the study of products used in the pediatric population, very little of these studies has translated into meaningful information regarding neonates (JAMA Pediatr 2014; 168: 130-36, thanks to Ben Gold for this reference).

This publication reviewed studies submitted to the FDA between 1997-2010.  The authors identified all drugs with pediatric studies that included neonates.  Subsequently, the use of these drugs was examined in a oohort of neonates admitted to 290 neonatal intensive care units (NICU) (Pediatrix Data Warehouse) in the U.S. form 2005-2010.

Key findings:

  • 28 drugs (in 41 studies) were examined in neonates. This led to 24 labeling changes.
  • 11 of 24 neonatal labeling changes included an approval for use in neonates, including 4 for HIV and 3 for anesthesia.
  • 13 of 24 labeling changes were the following: “safety and effectiveness have not been established.”  These drugs included several reflux medications: esomeprazole, lansoprazole, pantoprazole, and ranitidine.
  • In the Pediatrix database involving 446,335 hospitalized neonates, there were 399 different drugs identified that had been administered.  Of the 28 studied drugs, the gastroesophageal reflux medicines were used most frequently.  13 of the 28 studied drugs were not used at all in the NICUs.
  • Of the 11 drugs with a neonatal indication, 7 were never used in the Pediatrix neonatal population and the other 4 drugs were used infrequently.

Conclusions:

  • Neonates are a vulnerable and an understudied population
  • Most of the exposure to drugs was off-label for neonates.
  • Most often, off-label drugs were prescribed “despite studies indicating they were not effective…For example, ranitidine, lansoprazole, and inhaled nitric oxide (for the prevention of bronchpulmonary dysplasia) were the top 3 drugs used in neonates…none have FDA labelling for the indication studied because of lack of efficacy.”
  • Furthermore, drugs like ranitidine and lansoprazole” are associated with serious adverse effects in neonates.” (Clin Perinatol 2012; 39: 99-109)

Related blog entries:

Off-label medications in pediatrics

In the U.S., multiple legislative changes have been improving the information available for off-label use of medications (JPGN 2013; 56: 113-4).

The Pediatric Research Equity Act (PL 108-155) and the Best Pharmaceuticals for Children Act (PL 107-109) help the Food and Drug Administration (FDA) promote pediatric trials and better information.

  • Pediatric data must be included in labeling whether results are positive, negative or inconclusive
  • If pediatric trials are not completed because the drug would be ineffective or unsafe, this information must go into labeling
  • Public internet posting of certain FDA pediatric reviews is required regardless of whether the trials led to an approval

Despite these improvements, the data may be difficult to interpret.  The authors of this commentary note that only “48% of trials of products that had pediatric safety information added to the product’s labeling were reported in the peer-reviewed literature.”  Furthermore, in about half of the published articles, the studies did not emphasize the same information as the FDA labeling.

Even when a fair amount of data is provided, it is frequently ignored.  A specific example given by the authors: lansoprazole. Lansoprazole is not approved in patients younger than 1 year and labeling describes a negative trial in this age group. Yet, in the U.S., lansoprazole was dispensed off-label in this population approximately 358,000 times in 2010.

Pharmaceutical companies benefit whether the prescription is for an approved indication or for an off-label use.  Even with approved uses, there have been substantial concerns about adverse effects.  The likelihood of more risk and less benefit is much greater for off-label use.

So with the next prescription, it might be worth thinking about whether the medication works, whether there is sufficient data to support an approved indication, and how much risk is involved.

Related blog posts:

Treating reflux does not help asthma

Studies in adults have looked at the use of PPIs for asthma and have not shown improvement (see references below).  Now a trial of lansoprazole suggests the same is true in children (JAMA 2012; 307: 373-81).  This study was a randomized double-blind placebo-controlled study of 306 children with a mean age of 11; the participants were recruited from 19 academic medical centers in the US.  149 children received lansoprazole and 157 received placebo.  The dose of lansoprazole was 15mg in patients weighing less than 30kg, and 30mg in those weighing more than 30kg.

Those treated with lansoprazole did no better than placebo with regard to symptoms and lung function.  The main outcome was the asthma control questionnaire (ACQ) score. The lansoprazole group had a mean change in this score of 0.2 units which was not a meaningful change. More precise measures of lung function including forced expiratory volume also did not differ.

In a subgroup of 115 patients who had esophageal pH studies, the prevalence of GER was 43%.  Yet, no treatment effect for lansoprazole was observed for any asthma outcome.

Not only did lansoprazole not help, the treatment group experienced more adverse effects, including respiratory infections (relative risk 1.3), sore throats (RR 1.3), and episodes of bronchitis (RR 2.2).  Though not statistically significant, the treatment group had more activity-related fractures, six compared to one in the placebo group.

This study took several years to complete (2007-2010).  I congratulate the authors, especially the third author Benjamin Gold, for this excellent work.

http://www.ccdhc.org/doctors/gold.html

Additional references:

The Medical Pendulum and Gastroesophageal Reflux

GERD and respiratory/ENT issues:

  • Gastroenterology 2009; 137: 1844. Critical review of below NEJM article. ‘a subset of asthmatics will have objective detection of GERD without typical symptoms…work by Amer Lung Assn suggests that twice daily PPI will not be helpful’..however, ‘perhaps 3-6months of PPI may still be reasonable until we can accurately identify subgroups of pts who may respond.’ –Gary Falk, Cleveland Clinic
  • NEJM 2009; 360: 1487, 1551. Use of PPIs (nexium 40mg bid) in poorly-controlled asthma with no symptoms of GER –did not help w asthma control & pH studies were not predictive of response. n=412 adults. 40% c abnl pH studies in each group (nexium vs. placebo).
  • Clin Gastro & Hep 2007; 5: 1379. Review of ENT findings and reflux.
  • Am J Gastro 2007; 102: 716. Poor specificity of ENT findings for diagnosis of laryngopharyngeal reflux.
  • Aliment Pharm Ther 2007; 25: 385-92. meta-analysis. Rx c PPIs not more effective than placebo in resolving ENT symptoms presumed to be due to GER. Editorial suggests some patients may benefit, but better tools are needed to identify them.
  • Gastroenterology 2010; 139: 1887. PPIs decreased postnasal drainage compared to placebo. n=75. (50% vs 5%) age discrepancy in patient populations.
  • Clin Gastro & Hep 2010; 8: 741 (excellent editorial), 770 (article on rabeprazole improving heartburn Sx in pts with laryngitis), n=82. Editorial suggests 1-2month trial of BID PPI and if not effective, then little to offer. May change when studies looking at surgery (after impedance) outcomes.
  • Gastroenterology 2010; 139: 754. 716 (editorial). Acoustic cough & reflux. Study recorded cough during pH measurement. n=71. ‘causality cannot be established until effective treatment’ available.