Generic Name: Esomeprazole (no generic available — U.S. patent expires May 2014)
Common Brand Name: NEXIUM™ (AstraZenica Pharmaceuticals — U.S.)
Popularity: 23rd most commonly prescribed drug between 2002 — 2009 (U.S.)
Class: PPI (proton pump inhibitor)
Treatment Uses — Treatment of duodenal ulcer disease, GERD (gastroesophageal reflux disease) and erosive esophagitis. Prophylaxis against (and treatment of) gastric ulcers. Part of multidrug regimens for H. pylori eradication to reduce risk of duodenal ulcer recurrence. NSAID (non-steroidal anti-inflammatory drug) associated gastropathy prevention. Treatment of pathologic gastric hypersecretory conditions (such as Zollinger-Ellison syndrome). Used to improve pulmonary function in children with cystic fibrosis. May be used for treatment of Barrett’s esophagus. Esomeprazole has been studied for treatment of asthma but did not demonstrate effectiveness except when study patients also had GERD.
PPIs (proton pump inhibitors) work by blocking an enzyme that tells the stomach to produce more acid. Excessive amounts of acid cause heartburn, damage the lining of the stomach (leading to ulcers), and when regurgitated backwards up the esophagus, result in significant heartburn and damage to the lining of the esophagus. Other medications used to treat these symptoms include over-the-counter antacids and H2 blockers (a class of drugs that work to reduce stomach acid production through a different mechanism).
For long term (four to eight weeks or longer) relief of pain and for healing certain ulcers, PPIs are more effective than H2 blockers. Typical PPI doses block more than 90 percent of stomach acid secretion versus 50-80 percent blockade seen with H2 blockers. H2 blockers, however, work faster (45-60 minutes) than PPIs (days), which makes antacids or H2 blockers the preferred treatment for sporadic heartburn or when immediate symptom relief is desired. Clinically significant heartburn associated with GERD is defined as two or more incidences of heartburn each week for more than two months.
Dosing and Administration — For duodenal, gastric, and NSAID-associated ulcer treatment or erosive esophagitis from GERD, initial oral dosing in adults is 40 milligrams once daily. The manufacturer recommends a maintenance dose in adults of 20 milligrams once daily following initial treatment. Recommended treatment lengths span from four to 16 weeks, depending on the condition and response, followed by lower maintenance doses, not to exceed six months total duration.
Concerns about longer term use of PPIs stem from increased circulating levels of the hormone gastrin. In rats, this has accelerated growth rates of gastrointestinal cancers. Whether the same holds true for humans is unknown. Several conditions, like chronic heartburn from GERD, require prolonged or repeated courses of treatment since symptoms often return within five days of discontinuing PPI therapy.
Higher doses of esomeprazole are required for hypersecretory conditions, usually starting at 60 milligrams orally each day (for adults) up to 90 milligrams twice daily. Pediatric doses are lower than adult doses for all conditions and are both age and weight driven.
The starting dose for GERD with erosive esophagitis in children aged 1 to 11 years-old is recommended at 10 milligrams once daily for those weighing less than 20 kilograms, and 10 to 20 milligrams once daily for those over 20 kilograms. For GERD with persistent heartburn in children aged 12 and older, 20 to 40 milligrams once daily is the recommended starting dose for up to eight weeks. For ages 1 to 11 years, 10 milligrams once daily is recommended for up to eight weeks. There are no published data on the safety and efficacy of esomeprazole in children less than 1 year old.
In practice, the most common use of esomeprazole is for treatment of GERD or suspected GERD. While an initial starting dose of 40 milligrams once daily is typical, downward titration to the lowest effective dose should be the goal once symptoms are in good control. Resolution of symptoms is likely to take between four and eight weeks before downward dosing titrations can be attempted. Recent safety data have led the FDA to recommend against more than three courses of esomeprazole therapy per year in any patient (see Cautions and Warnings below) although, in the real world of GERD, many patients require continuous dosing to control symptoms.
The most common form of esomeprazole is a delayed-release capsule. It is also available as a packet used to prepare a delayed-release oral suspension. All contain enteric-coated granules or microgranules that should not be crushed or chewed. An intravenous form of esomeprazole is available for either bolus or continuous infusion.
Esomeprazole should be taken in the morning on an empty stomach to optimize benefits. In two studies, taking esomeprazole with a meal or within 30 minutes after eating reduced the peak levels of drug in the blood by 50 percent. Delayed-release esomeprazole capsules should be swallowed whole; the granules in the capsule should not be chewed or crushed. If unable to swallow, the capsule can be opened and the intact granules sprinkled on applesauce, pudding, cottage cheese, or yogurt.
The mixture should be swallowed immediately. Capsules can also be opened and mixed into 2 ounces of orange, apple, tomato, V-8, grape, pineapple, or prune juice then consumed within 30 minutes. Esomeprazole capsules can be opened and placed in a 60 milliliter catheter tipped syringe then mixed with 50 milliliters of water for administration down a feeding or gastric tube. It is important to flush the tube after administering the medication to assure all granules are washed from the lumen of the tube to prevent clogging.
No dosage changes are necessary in patients with renal failure. Dosage reductions of esomeprazole should be considered in patients with liver dysfunction (hepatic insufficiency) because the drug is extensively metabolized in the liver with starting doses recommended at 20 milligrams daily (instead of the 40 milligrams daily for healthy adults). Although clearance is reduced in geriatric patients, repeated daily dosing does not seem to accumulate esomeprazole; dosage adjustments are not necessary in the elderly.
Overdoses ranging up to 2,400 milligrams in adults have caused confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth and other side effects often experienced with normal dosing. Esomeprazole is unlikely to be removed from the body by hemodialysis. Treatment should be supportive.
Pharmacology/Pharmacokinetics/Stability — After oral administration of esomeprazole, peak concentrations are seen in the bloodstream within 1 to 1.6 hours although actual therapeutic effects of this drug do not correlate well with blood concentrations. Initial inhibition of gastric acid secretion occurs one to two hours after a single oral dose, and improves with consecutive dosing.
With 40 milligram dosing, mean time to a sustained reduction in heartburn (GERD) is five days; healing of erosive esophagitis occurs in the majority of patients within four weeks. Times are slightly longer with 20 milligram dosing. The duration of acid secretion inhibition is at least 17 hours after a 40 milligram dose and 11 hours after a 20 milligram dose. The liver is responsible for nearly all esomeprazole metabolism. About 80 percent of esomeprazole is excreted in the urine, and 20 percent in the feces. Esomeprazole is believed to be excreted in human breast milk; hence there may be risks to breastfed infants. Maternal benefit should be weighed against possible infant risk when breast feeding.
Multiple rabbit and rat esomeprazole studies have shown no congenital abnormalities or adverse pregnancy outcomes. These include 57 times human doses in rats and 35 times human doses in rabbits. Studies comparing pregnant women taking esomeprazole to women not using a PPI during pregnancy show no differences in congenital abnormalities in their newborns. There are no adequate, well-controlled esomeprazole human studies in pregnancy although another PPI (omeprazole, a racemic compound of esomeprazole) has had several reports of congenital abnormalities believed associated with the drug and, in high dose rat and rabbit studies, omeprazole also produced embryo/fetal toxicity. Absent further study, esomeprazole should only be used during pregnancy if absolutely needed.
The mechanism of action of esomeprazole is through binding to digestive tract enzymes known as the proton pump resulting in a blockade of the final stage of acid production in the gastric cells. Unlike H2 blockers, PPIs like esomeprazole do not have anticholinergic or histamine blocker properties.
NEXIUM is supplied as 20 and 40 milligram delayed-release capsules that are opaque, hard gelatin purple colored capsules, hence the common nickname, the “Purple Pill.” The 20 milligram capsules have two radial bars in yellow around them with the word NEXIUM 20 mg in the yellow.
The 40 milligram caps have three yellow radial bars with NEXIUM 40 mg in the yellow. Delayed release oral suspension is supplied as a fine yellow powder mixed with white to pale brown and yellow granules packaged in a unit dose packet. NEXIUM should be stored at room temperature between 59-86 F and protected from light and moisture using a tight, light-resistant container.
Cautions and Warnings — In most patients, PPIs are relatively safe. Years of use recently revealed two troubling side effects, both affecting older patients. In May this year, the FDA issued a safety warning and revised labeling for all PPIs alerting prescribers and patients of a possible increased risk of hip, wrist, and spinal fractures with long term PPI use. Those at greatest risk appear to be patients over 50 years old taking PPIs for more than one year or those using higher doses.
PPIs have also recently been implicated in reducing the effectiveness of clopidogrel (Plavix®), a platelet inhibitor given to patients at risk of thrombus (blood clots). The nearly half reduction in Plavix effectiveness when taken with a PPI leads to a significant increased incidence of strokes, heart attacks, blood clots, stent clotting and overall cardiovascular deaths.
It is not possible to attenuate inhibiting effects by staggering dose times of Plavix and a PPI. Until more data are available, PPIs should be avoided when possible in patients who require Plavix. PPIs have also been implicated in an increased incidence of both community acquired and hospital acquired pneumonias (CAP and HAP).
CAP risk increases with short-term use (therapy started within the past 30 days), but does not continue with long-term use. HAP risk is increased in non-intubated patients taking a PPI. Previous studies suggesting increased risk of cardiovascular events in patients taking PPIs were reviewed by the FDA in 2007.
Patients taking esomeprazole were found not to have any increased risk of cardiovascular problems. Caution should be observed in the presence of liver dysfunction. Perhaps the most important warning about esomeprazole applies to all PPIs, “symptomatic response does not exclude malignancy.”
When symptoms appear caused by gastric acid irritation, it is not uncommon to prescribe a trial period of PPI therapy prior to considering costly, invasive tests. When PPI therapy resolves symptoms, the positive response may lead to a conclusion that the responsible culprit is indeed GERD, a hypersecretory condition, or even an ulcer that has begun healing.
Unfortunately, symptoms from esophageal and gastric cancers often respond well to PPI therapy. Hence, the warning: symptomatic response to esomeprazole does not exclude the presence of cancer.
Important Side Effects and Interactions — The most common side effects of esomeprazole are headache (5 to 5.5 percent of patients), diarrhea (4.3 percent), abdominal pain (3.8 percent), nausea (1 to 10 percent), and constipation (1 to 10 percent). Rarely, more serious side effects have been reported, but whether esomeprazole played a causal role in most of these cases is uncertain.
Seventeen drugs are reported to interact with esomeprazole, few of which are supported by good documentation. As mentioned earlier, esomeprazole should be taken on an empty stomach, preferably in the morning. Because PPIs reduce stomach acidity, they can potentially interfere with absorption of drugs where acid is an important component of assimilation.
One such drug is iron supplements and, although theoretical, gastroenterology clinicians consistently discover iron deficiency anemias in long term PPI users. Iron supplementation may be needed, and patients taking a PPI should maintain a high index of suspicion for signs of anemia (general weakness, tiredness). Taking this drug with food significantly reduces effectiveness. Of reported food-drug interactions with esomeprazole, cranberry juice increased gastric acid so significantly that regular consumption of cranberry juice should be avoided during PPI therapy.
Average Costs — U.S.
• 20 mg /40 mg delayed release capsule (brand name NEXIUM)
Patient cost: $6.30 per 20 mg capsule/$5.90 per 40 mg capsule
Large Hospital cost: $0.24 for either strength
*( Wal Mart® and Target don’t include esomeprazole in their $4/month programs)
Consumer Reports, in conjunction with the Oregon Health & Science University Drug Effectiveness Review Project (DERP), sponsor a website called Best Buy Drugs (see references). This site provides consumers plain English reviews of scientific and evidence based literature on the effectiveness and safety of commonly prescribed drug classes.
There is no evidence that any one of the five PPIs available in the US is better than another when used at comparable doses. One PPI (omeprazole) is available over-the-counter (OTC) at an average cost of $0.64 per tablet. Compared to over $6 per dose of esomeprazole, Consumer Reports notes that considerable savings could be available, especially for people without insurance coverage for PPIs.
References:
1. MICROMEDEX Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed September, 2010).
2. Albany Medical Center Pharmacy, Albany, New York.
3. Consumer Reports Best Buy Drugs. The Proton Pump Inhibitors. May, 2010 update. Available online: www.CRBestBuyDrugs.org.
