Jeff Prescott, PharmD, RPh

This article was sponsored by AbbVie, Inc.

 These are some of the ongoing challenges associated with pancreatic enzyme replacement therapy (PERT) that highlight the clear need for increased pharmacist-to-patient engagement. In this article, we will discuss appropriate medication administration and the role of pharmacists in managing PERT (TABLE 1

DIGESTIVE ENZYME SECRETION ORIGINATES IN THE PANCREAS

In healthy adults, normal pancreatic functioning enables the body to properly digest and absorb nutrients.

 The primary role of the pancreas is exocrine function, with 85% of the organ responsible for the secretion of digestive enzymes, water, and bicarbonate into the duodenum.

 The release of enzymes helps people properly digest fats, carbohydrates, and proteins.

WHEN EXOCRINE PANCREATIC FUNCTION IS INSUFFICIENT

Exocrine pancreatic insufficiency (EPI) occurs when the pancreatic enzyme activity in the intestinal lumen is reduced below the minimum level needed to maintain normal digestion.

 Certain underlying conditions that affect the pancreas are associated with EPI (TABLE 2

 Two major effects of EPI include maldigestion of fat and malabsorption of nutrients, such as fat-soluble vitamins, including A, D, E, and K.

 Patients with EPI may experience symptoms resulting from undigested fat passing through the gastrointestinal tract.

These symptoms can vary, but may include steatorrhea (bulky, oily, foul-smelling stools), diarrhea, unexplained weight loss, flatulence, bloating, and abdominal pain.

From March 1, 2010, to February 1, 2016, more than 7 million PERT prescriptions were filled in the United States (FIGURE

PERT is prescribed to help mimic the physiological pattern of pancreatic exocrine secretion, delivering enzymes into the duodenum together with food.

 PERT includes 3 types of enzymes: lipases, amylases, and proteases, which help the body break down and absorb fats, carbohydrates, and proteins, respectively.

To be effective in managing EPI, PERT must be taken appropriately to ensure that both enzymes and food reach the duodenum at the same time.

ACCURATE DOSING OF PERT IS ESSENTIAL FOR EPI MANAGEMENT

The prescribed PERT dose should be individualized and adjusted based on weight, fat content of the patient’s diet, degree of steatorrhea, and clinical symptoms.

 These criteria should also be used for titrating patients to the appropriate dose.

According to the Cystic Fibrosis Foundation (CFF) Consensus Conference Guidelines, weight-based enzyme dosing for patients 4 years or older should begin at 500 lipase units/kg/meal, adjusting to a maximum of 2500 lipase units/kg/meal, if needed (TABLE 3

 The total daily dose should not exceed 10,000 lipase units/kg.

Using a fat-content-of-the-diet approach, patients will typically need between 500 lipase units and 4000 lipase units per gram of fat ingested per day.

The total daily PERT dose should reflect consumption of approximately 3 meals and 2 or 3 snacks per day.

 Typically, only half the prescribed dose is needed for snacks.

Although PERT has been proven efficacious in the treatment of EPI, nutrient and fat absorption depend on appropriate weight-based dosing.

 It is important to continue to assess a patient’s response to therapy to help ensure accurate dosing.

If patients are still experiencing symptoms after PERT initiation, they should be encouraged to have a follow-up visit with their physician.

THE REALITY OF PATIENT EXPERIENCE ON PERT

Despite PERT being the standard of care for EPI treatment, a review of prescription data shows that nearly 37% of new PERT patients (not including those with cystic fibrosis) did not refill their prescription.

The CFF Consensus Conference Guidelines define poor response to therapy as patients continuing to experience abdominal complaints (such as pain, bloating, and flatus), abnormal stool movement (such as loose or frequent stools, overt diarrhea, and symptomatic steatorrhea), and/or poor development in children (caused by malnutrition) despite treatment with PERT.

 If patients are experiencing any of these symptoms, there may be possible factors that are causing them to have a poor response to treatment (TABLE 4

Consumption of PERT with food contributes to the effectiveness of managing EPI.

 PERT has been proven to be effective when taken in tandem with high-fat diets compared with low-fat diets.

 Low-fat diets can also be connected to insufficient intake of fat-soluble vitamins.

 Therefore, it is important to note that fat reduction is no longer considered a part of the management plan for EPI due to chronic pancreatitis.

It is essential that patients understand the importance of taking PERT with milk or snacks that contain fat, at a dose that is typically half of their prescribed dose.

Here is what patients should know before starting PERT

PERT should be taken with every meal and snack

Sporadic doses (not taken with food) should be avoided

Dosage should not be changed or increased without physician direction

Patients who are prescribed PERT should also consider seeing a dietitian to ensure they are consuming the recommended amounts of fats and calories.

For example, in patients with cystic fibrosis, the CFF Consensus Conference Guidelines recommend that “patients should consume a high-calorie diet with unrestricted fat which is appropriate for age and clinical status.”

Articles

Pancreatic Enzyme Replacement Therapy: A View From Behind the Counter

Ilevro (nepafenac ophthalmic suspension) is approved to reduce pain and inflammation resulting from cataract surgery.

The FDA approved Alcon Laboratories, Inc’s, Ilevro (nepafenac ophthalmic suspension) 0.3% to reduce the pain and inflammation resulting from cataract surgery. The original approval took place in October 2012, but a labeling revision was made in December, and the official drug marketing launched in late January 2013. The lower strength nepafenac 0.1% is also available as branded Nevanac ophthalmic suspension and was approved by the FDA in 2005 for inflammation associated with cataract surgery.

Ilevro is a topical non-steroidal anti-inflammatory prodrug that penetrates the cornea and is converted to a potent active metabolite, amfenac, by ocular hydrolases. Surgical trauma that occurs in ophthalmic surgery activates cyclooxygenase (COX) enzymes that yield prostaglandins, or inflammatory mediators. Both compounds are thought to inhibit COX enzymes, which results in inhibition of prostaglandin production. An advantage of Ilevro is its non-polar structure, which allows effective corneal penetration to a greater extent than other NSAIDs. Ilevro’s rapid penetration minimizes contact time with the cornea, resulting in less corneal damage and fewer adverse effects. Peak concentration of Ilevro occurs between 30 and 45 minutes. Concentrations of Ilevro many times higher than therapeutic levels were not shown to affect CYP45 metabolism; therefore, drug—drug interactions involving this pathway are unlikely.

Ilevro is only available as a sterile ophthalmic suspension in a 1.7-ml and 4-ml bottle. Patients should shake well before use and instill 1 drop of Ilevro into the affected eye once daily starting 1 day before cataract surgery, on the day of surgery, and up to 2 weeks into the postoperative phase. It is also recommended to instill 1 drop into the affected eye at least 30 to 120 minutes prior to surgery. There are no drug interactions between Ilevro and other ophthalmic agents such as beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, cycloplegics, or mydriatics. However, if more than 1 agent is administered, they should be instilled at least 5 minutes apart to ensure adequate drug delivery.

A double-blind randomized controlled trial assessed efficacy between nepafenac 0.3%, nepafenac 0.1% (Nevanac), and a nepafenac vehicle given 1 day prior to surgery, administered on the day of surgery, and continued into the first 2 weeks of the postoperative period. The primary outcome was clinical cure of inflammation at 14 days postoperative, defined as a score of 0, indicating no aqueous flares or aqueous cells were present. Other outcomes included clinical cure at 7 days postoperative and maintenance of clinical cure at 4 separate visits post—treatment cessation. Results concluded that inflammation and pain resolution were similar between Ilevro and Nevanac, but significantly improved between Ilevro and the vehicle alone. A second randomized controlled trial comparing only Ilevro and a vehicle confirmed these results. Ilevro was superior to the vehicle in resolving inflammation and pain at 7 and 14 days post-surgery. The benefit of Ilevro was demonstrated as early as 1 day post-surgery compared with vehicle. The patient was considered successful if they were declared cured and remained cured at subsequent visits. Additional clinical trials are ongoing to determine clinical significance in ocular surgeries other than cataract surgery.

Contraindications, Warnings, and Precautions

Ilevro is only contraindicated in patients with known hypersensitivity to any of its ingredients or other NSAIDs. The most serious adverse effects that may result from Ilevro are delayed healing, increased bleeding time, and keratitis or corneal inflammation. Contact lenses should not be worn while administering Ilevro. Serious damage can occur to the eyes if the bottle becomes contaminated, so taking measures to prevent contamination is essential (ie, avoid touching tip of dropper to eye). Ilevro has not been shown to cause teratogenic effects in rat and rabbit models; however, since no well-controlled studies have been performed in women, Ilevro is pregnancy category C but should be avoided in late pregnancy and in nursing women. Safety in pediatric patients aged under 10 years has not been established and there were no observed differences in the elderly population.

Jeff Prescott, PharmD, RPh, is senior vice president of clinical and scientific affairs at

 Nicole Braccio is a PharmD candidate at the Ernest Mario School of Pharmacy at Rutgers University.

Alcon Laboratories, Inc's Ilevro

Eliquis (apixaban) tablets are approved to reduce the risk of stroke and systemic embolism in adults with nonvalvular atrial fibrillation.

The FDA approved Bristol-Myers Squibb’s and Pfizer’s Eliquis (apixaban) tablets to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation. The December 2012 approval excludes atrial fibrillation as a result of a heart valve defect, as these patients were not studied in clinical trials. Atrial fibrillation is a serious heart rhythm disorder that has traditionally been treated with warfarin, an older-generation anticoagulant with a narrow therapeutic index, monitoring requirements, and many drug and food interactions. Eliquis is the third addition to a new generation of anticoagulant drugs inciting market competition with Pradaxa (dabigatran), a direct thrombin inhibitor, and Xarelto (rivaroxaban), another factor Xa inhibitor.

Apixaban is a reversible and selective inhibitor of free and clot-bound factor Xa, which decreases thrombus development and indirectly inhibits thrombin-induced platelet aggregation. Apixaban’s prolonged absorption yields a 12-hour half-life, allowing twice-daily dosing to provide adequate anticoagulation. Apixaban is 50% bioavailable and maximum concentrations are achieved 3 to 4 hours after administration. Apixaban is metabolized mainly through CYP3A4 pathways with no active metabolites and is also a substrate of P-glycoprotein. Co-administration with strong CYP3A4 inhibitors may require dosage adjustment, and use with strong inducers is not recommended.

Eliquis is available in 2.5-mg and 5-mg tablets. The recommended dose for most patients is 5-mg orally twice daily with or without food. The recommended dose is 2.5 mg twice daily for patients concomitantly taking CYP3A4 or P-gp inhibitors or for patients with 2 of the following characteristics: age >80 years, body weight <60 kg, or serum creatinine >1.5 mg/dL. The tablets should be swallowed whole with a glass of water and not crushed, chewed, or dissolved. Use in hepatically impaired patients has not been studied and Eliquis should be avoided in severe impairment.

The ARISTOTLE study, a double-blind randomized controlled trial with more than 18,000 patients, compared efficacy of Eliquis 5 mg or 2.5 mg twice daily to warfarin dosed to target INR of 2.0-3.0. Outcomes included incidence of hemorrhagic stroke or systemic embolism as well as major bleeds. After an average duration of 1.8 years, the study determined that fewer patients experienced stroke while taking Eliquis, 1.27% per year, versus warfarin, 1.6% per year. Also, fewer patients in the Eliquis group were observed with major bleeds, 2.13% per year, compared with warfarin, 3.09% per year.

The ARISTOTLE study concluded that Eliquis is non-inferior to warfarin for stroke and embolism prevention as well as better tolerated with less therapeutic monitoring, fewer drug and food interactions, and a wider therapeutic index. The other new anticoagulants, dabigatran and rivaroxaban, showed similar results with respect to stroke prevention; however, Eliquis also decreased risk of major bleeds, including intracranial hemorrhage.

Eliquis is contraindicated in patients with active bleeding or severe hypersensitivity. The most prominent adverse effect of Eliquis is the increased bleeding potential. Inform patients on identifying signs of bleeding such as blood in the vomit or stool, unexpected pain, or unexpected bleeds that may last a long time. Other medications used for treatment or prevention of blood clots may enhance the bleeding risk. There is no known agent to reverse the anticoagulant effects of Eliquis, which may persist for up to 24 hours after the last dose; however, activated charcoal may be useful in an overdose or accidental ingestion.

Other adverse effects observed in clinical trials include hypersensitivity reactions involving skin rash, syncope, and anaphylaxis in <1% of patients.

 It is important to inform patients that abruptly stopping treatment with Eliquis can increase their chance of having a stroke. Eliquis holds a pregnancy category B, although no well-controlled studies have been conducted in pregnant women. Women should not breast-feed while taking Eliquis because it is unknown whether the drug passes into breast milk. Eliquis has not been studied in pediatric patients and is not approved for this population.

Jeff Prescott, PharmD, RPh, is Senior Vice President of Clinical and Scientific Affairs at Intellisphere, LLC. Nicole Braccio is a PharmD Candidate at the Ernest Mario School of Pharmacy at Rutgers University.

		Eliquis [package insert]. Bristol-Myers Squibb Company, Princeton, NJ; December 2012. http://packageinserts.bms.com/pi/pi_eliquis.pdf. Accessed February 7, 2013.

		Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. 

		Walsh S. FDA approves Eliquis to reduce the risk of stroke, blood clots in patients with non-valvular atrial fibrillation [press release]. US Food and Drug Administration website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333634.htm. Accessed February 7, 2013. 

Bristol-Myers Squibb's and Pfizer's Eliquis

Helping patients understand their regimen can boost adherence.

What are anticlotting agents? They are medications that are used to prevent clots from forming in the blood or to shrink clots that have already formed. You may have heard these medications called “blood thinners.” There are different types—antiplatelets and anticoagulants&mdash;and the reason why a person may have to take them depends on the doctor’s diagnosis.

Anticlotting drugs are very important, even though taking them may not make you feel any different. Severe consequences could occur if treatment is not taken seriously. For many people, adding this drug regimen—and sticking to it&mdash;is lifesaving.

There are many proteins, chemicals, and clotting factors in blood that are normally in balance, allowing your blood to flow properly and nourish your cells. Some help the blood clot when you get an injury, and others break the clots down when you are healing. This is normal. Problems arise when clots form and fail to dissolve.

Clots in the veins can occur when there is low blood flow, along with too much clotting factor in the blood. Clots in the arteries happen due to artery plaque buildup and cardiovascular disease. These situations can become damaging and even life threatening, especially when the clots block blood circulation from the legs or major organs such as the brain, the heart, or the lungs. Dangerous clots can occur without warning.

In the brain, a clot is known as a stroke, and in the heart, it is called a myocardial infarction or heart attack. You may be at higher risk for a heart attack or stroke if you:

• Have a family history or previous history of heart attack or stroke

• Have certain conditions, such as diabetes, irregular heartbeats, high blood pressure, high cholesterol, or plaque in your arteries

In the lungs, a clot is called a pulmonary embolism (or PE), and in the legs, it is known as a deep vein thrombosis (or DVT). The risk for these conditions doubles every decade past 50 years of age. You may also be at higher risk for a PE or DVT if you:

• Are pregnant or take drugs containing estrogen

• Have a severe illness or cancer or are bedridden or paralyzed

To prevent these events from happening, your doctor will prescribe you medications that he or she thinks will be the safest and most effective for you. Remember that medication alone is not the only answer to improving your health. It is very important for you to have a healthy lifestyle with proper nutrition and exercise.

Anticoagulants such as warfarin, heparins, fondaparinux, or dabigatran work by blocking vitamin K or inactivating other clotting factors in the blood. Antiplatelets such as aspirin, dipyridamole, ticlopidine, and clopidogrel prevent clotting by blocking thromboxane, a chemical that rounds up clotting cells in the blood.

These medications all require careful management because they “thin out” your blood and can make you bleed more easily. Avoiding situations where you may fall or become injured is crucial to preventing these serious bleeding events.

If you notice unusual bleeding, such as blood in your urine or stool, if you are coughing up or vomiting blood, or if you have unexplained severe bruising, skin color changes, headache, dizziness, reoccurring nosebleeds, or heavier than normal menstrual bleeding, seek medical attention. There are specific instructions on how you can manage each medication, so talk to your doctor or pharmacist for more details

Ms. Chen is a PharmD candidate at the Ernest Mario School of Pharmacy at Rutgers University, and Dr. Prescott is vice president of Clinical and Scientific Affairs for Pharmacy Times.