INTRODUCTION

Did you know that all living cells need potassium to maintain cellular fluid balance? Potassium has many benefits. First, it helps muscles to contract. Second, it helps maintain blood pressure. Third, it helps regulate bodily fluids inside cells (intracellular). However, having too much potassium (hyperkalemia) may have a negative impact. Hyperkalemia may cause arrhythmia (irregular heart rhythm), which could be life-threatening. Hyperkalemia can be categorized into two main types: acute and chronic. Patients with chronic kidney disease are especially prone to elevated potassium levels.¹

Consider these situations:

• Gonzalez comes to your pharmacy with a prescription for patiromer. The pharmacy technician attempted to bill her insurance, but the drug required prior authorization. What do you do next? What are the elements of a prior authorization process?
• Williams comes to your pharmacy complaining about edema (swelling due to excess fluid). He has been taking sodium polystyrene sulfonate (SPS). His doctor asks you, the pharmacist, to recommend an alternative to SPS because of the sodium load concern. What would your response be? What would you recommend to replace SPS?

Acute and chronic hyperkalemia continue to present as major medical dilemmas for healthcare professionals. There is no universally accepted guideline to treat them, and there is no universally accepted classification and monitoring frequency for hyperkalemia. Newer potassium binders, such as patiromer and sodium zirconium cyclosilicate (SZC), may allow optimal use of renin-angiotensin-aldosterone system inhibitor (RAASi) therapy in patients with hyperkalemia. However, these newer therapies are costly alternatives to traditional treatment.

Helping patients navigate the health insurance prior authorization process to seek coverage is a challenging task for pharmacists and pharmacy technicians. If a patient comes to your pharmacy with a prescription for a potassium binder, are you fully equipped to provide the patient with information regarding dosing, storage, and insurance authorization?

Simply put, hyperkalemia is a general medical term that describes a higher-than-normal potassium level in the blood. Normally, a person’s extracellular (outside the cells/in the blood) potassium concentration falls between 3.5 to 5 mmol/L. Mild, moderate, and marked hyperkalemia are defined as potassium levels between 5 to 5.9 mmol/L, 6 to 7 mmol/L, and exceeding 7.0 mmol/L, respectively. While mild hyperkalemia requires monitoring and diet restriction, moderate and severe hyperkalemia may cause cardiac complications.²

 

Epidemiology of Hyperkalemia

Hyperkalemia is a common occurrence. A 2016 American study of 194,456 outpatients found that over a 3-year period, 10.8% of patients had potassium levels greater than 5 mEq/L and 2.3% of the patients had potassium levels greater than 5.5 mEq/L.³ A 2017 study conducted in a large Swedish healthcare system followed 364,955 participants over three years.⁴ The researchers defined hyperkalemia as potassium exceeding 5 mmol/L and moderate/severe hyperkalemia as potassium exceeding 5.5 mmol/L. Hyperkalemia occurred in 25,461 individuals (7%), and 9,059 individuals (2.5%) had moderate/severe hyperkalemia.⁴

 

Elevated potassium levels are more common in patients with chronic kidney disease (CKD) than in patients without CKD. One study involving four clinical centers and 820 patients in the United States (U.S.) found that 8% of patients with CKD had hyperkalemia.⁵ A study involving 55,266 patients with glomerular filtration rate (GFR) less than 60 (an indicator of kidney dysfunction) enrolled in a managed care organization in the U.S. found that 5% of patients had potassium levels at or exceeding 5.5 mEq/L and 20% experienced potassium levels at or exceeding 5 mEq/L.⁵ A French study involving 1,038 patients found that 17% of those with stage 2 through 5 CKD had potassium levels at or exceeding 5 mEq/L.⁵ An additional study that enrolled 36,359 patients with stage 3 or 4 CKD found that 3% had potassium levels at or exceeding 5 mEq/L.⁵

Hyperkalemia’s History

Sir Humphry Davy at the Royal Institution in London first isolated potassium in 1807 using electrolysis of dry molten caustic potash (KOH, potassium hydroxide). Potassium is an alkali metal and silvery-white in color. It consists of 19 electrons and 19 protons. At 20°C, it has a density of 0.862 g/cm. Potassium is present in all meats, plants, and dairy products and is abundant in fruits and vegetables.⁶

 

Potassium is important for maintaining cellular function. All cells have a sodium-potassium ATPase (Na+ -K+ ATPase) exchanger, which is partially responsible for maintaining the membrane potential. This serves as a basis for conduction of nerve impulse and stabilization of blood pressure.⁷ A diet rich in potassium has been associated with reducing blood pressure, lowering the risk of stroke and nephrolithiasis (kidney stones), and improving bone health.

 

The body maintains potassium homeostasis through various means. Total body potassium content is achieved by alterations in renal (kidney) excretion of potassium in response to potassium intake. Insulin and beta-adrenergic tone (responsiveness of the autonomic nervous system) help regulate extracellular and intracellular content of potassium.⁷ In short, extreme low and high potassium levels are not compatible with life.

 

PAUSE and PONDER: Did you know that a higher-than-normal potassium level (hyperkalemia) can cause neuromuscular symptoms such as muscle cramps and cardiovascular symptoms such as irregular heartbeat? What causes hyperkalemia?

 

Causes and Clinical Manifestations

Hyperkalemia has many causes, including but not limited to, tissue injury, insulin deficiency, exercise, medications, and excess dietary potassium intake^8,9:

• Trauma, massive hemolysis (destruction of red blood cells), and tumor lysis (rapid breakdown of cancer cells) may cause tissue injury, which in turn may cause hyperkalemia.
• Insulin deficiency may cause hyperkalemia. Insulin regulates glucose concentration in the plasma and also causes potassium to move into cells until the kidneys have sufficient time to excrete the dietary potassium load and re-establish total-body potassium content.
• During exercise, potassium is released from skeletal muscle cells and accumulates in the interstitial compartment (a small space in a tissue or between parts of the body), where it exerts a vasodilatory effect (widening of blood vessels).
• Medications may cause hyperkalemia by interfering with the renin-angiotensin-aldosterone system (RAAS). RAAS is a normal cascade that functions in the homeostatic control of arterial pressure, tissue perfusion, and extracellular volume. While many medications may offer cardiovascular benefits by deregulating the RAAS, they can cause concurrent hyperkalemia because the RAAS facilitates potassium excretion in the kidneys.
• Medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), beta-blockers (e.g., atenolol, metoprolol, propranolol), cyclosporine, and tacrolimus may cause hyperkalemia by impairing the release of renin.
• Angiotensin-converting-enzyme inhibitors (ACEi) such as benazepril, captopril, enalapril, lisinopril, perindopril, and quinapril block the formation of angiotensin II. Angiotensin-receptor blockers (ARBs) such as azilsartan, candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan prevent angiotensin II from binding to its adrenal receptor. Both mechanisms contribute to the development of hyperkalemia.
• Heparin causes hyperkalemia by interfering with aldosterone biosynthesis in the adrenal gland.
• Amiloride, pentamidine, triamterene, and trimethoprim block sodium reabsorption in the collecting tubule and reduce the negative potential of the lumen. By doing so, they reduce potassium secretion from the kidneys.
• Spironolactone and eplerenone prevent aldosterone from binding with its receptor and increase the likelihood of hyperkalemia.

Excess potassium intake contributes the development of hyperkalemia. Table 1 lists foods and their elemental potassium contents. Patients with CKD should adhere to a low potassium diet, but patients often find this difficult in real-world scenarios.¹⁰ In addition, potassium-rich diets (foods with more than 200 mg per serving are considered potassium-rich) have numerous health benefits including blood pressure reduction, reduction in risk of CKD progression, and cardiovascular disease and stroke prevention. A low potassium diet may present a treatment dilemma because it may prevent patients from receiving these benefits.¹⁰

To prevent hyperkalemia, limited dietary potassium intake is necessary. Patients who are diagnosed with hyperkalemia or at risk of developing hyperkalemia should limit potassium intake from all sources including food, salt substitutes, and supplements to about 40 to 60 mEq (mmol) per day.¹¹

 

Table 1. Potassium Content of Selected Common Food and Salt Substitutes¹²

Food	Elemental Potassium Content
	Milligrams (mg)	Milliequivalents (mEq)*
Milk	350	9
Apricot (5)	480	12
Avocado	300	7-10
Banana	451	12
Cantaloupe (1/4)	412	11
Kiwi	252	6
Nectarine	288	7
Orange	300	7
Papaya (1/4)	390	10
Peach	305	8
Prunes, 5 dried	365	9
Raisins (1/2 cup)	553	14
Watermelon (1/16)	560	14
Juices (serving size 4oz = 1/2 cup = 120ml)
Apple juice	148	4
Grapefruit juice	210	6
Orange juice, frozen	252	7
Pineapple juice	148	4
Prune juice	301	8
Tomato juice	225	6
Nuts (serving size 1oz = 30 g)
Almonds, dry roasted	210	5
Cashews	187	4
Salt substitutes (serving size ¼ cup)
Examples: NoSalt, Nu-Salt	610-795	15-20
Vegetables (Serving size 8 oz = 1 cup = 240ml)
Acorn squash, cooked	896	23
Beets	530	13
Broccoli, frozen, cooked	332	9
Brussel sprouts, cooked	494	13
Butternut squash, cooked	583	15
Collards, frozen, cooked	427	11
Kidney beans, cooked	713	18
Lentil, cooked	731	19
Lettuce, 1 head Boston	419	10
Mushrooms	550	14
Pinto beans, cooked	800	20
Potato, baked with skin	844	21
Potato without skin	600	15
Pumpkin, canned	506	12
Soybeans, cooked	972	24
Spinach, raw or cooked	838	21
Split peas, cooked	710	18
Sweet potato, baked with skin	350	9
Tomato	251-273	7
White navy beans, cooked	669	18
Zucchini, cooked, sliced	456	12

*Also equivalent to millimoles (mmol)

 

PAUSE AND PONDER: In a reported case, an individual chewed and ingested burnt match heads in a condition called cautopyreiophagia. This activity resulted in a plasma potassium concentration of 8 mmol/L and contributed 80 mmol of daily potassium intake. What signs of hyperkalemia did he probably experience?

Hyperkalemia is usually asymptomatic. However, neuromuscular and cardiac abnormalities may develop as hyperkalemia worsens. Neuromuscular manifestations of hyperkalemia can include paresthesia (tingling or prickling) and fasciculations (muscle twitching) in the arms and legs.⁸ Severe hyperkalemia can cause paralysis that leads to flaccid quadriplegia (paralysis of all four limbs).⁸ In addition to neuromuscular abnormalities, hyperkalemia may lead to electrocardiogram (ECG) changes. Hyperkalemia causes ECG changes in a dose-dependent manner ¹³:

• Potassium levels between 5.5 to 6.5 mEq/L: ECG will show tall, peaked T waves
• Potassium levels between 6.5 to 7.5 mEq/L: ECG will show loss of P waves
• Potassium levels between 7 to 8 mEq/L: ECG will show widening of the QRS complex
• Potassium levels between 8 to 10 mEq/L: ECG will produce cardiac arrhythmias, sine wave pattern, and asystole

 

These cardiac abnormalities can lead to dysrhythmias and death.¹³

TREATING HYPERKALEMIA

In acute hyperkalemia, patients with potassium levels exceeding 6 mmol/L or patients have who hyperkalemia with any new ECG changes should be referred to a healthcare facility with cardiac monitoring. Kidney Disease: Improving Global Outcomes (KDIGO) recommends monitoring vital signs and cardiac changes.¹⁴ In hyperkalemic patients with ECG changes, KDIGO recommends treatment with calcium chloride, insulin, and beta-agonists. In patients with concomitant metabolic acidemia (lower blood pH), KDIGO recommends sodium bicarbonate. Subsequently, KDIGO considers the use of potassium-binding drugs and loop diuretics. KDIGO suggests dialysis in cases of persistently elevated potassium concentrations exceeding 6 mmol/L or ECG changes that are unresponsive to medical management.¹⁴

Treatment of Acute Hyperkalemia

Acute hyperkalemia is generally defined as a serum potassium concentration exceeding the upper limit of normal that is not known to be chronic.¹⁴ Currently, clinicians use no universal classification or monitoring for hyperkalemia. Similarly, no universally accepted treatment guidelines for acute and chronic hyperkalemia exist. Clinicians should not initiate treatment of acute hyperkalemia solely based on serum level of hyperkalemia; they should also consider patients’ clinical manifestations (e.g., ECG changes). Treatment options for acute hyperkalemia may include intravenous calcium gluconate, insulin, inhaled beta-agonists, intravenous sodium bicarbonate, and dialysis. Table 2 expounds on these treatment options.¹¹

 

Table 2. A Summary of Treatment Options for Acute Hyperkalemia¹¹

Treatment Option	Dosage	Advantage(s)	Disadvantage(s)
Intravenous calcium gluconate	1 gram via IV piggyback (small bag of solution attached to primary infusion line). Repeat in 5 minutes if needed	Fast onset	Dose not lower potassium level, only normalizes ECG changes
Intravenous insulin	5–10 units or 0.1 units/kg, maximum 10 units	Fast onset, most reliable treatment	Usually given with dextrose to minimize hypoglycemia
Inhaled beta-agonists (e.g., albuterol)	10–20 mg via nebulizer	Fast onset	Inconsistent effect, nonselective beta-blockers such as propranolol and sotalol may be less effective
Intravenous sodium bicarbonate	50 mEq, which is equivalent to 50 ml of 8.4 % sodium bicarbonate over 5 minutes. Repeat in 30 minutes as needed	Work best with acidosis (pH < 7.2)	Variable onset of action
Dialysis	Treatment given daily or a few days a week	Reliable treatment to remove waste, effective method to attain norkalemia	Extensive equipment and knowledge required to conduct treatment

ECG, electrocardiogram; IV, intravenous.

Intravenous calcium gluconate for acute hyperkalemia works by stabilizing membrane potential and normalizing ECG changes to prevents irregular heart rhythm. However, it does not lower serum potassium levels. It’s duration of effect ranges from 15 minutes to one hour. It may cause adverse effects such as local irritation, hypercalcemia (elevated calcium levels), hypotension (low blood pressure), and bradycardia (slowed heart rate). If no effect is observed in five minutes, another dose may be given.¹⁰

Intravenous insulin works by shifting potassium from extracellular to intracellular space. It has an onset of 15 to 30 minutes and a duration of four to six hours. It may cause hypoglycemia (low blood sugar) and hypokalemia (low potassium levels). Clinicians typically give intravenous insulin with glucose to prevent hypoglycemia during acute hyperkalemia treatment.¹⁰

Inhaled beta-agonists act within 30 minutes to redistribute potassium from the extracellular to intracellular space. It has an onset of 30 to 60 minutes and duration of effect from two to four hours. Adverse effects include tachycardia (elevated heart rate), tremor, vasoconstriction (narrowing of blood vessels), and hyperglycemia.¹⁰

Intravenous sodium bicarbonate is another option to treat acute hyperkalemia. It lowers serum potassium levels by increasing potassium elimination through the urine. It has an onset of action of 30 minutes to four hours and a duration of effect of approximately two hours. Possible adverse events include hypocalcemia, metabolic alkalosis (elevated blood pH), hypernatremia (elevated sodium), fluid overload, worsening hypertension, and heart failure.¹⁰

Patients may receive one of two types of dialysis: peritoneal dialysis or hemodialysis. Peritoneal dialysis uses the lining of the abdominal cavity to filter body waste. A surgeon places a catheter in the abdominal cavity. The dialysis solution enters the abdominal cavity through the catheter and will drain out of the abdominal cavity. Hemodialysis, uses a machine to remove excess water and waste products. A machine removes blood from the body and infuses it through a filter. A dialysate solution flows on the other side of the membrane and draws impurities from the blood. Dialysis is an effective treatment for hyperkalemia.¹⁵

Pause and Ponder: SPS used to be the “gold standard” in treating chronic hyperkalemia. What are the newer potassium binders? Are they safe and effective?

Treatment of Chronic Hyperkalemia

Chronic hyperkalemia is defined as recurrent episodes of elevated serum potassium concentrations.¹⁰ Treatment options include loop diuretics, RAASi dose modification, identification and removal of hyperkalemia-causing medications, and potassium binders.¹⁰

Loop diuretics—often used for other indications, such as hypertension and heart failure—increase urinary potassium excretion at the collecting duct of the kidney. Providers commonly use furosemide, a loop diuretic, in chronic hyperkalemia. They often prescribe them with thiazides, ACEIs, and ARBs. However, loop diuretics have their limitations. They may cause volume depletion (reduced blood volume) and their effectiveness declines as renal function declines.¹¹

Another treatment option for chronic hyperkalemia is the modification of dosage or interruption of RAASi therapy. No generally accepted guidelines regarding this strategy in patients who experience hyperkalemia exist. However, the European Society of Cardiology recommends patients continue or titrate RAASi treatment to optimal doses in the event of mild hyperkalemia levels between 5.1 and 5.5 mEq/L and moderate hyperkalemia levels between 5.6 and 6 mEq/L.¹⁶

Potassium binders—including SPS, SZC, and patiromer—are one of the most promising treatments for chronic hyperkalemia. In general terms, a patient will consume fluids with potassium binders. Potassium binders bind to potassium in the bowel and exchange with calcium, sodium and/or hydrogen, usually at the colon. The body will then excrete the potassium in the feces.¹⁷ Table 3 displays onset of action, mechanism of action, and common adverse effects of potassium binders.¹⁰ Note that all potassium binders have a relatively slow onset of action, making them inadequate therapies for acute hyperkalemia.

 

Table 3. Selected Characteristics of Available Potassium Binders^{10, 20, 18, 19}

Drug	Onset of Action	Mechanism of Action	Adverse Effects	Usual adult starting dose
Patiromer	7 hours	Potassium binding in exchange for calcium in GI tract	Abdominal discomfort, constipation, diarrhea, nausea, flatulence, hypomagnesemia	8.4 grams orally once daily
Sodium zirconium cyclosilicate (SZC)	1–6 hours	Potassium binding in exchange for hydrogen and sodium in GI tract	Constipation, diarrhea, nausea, vomiting, mild-to-moderate edema	5 grams orally once daily
Sodium polystyrene sulfonate (SPS)	2-6 hours	Potassium binding in exchange for sodium in GI tract	constipation, diarrhea, nausea, vomiting, gastric irritation, hypomagnesemia, hypocalcemia, edema, hypokalemia, systemic alkalosis, intestinal necrosis	15 to 60 grams orally daily

GI, gastrointestinal.

 

SPS, approved by the Food and Drug Administration (FDA) in 1958, has been the “gold standard” and the lone potassium binder for several decades. Its mechanism of action is potassium binding in exchange for sodium in the gastrointestinal (GI) tract. However, its adverse effect profile is unfavorable and erratic. In fact, the FDA issued a warning for SPS regarding the risk of colonic necrosis (tissue death) and other GI adverse effects when used with sorbitol in 2009.¹⁰

Patiromer is a potassium binder approved by the FDA in 2015. It works by binding potassium in exchange for calcium in the GI tract. To date, it has not caused serious adverse effects. Most of the adverse effects are GI disorders (e.g., constipation).¹⁰ Approved in 2018 by the FDA, SZC is the newest potassium binder. Its mechanism of action differs from patiromer. It binds potassium in exchange for hydrogen and sodium in the GI tract and its main site of action is in the small and large intestines. No serious adverse effects have been reported. Adverse effects are mild and usually GI disorders such as constipation.¹⁰ Veltassa (patiromer) comes in single-use packets containing 1 gram, 8.4 grams, 16.8 grams, or 25.2 grams. User should store Veltassa in the refrigerator at 2°C to 8°C (36°F to 46°F).²⁰

Lokelma (SZC) comes in packets containing 5 grams or 10 grams. User should store Lokelma at 15°C to 30°C (59°F to 86°F).¹⁸

COMPARING PATIROMER AND SZC

Patiromer and SZC are safe and effective treatments for chronic hyperkalemia. They allow for continuance and optimal doses of RAASi in patients who develop hyperkalemia secondary to RAASi use. They also enable patients to experience optimal hemodialysis outcomes and can ease the dietary potassium restriction. Providers select a potassium binder based on safety and efficacy, cost, insurance coverage, and roles in the treatment of chronic hyperkalemia, which are discussed in detail below.

Cost and Insurance Coverage

Newer potassium binders are costly alternatives to traditional drugs for hyperkalemia. Table 4 lists their estimated out-of-pocket costs as of December, 25, 2023 according to GoodRx. The cost difference between patiromer and SZC is relatively small.²¹

Table 4. Estimated Out-of-Pocket Costs of Patiromer and SZC²²

Drug	Units	Cost
Patiromer	8.4 g x 4 Packs	$ 181.53
	8.4 g x 30 Packs	$ 940.61 – 989.34
	16.8 g x 30 Packs	$ 940.61 – 989.34
	25.2 g x 30 Packs	$ 940.61 – 989.34
Sodium zirconium cyclosilicate (SZC)	10 g x 11	$ 289.27 – 324.67
	10 g x 30	$ 782.16 – 871.05
	5 g x 11	$ 289.40 – 324.67
	5 g x 30	$ 781.61 – 782.16

 

Typical monthly costs associated with patiromer and SZC might be unaffordable for many Americans. However, the vast majority of patients have health plan coverage. (Note that the insurance discussions below are current as of January 2023.)

The Humana website reveals that some Humana Medicare plans cover all doses of patiromer at tier 3 (i.e., they are covered with a prior authorization), while some plans cover only select doses of SZC. These Humana plans include, but are not limited to, Humana Gold Plus HMO H5619-150, Humana Community H7621-002, Humana Gold Plus HMO H5619-148, Humana Walmart Value Rx Plan PDP, Humana Basic Rx Plan PDP, and Humana Premier Rx Plan PDP.²³ (Note that an HMO is a type of insurance with a network of contracted physicians and a PDP is a Medicare Part D prescription drug plan.)

A cursory check on Scan Health Plans website reveals that Scan Medicare plans appear to cover all doses of patiromer at tier 3, while SZC is not on formulary. These Scan health plans include but are not limited to, Village Health, Scan Classic, and Scan Venture. These plans require a prior authorization on patiromer.²⁴

The Wellcare website indicates that Wellcare Medicare plans cover patiromer at tier 3 without a prior authorization. These plans include but are not limited to Wellcare Classic PDP, Wellcare Value Script PDP, and Wellcare Medicare RX Value Plus PDP. Interestingly, the Wellcare Dual Align 129 plan covers SZC at tier 1 and it requires no prior authorization. It’s important to remember that a covered drug does not mean free. Patiromer’s yearly copay costs (what a patient is required to pay) may exceed $2000, and SZC can cost patients more than $1000 annually.²⁵

Manufacturers of both SZC and patiromer offer $0 per month copay savings cards. To use these cards, patients must have commercial insurance that does not cover the full prescription cost or be uninsured and responsible for the full prescription cost. Patients who are ineligible for these savings cards include those who are^26,27

• enrolled in Medicare Part D, Medicaid, Medigap, Veterans Affairs, Department of Defense programs, or TriCare
• Medicare eligible and enrolled in an employer-sponsored group waiver health plan or government-subsidized prescription drug benefit program for retirees

Pharmacy staff can assist cash-paying patients without insurance contact drug manufacturers to inquire about their patient assistance programs.

Breaking Down the Prior Authorization Process

As noted, some health insurance plans require a prior authorization to cover the newer potassium binders such as patiromer and SZC. This means the insurance company requires extra steps to determine whether a specific medical treatment, procedure, medication, or service is medically necessary and covered under a patient's health insurance plan. Pharmacists and pharmacy technicians can initiate the prior authorization process. Familiarity with the prior authorization process for various insurance plans is imperative for pharmacy staff. Although insurance plans have different forms and requirements within the prior authorization process, the basic steps are the same.

The major steps of the prior authorization process are as follows:

1. Download prior authorization forms from the insurance company website to determine what they require
2. Collect laboratory values, medical history, diagnosis, medical justification, drug history, rationale for request, and other pertinent patient information
3. Complete the prior authorization forms
4. Fax completed prior authorization forms to the insurance company or upload them via online platforms
5. Start the appeal process if denied

Pharmacists can enlist pharmacy technicians’ help to perform most or all of these steps.

The prior authorization process can take up anywhere from one day to more than a week. It is important to explain to patients that a prior authorization requirement does not mean a medication is not covered. It simply means that the insurance company might need more information before it covers the medication.

Pharmacy staff can sometimes initiate an appeal process if the insurer denies the medication. The most common reason for rejection/denial is insufficient supporting information. The other common reason for rejection/denial is drug class exclusion. For example, some Medicare part D plans do not cover certain drug classes. Once the provider or pharmacy submits an appeal, the insurance company usually takes one to two days to respond. Remember that manufacturer sponsored patient assistance programs can help patients who cannot afford the copay and patients who do not have insurance, and pharmacy staff can help patients with enrollment.

Table 5 lists the contact information for selected insurance plans. However, most tasks or inquiries can be handled online.

Table 5. Contact Information on Selected Insurance Plans^28,23,24,25

Plan	Department	Phone number
Humana	Humana Clinical Pharmacy Review Department	800-555-2546
Express Scripts	Express Scripts Coverage Review Department	800- 753-2851
Scan	Medical Reviews Department	844-424-8886
WellCare	Pharmacy Appeals Department	855-538-0453

 

Safety and Efficacy of Patiromer

The phase 2, multicenter, open-label, randomized AMETHSYT-DN trial determined patiromer starting doses for a phase 3 study and evaluated the long-term safety and efficacy of patiromer in 306 outpatients with hyperkalemia. The mean reduction from baseline in serum potassium level at week 4 or time of first dose titration in patients with mild hyperkalemia was 0.35, 0.51, and 0.55 mEq/L for groups starting at 4.2 g twice daily, 8.4 g twice daily, and 12.6 g twice daily, respectively.²⁹ For patients with moderate hyperkalemia, the reduction was 0.87, 0.97, and 0.92 mEq/L for patients starting at 8.4 g twice daily, 12.6 g twice daily, and 16.8 g twice daily, respectively.²⁹

From week four through week 52, AMETHYST-DN researchers observed statistically significant mean decreases in serum potassium levels. Over the 52-week-long trial, hypomagnesemia (7.2%) was the most common treatment-related adverse event and mild to moderate constipation (6.3%) was the most common GI adverse event. The researchers concluded that patiromer starting doses of 4.2 to 16.8 g twice daily resulted in statistically significant decreases in serum potassium levels after four weeks of treatment, lasting through 52 weeks.²⁹

The OPAL-HK clinical trial assessed the safety and efficacy of patiromer with an initial treatment phase and a withdrawal phase.³⁰ Among 237 patients in the initial treatment phase, the mean change in serum potassium level was -1.01 mmol per liter. Among 107 patients in the randomized withdrawal phase, the median increase in potassium levels from baseline of that phase was greater with placebo than with patiromer. The most common adverse effect in the initial treatment phase was constipation (11%), followed by diarrhea (3%), hypomagnesemia (3%), and nausea (3%). The most common adverse effects of the randomized withdrawal phase in the patiromer group were headache, supraventricular extra systoles (heart rhythm irregularities), constipation, diarrhea, and nausea; all occurred in 4% of all patients.³⁰

Safety and Efficacy of SZC

The phase 3, multicenter, randomized, double-blind, placebo-controlled HARMONIZE clinical trial evaluated SZC’s efficacy and safety for 28 days in outpatients with hyperkalemia at 44 sites in the U.S., Australia, and South Africa over six months.³¹ Patients received 10 g of SZC three times daily in the initial 48-hour open-label phase. Of the 258 patients, 237 patients achieved normokalaemia (normal potassium levels) with levels between 3.5 and 5 mEq/L and were randomized to receive SZC 5 g, 10 g, or 15 g or placebo daily for 28 days. In the open-label phase, serum potassium levels declined from 5.6 mEq/L at baseline to 4.5 mEq/L at 48 hours. In the randomized phase, serum potassium was significantly lower during days 8 through 29 with all SZC doses compared to placebo. Adverse events were comparable between SZC and placebo. Edema occurred more often in the 15 g group. Compared with placebo, all three doses of SZC resulted in lower potassium levels and a higher proportion of patients with normal potassium levels for up to 28 days.³¹

The double-blind, placebo-controlled, phase 3b multicenter DIALIZE study evaluated SZC for the management of hyperkalemia in patients undergoing hemodialysis.³² The researchers randomized adults with end-stage renal disease (ESRD) who were managed with hemodialysis three times weekly to SZC or placebo. These patients had pre-dialysis hyperkalemia and received SZC 5 g once daily on non-dialysis days. The researchers titrated doses to maintain normokalaemia over four weeks in 5 g increments to a maximum of 15 g. About 41.2% of patients in the SZC group responded to treatment compared with 1% of the 99 patients receiving placebo. Serious adverse events occurred in 7.3% of patients in the SZC group and 8.1 % of patients in the placebo group.³²

CASE STUDIES

Hyperkalemia usually occurs as a result of other illnesses. Certain medical conditions such as advanced stages of CKD, heart failure, hypertension, diabetes, myocardial infarction, and/or any combinations of these conditions increase the risk of hyperkalemia.¹⁰ Treating the underlying diseases may alleviate the severity of hyperkalemia. While it’s critical to treat the whole patient, certain comorbidities are of utmost importance, including those imposing the greatest risks of morbidity and mortality. The key is to prioritize treatments according to the risks. Heart diseases, stroke, diabetes, and kidney diseases ranked first, fifth, eighth, and tenth, respectively, in the top 10 leading causes of death in the U.S. in 2021.³³

Case Study #1

Joan Smith is a female patient born on June 18, 1956. She has been diagnosed with type 2 diabetes, ESRD, osteoarthritis, hypertension, atrial fibrillation, and hyperkalemia. Dr. Bach contacted the pharmacist to conduct a comprehensive medication therapy management (MTM) and suggest an alternative to replace SPS.

Below is a list of selected recent lab values for Joan:

Item	Result	Units	Interval
A1C	9.6 (H)	N/A	< 6.5
BUN	28 (H)	mg/dL	8 – 27
Creatinine	2.3 (H)	mg/dL	0.76 – 1.27
Potassium	5.3 (H)	mmol/L	3.5 – 5.2
Sodium	145 (H)	mmol/L	134 – 144
Chloride	99	mmol/L	96 – 106
Carbon dioxide	26	mmol/L	20 – 29
Calcium	9.1	mg/dL	8.6 – 10.2
Protein, total	8.2 (H)	g/dL	6.8 – 8.0
Albumin (A)	5.0 (H)	g/dL	3.8 – 4.8
Globulin (G), total	3.3	g/dL	1.5 – 4.5
A/G ratio	1.6	N/A	1.2 – 2.2
Bilirubin, total	0.4	mg/dL	< 1.2

A₁C, hemoglobin A1C; BUN, blood urea nitrogen.

Joan is taking the following medications:

• NPH/regular human insulin 70/30 50 units subcutaneously twice daily
• Lisinopril 20 mg orally once daily
• SPS 60 mL orally as needed
• Nephro-Vite 1 tablet orally once daily
• Apixaban 5 mg orally twice daily
• Aspirin 81 mg orally once daily
• Ibuprofen 600 mg orally three times daily

 

Joan’s A₁C is out of range, so she would benefit from tighter blood sugar control. The pharmacist recommended changing NPH/regular human insulin (70/30) to lispro 16 units subcutaneously three times daily before meals and glargine 50 units subcutaneously once daily at bedtime. For Joan’s osteoarthritis, changing ibuprofen to acetaminophen 650 mg by mouth every eight hours is prudent because ibuprofen, an NSAID, may precipitate the development of hyperkalemia. While NSAIDs are not contraindicated in patients with kidney disease, clinicians should use the lowest dose possible for the shortest duration and avoid using NSAIDs at all in patients with severe kidney disease. Clinicians can consider a topical NSAID for mild osteoarthritis pain in smaller joints.³⁴ Joan had mild hyperkalemia as indicated by her laboratory result. Her elevated BUN and creatinine values indicate that her renal function is insufficient. Joan’s sodium level is also elevated at 145 mmol/L. Both SPS and SZC can cause sodium overload, so they might not be the most appropriate choice for Joan. It may not be prudent to discontinue or reduce Joan’s lisinopril dose (RAASi therapy). Joan was advised to follow up with Dr. Bach at the next office visit.

After a thorough teleconference with Dr. Bach, the pharmacist recommends starting patiromer with an initial dose of 8.4 g once daily after discontinuing the SPS. Upon consultation with the patient and her caregiver, the technician reminds them to store patiromer in the refrigerator at 2°C to 8°C (36°F to 46°F). If stored at room temperature (25°C ± 2C° [77°F ± 4°F]), they must use the patiromer within three months. For either storage condition, they must not use patiromer after the expiration date printed on the packet and avoid exposing it to excessive heat greater than 40°C (104°F).²⁰

In addition, the pharmacist inquired about Joan’s use of over-the-counter herbal medications. The pharmacist informed Joan that certain herbal medications or supplements such as noni juice may cause or exacerbate hyperkalemia.³⁵ Unconventional over-the-counter traditional Chinese medicines such as dried skin of toads (Chinese name: Chan Su) may cause poisoning and result in hyperkalemia.³⁶

Case study #2

John Williams is a male patient born on August 29, 1965. He has been diagnosed with hyperkalemia, ESRD, hyperlipidemia, type 2 diabetes, erectile dysfunction, hypertension, and heart failure. His most recent lab values are presented below.

Item	Result	Units	Interval
A1C	11.1 (H)	N/A	< 6.5
BUN	29 (H)	mg/dL	8 – 27
Creatinine	2.45 (H)	mg/dL	0.76 – 1.27
Potassium	4.8	mmol/L	3.5 – 5.2
Sodium	135	mmol/L	134 – 144
Chloride	98	mmol/L	96 – 106
Carbon dioxide	27	mmol/L	20 – 29
Calcium	11.0 (H)	mg/dL	8.6 – 10.2
Protein, total	8.2 (H)	g/dL	6.8 – 8.0
Albumin (A)	5.1 (H)	g/dL	3.8 – 4.8
Globulin (G), total	3.4	g/dL	1.5 – 4.5
A/G ratio	1.5	N/A	1.2 – 2.2
Bilirubin, total	0.5	mg/dL	< 1.2

A₁C, hemoglobin A1C; BUN, blood urea nitrogen.

John is taking the following medications:

• Patiromer 16.8 mg orally once daily
• Metoprolol succinate ER 100 mg orally once daily
• Simvastatin 40 mg orally once daily
• Sildenafil 50 mg orally as needed for sexual activity
• Sacubitril-valsartan 97-103 mg orally twice daily
• Spironolactone 100 mg orally once daily
• Insulin glargine 40 units subcutaneously at bedtime
• Insulin lispro 14 units subcutaneously 15 minutes before each meal
• Semaglutide 2 mg subcutaneously once weekly
• Empagliflozin 25 mg orally once daily
• Calcifediol 30 mg orally once daily

 

John first experienced high sodium levels while on SPS due to the sodium load per dose. Subsequently, John was prescribed patiromer and experienced stomach upset. Dr. Kidd contacts the pharmacist to conduct a comprehensive MTM and suggest an alternative to replace patiromer.

John’s potassium level was within range and his condition has been stable. However, the calcium level (11.0 mg/dL) is elevated. Patiromer might not be the most appropriate choice. The pharmacist recommended considering SZC. John can start on an initial dose of 10 g orally 3 times daily for 48 hours, followed by 10 g once daily thereafter. Sacubitril-valsartan (RAASi therapy) reduces the risk of hospitalization and spironolactone substantially lowers the risk of both morbidity and death among patients with severe heart failure.³⁷ As a result, the pharmacist recommended that John remain on sacubitril-valsartan and spironolactone as prescribed.

John’s glucose level (A₁C) was out of range at 11.1. He would benefit from continuous glucose monitoring (CGM). The pharmacist introduced a commercially available CGM device to John and encouraged him to monitor his glucose level after meals, at bedtime, and at any time John feels there is a need to monitor. To reach A₁C target, John should titrate his basal insulin (glargine) by increasing 2 units every three days and prandial insulin (lispro) by 1 to 2 units twice weekly without hypoglycemia.

The pharmacist asked John about the use of salt substitutes and advised him that some salt substitutes may cause hyperkalemia. Regarding erectile dysfunction, John stated that sildenafil was, “…working somewhat but I need a bit more help. My sex life is not what it used to be. Maybe I can purchase something over-the-counter to spice it up!” The pharmacist discouraged the use of commercially available over-the-counter aphrodisiacs containing digoxin-like substances. Atrial fibrillation, ventricular fibrillation, and death have been reported with their use.³⁸

CONCLUSION

No universally accepted guidelines exist for monitoring and classification of hyperkalemia. Similarly, no universally accepted guidelines exist for dosage modification of RAASi therapy. When selecting drugs to treat hyperkalemia, healthcare professionals should consider factors such as co-existing diseases, duration of action, onset of action, cost, drug interactions, food interactions, cardiovascular benefits, and renal benefits. Newer potassium binders may help optimize RAASi therapy and provide a safe and reliable chronic hyperkalemia treatment option. The use of these newer potassium binders and the optimal use of RAASi therapy may improve cardiovascular outcomes.

 

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INTRODUCTION

“I’ve been shot, and I’ve been stabbed; nothing compares to gout pain.”

This is how Jim, a 77 year old man, describes his pain as he hobbles into the pharmacy to refill his prescription for colchicine. Jim complains that colchicine is not controlling his gout. He is wearing slippers that show his red swollen joint around his right big toe that is warm and painful to touch. Jim says his physician explained that these symptoms are due to podagra, uric acid crystallization and settling in the joint between his foot and big toe.¹ As Jim speaks, his breath projects a strong alcohol smell.

Gout is the most common form of inflammatory arthritis affecting about 9.2 million adults in the United States (US) and is the result of hyperuricemia.^2,3 Men are at higher risk of developing gout than women.⁴ Other risk factors include post-menopause, genetics, end-stage renal disease, and major organ transplant.

Uric acid overproduction, under-excretion, or both, elevate serum uric acid levels.⁵ Underexcretion of uric acid accounts for about 90% of gout cases.⁶ Human bodies produce uric acid as they break down dying tissues.⁴ Other sources of uric acid are foods high in purines, such as meats, seafood, and alcoholic beverages.^{7, 8} Ancient Greek history states that only rich people, who could afford these expensive foods, experience gout.⁹ Therefore, in the 5^th century before Christmas (B.C.), people referred to gout as “the disease of kings.”¹⁰

PATHOGENESIS

Uric acid circulates in the blood as monosodium urate.¹¹ In the kidneys, uric acid and urate undergo filtration and secretion into the filtrate followed by about 90% reabsorption into the blood.¹² The American College of Rheumatology (ACR) guideline defines hyperuricemia as serum uric acid of 6.8 mg/dL or greater, the level above which urate becomes insoluble in the blood.⁴

Gout results from the chronic deposition and crystallization of urate in the joints and tissues.^4,13 Insoluble monosodium urate crystals form stone-like deposits, known as tophi, in soft tissues, synovial tissues, or bones.^14,15 Tophi trigger an inflammatory response, which presents as an acute gout attack.^15,16 However, hyperuricemia does not always result in gout.⁴

Although gout can affect any joint, initial attacks usually involve the big toe joint. Gout attacks are sudden and very painful.¹⁷ Acute gout attacks reach maximum pain level in 12 to 24 hours and may last 3 to 14 days if patients do not seek therapy.¹⁸ For this reason, all healthcare providers including those on pharmacy teams need to educate patients to seek medical care. Effective gout management reduces the risk of long-term complications like degenerative arthritis, urate nephropathy, infections, renal stones, joint fractures, and nerve or spinal cord impingement.¹⁹

 

DIAGNOSIS OF GOUT

Clinicians diagnose gout by collecting patient history, examining the patient, laboratory workup, and imaging.¹⁹ Uric acid crystals in the synovial fluid or tophi in tissues and/or bones confirm gout diagnosis regardless of the uric acid level.⁴

TREATMENT OF GOUT

The ACR guideline describes 3 treatment goals for patients with gout²⁰:

1. Terminating the acute gout attack
2. Preventing future attacks
3. Lowering the serum uric acid level

Terminating the Acute Gout Attack

The ACR published the most recent guideline for the management of gout in 2020. The ACR guideline recommends colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or glucocorticoids (oral, intraarticular, intramuscular) as first-line agents for the treatment of gout flares.²⁰  Patient-specific factors guide the drug choice among the first-line agents. Interleukin-1 (IL-1) inhibitors or adrenocorticotropic hormone (ACTH) are alternative agents.²⁰  If a first-line agent is ineffective, intolerable, or contraindicated, the ACR guideline recommends switching to another first-line agent before trying alternative agents. Topical ice is an adjunct to pharmacologic therapy. The severity of the gout flare guides the treatment duration.

 

Colchicine

Colchicine exerts its anti-inflammatory effects by binding to free tubulin dimers leading to microtubule polymerization inhibition, which affects cellular function.^{21, 22} Colchine has had an interesting history, as the SIDEBAR explains. Common side effects of colchicine are dose-dependent and include diarrhea, nausea, and vomiting.  Because of its mechanism of action, toxic levels of colchicine inhibit cellular division leading to failure of multiple organs .²² Colchicine doses of 0.8 mg/kg are lethal.²³ Colchicine undergoes extensive tissue distribution and therefore, a lower dose can be toxic in patients with liver or renal failure. Some unchanged colchicine undergoes renal excretion through glomerular filtration and therefore, requires dosage adjustment for renal dysfunction.^{21, 24}  Cytochrome P450 3A4 hepatic enzymes metabolize colchicine.^{21, 25} P-glycoprotein facilitates colchicine removal from the body.²⁶ Co-administration of medications that inhibit CYP3A4 enzyme activity (example: grapefruit juice, azole antifungals, erythromycin, verapamil) increase the risk of colchicine toxicity.^{21, 25} In addition, co-administration of colchicine with P-glycoprotein inhibitors (example: digoxin) increases the risk of colchicine toxicity.²⁶ Toxic symptoms are dose-dependent with increasing severity.²⁷ Patients with toxicity may present with gastrointestinal symptoms (nausea, vomiting, diarrhea), hypotension, lactic acidosis, or acute kidney injury.^{22, 27} To decrease the risk of toxicity, colchicine’s prescribing information recommends avoiding its co-administration with P-glycoprotein inhibitors or CYP3A4 inhibitors in patients with renal or hepatic impairment.²⁸ For other patients, the prescribing information recommends weighing risks versus benefits before co-administering colchicine with medications that pose a significant drug interaction.

 

SIDEBAR: HISTORY OF COLCHICINE

Colchicine is derived from a plant, Colchicum automnale.²⁹ Other names for this plant include Autumn Crocus, meadow saffron, naked lady, and colchicum.³⁰ Ebers Papyrus, an Egyptian medical document on herbs dating back to 1500 BC, indicates the use of C. automnale for joint pain.³¹ In 1833, a German pharmacist analyzed the substance and gave it the name colchicine.²⁹ In France, in 1819, a chemist and a pharmacist isolated colchicine from the plant. In 1884, a French pharmacist produced and sold colchicine as 1 mg granules, which is still available in some countries.^29,32 Colchicine accounts for about 0.1-0.6% of the plant content.³³ Non-surprisingly, the C. automnale plant is poisonous. Humans should not ingest the plant. Symptoms of C. automnale toxicity resemble the side effects or toxicity of colchicine.³⁴ These symptoms range from diarrhea, nausea, and vomiting to organ failure and death.

Colchicine was available for decades in the US without a U.S. Food and Drug Administration (FDA) approved labeling.³⁵ Despite the Food, Drug, and Cosmetics Act requiring the FDA to approve medications based on efficacy and safety data, colchicine was grandfathered in. Grandfathered drugs were medications available on market before the Food, Drug, and Cosmetics Act of 1938 or its amendments in 1962.

In 2006, the FDA initiated the unapproved drug initiative (UDI).³⁶ The goal of the UDI program was to decrease the number of medications in the United States that do not carry FDA approval. Under the UDI program, the FDA allowed exclusive marketing to manufacturers who obtain FDA approval. Some pharmacists and pharmacy technicians may recall colchicine shortage as manufacturers of colchicine received warning letters from the FDA to stop selling colchicine.³⁷ Mutual Pharmaceutical Company submitted a new drug application (NDA) for colchicine in November 2008.³⁸ The UDI did not require manufacturers to conduct new clinical trials to obtain FDA approval. Mutual Pharmaceutical Company’s NDA included data from randomized controlled trials in 1974 and 2004 that proved the safety and efficacy of colchicine. As a result, in July 2009 the FDA approved colchicine for the treatment of gout and familial Mediterranean fever. Colchicine came back to the US market under brand name Colcrys.³⁹

 

Colchicine is light sensitive. Pharmacies should protect colchicine from light and dispense it in a light-resistant container.²⁸ The FDA requires pharmacies to distribute a medication guide to patients when dispensing colchicine.⁴⁰ Medication guides inform patients of potential serious adverse reactions and harm mitigation strategies. The Institute for Safe Medical Practices (ISMP) lists colchicine on the look-alike sound-alike (LASA) list due to potential for confusion with Cortrosyn, which is the brand name for cosyntropin.⁴¹  Of note, cosyntropin is a synthetic adrenocorticotropin hormone that has anti-inflammatory properties and is an alternative agent for gout attacks.⁴² In patients with a history of gout, the ACR guideline recommends a “medication-in-pocket” (discussed below) approach to allow early initiation of an anti-inflammatory drug at the onset of a gout flare.²⁰ Since colchicine has anti-inflammatory properties, it is an option for the “medication-in-pocket” approach.

The pharmacist takes a close look at Jim’s prescription refill history to figure out why colchicine is not working for Jim. The pharmacist explores several possibilities:

• Is Jim adhering to his urate-lowering therapy (ULT)?
• Is Jim refilling his colchicine as part of a gout flare prophylactic therapy upon initiating ULT?
• Is Jim asking for colchicine as a “medication-in-pocket” approach?
• Is Jim consuming excessive alcohol?
• Is Jim eating foods rich in purines?
• Is Jim taking any prescription or over-the-counter medications that may increase his uric acid level?

NSAIDs

The FDA has approved indomethacin, naproxen, and sulindac for the treatment of acute gout flare.^{43,44, 45} However, the guideline does not recommend a specific NSAID.²⁰ Choice of agent depends on patient-specific factors including cardiovascular (CV) risk, gastrointestinal (GI) risk, cost, and availability without a prescription.⁴⁶ Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor and therefore carries a low GI risk but is associated with a dose-dependent increase in CV risk.^{47, 48} Ibuprofen carries a low GI risk. Indomethacin, naproxen, diclofenac, and sulindac carry a moderate GI risk.^{49, 50} Among the nonselective NSAIDs, CV risk is highest with diclofenac and lowest with naproxen.⁵¹ Despite differences in CV risk among nonselective NSAIDs, the FDA mandates a boxed warning for all NSAIDs about increased  risk of thrombosis, myocardial infarction (MI), and stroke.^{52, 53} In addition, the FDA requires pharmacies to distribute a medication guide to patients when dispensing a prescription for NSAIDs.⁵⁴ Any NSAID is an option for the “medication-in-pocket” approach.²⁰

Glucocorticoids

The ACR guideline does not recommend a specific oral glucocorticoid.²⁰ Parenteral glucocorticoids (intramuscular, intravenous, or intraarticular) are alternative options for patients who cannot tolerate oral therapy. Glucocorticoids (example: prednisone, methylprednisolone) are an attractive option for patients with chronic kidney disease (CKD) or those who cannot tolerate colchicine or NSAIDs.^1,55 Short-term glucocorticoids do not cause significant side effects.^{56, 57} Glucocorticoids are an additional option for the “medication-in-pocket” approach, including injectable formulations for patients who cannot take oral medications.²⁰ Methylprednisolone is available in different dosage forms such as oral, intramuscular (as acetate or succinate), intravenous (as acetate), and intraarticular (as acetate).⁵⁸

Anakinra

Anakinra is an IL-1 receptor antagonist.⁵⁹ It blocks the activity of the inflammatory mediatory IL-1. Anakinra has an off-label indication for gout attacks at a dose of 100 mg subcutaneously daily for 3 to 5 days.^{60, 61} The ACR guideline classifies anakinra as an alternative agent, particularly due to cost.²⁰ The manufacturer recommends storing anakinra in the refrigerator and protecting from light until ready for administration.⁶² Patients can self-administer anakinra after demonstrating proper administration technique.⁵⁹

ACTH

Adrenocorticotropic hormone (ACTH) binds to melanocortin receptors, which triggers the release of endogenous steroids, thus decreasing inflammation.⁶³ The ACR guideline recommends ACTH as an alternative agent.^20,63 ACTH is available as an intramuscular or subcutaneous injection.⁶⁴ The purified cortrophin formulation carries an indication for acute gouty arthritis.⁶⁵ The manufacturer does not provide a dosing recommendation specific for gout and recommends caution in patients with renal insufficiency.^64-66 The manufacturer recommends storing ACTH in the refrigerator until ready for administration and warming to room temperature before injecting.⁶⁷

Table 1 summarizes the first-line agents for the treatment of gout flares.

Table 1. First-line Agents for the Treatment of Gout Flares20, 24, 44-46, 56, 68-71
Therapy	Dose	Comment	Monitoring parameters
Colchicine	·        Day 1 of therapy: Use treatment dose of 1.2 mg by mouth (PO) as soon as possible then 0.6 mg after one hour. Maximum dose 1.8 mg/day. ·        Day 2 and until flare resolves, use prophylactic dose of 0.6 mg PO once or twice daily.	If creatinine clearance (CrCl) < 30 mL/min:   ·        Use 1.2 mg PO as soon as possible then single dose of 0.6 mg after one hour. Avoid repeating therapy within a 14-day period. ·        Alternatively, use 0.3 mg PO as soon as possible as a single dose. Avoid repeating therapy within 3-7 days.   If patient is on dialysis: ·        Use 0.6 mg PO as a single dose. Avoid repeating therapy within a 14-day period.	Monitor patients with CrCl ≤ 80 mL/min closely for adverse effects.
NSAIDs	·        Indomethacin: 50 mg three time daily until pain is tolerable (usually, 3 to 5 days). ·        Sulindac: 200 mg twice daily until attack resolves (usually, 7 days). ·        Naproxen: 750 mg x 1 dose then 250 mg every 8 hours until attack resolves (usually, 2 days).	·        The manufacturer does not provide recommendations for renal dosage adjustment. ·        The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommends avoiding use of NSAIDs If CrCl < 30 mL/minute.	Monitor GI, renal, and CV toxicity in elderly patients. Prescribe lowest effective dose for the shortest duration possible.
Glucocorticoids	·        Follow specific glucocorticoid dosing recommendation.	Safest option in patients with CKD.	Monitor serum glucose, blood pressure, electrolytes, mood changes, and recurrent infections.

 

Interestingly, a panel consisting of eight patients with gout participated in the development of the 2020 ACR guidelines.²⁰ The patient panel provided valuable input from a patient perspective regarding therapy preference for patients with an established gout diagnosis. The patient panel strongly favored a medication-in-pocket approach for the treatment of acute gout flares. With this approach, the clinician prescribes an anti-inflammatory medication that the patient keeps on hand for use as needed.⁷² Moreover, the patient panel favored an injectable dosage form for the medication-in-pocket to control the pain faster in patients who can take nothing by mouth. The medication-in-pocket approach ensures that patients have quick access to an anti-inflammatory medication at the first onset of gout attack symptoms.²⁰

Jim’s colchicine regimen is consistent with the “medication-in-pocket” to treat an acute gout flare.

MANAGEMENT OF CHRONIC GOUT

The goal of chronic gout management is to lower the serum uric acid level with ULT, if indicated, and to prevent future attacks.²⁰ ULT includes medications that decrease uric acid production or promote uric acid excretion.⁷³ The ACR 2020 guideline recommends a “treat-to-target” approach that guides ULT dose titration and maintenance to achieve serum uric acid of less than 6 mg/dL.²⁰ Lower ULT initial dosing with subsequent titration decreases the risk of gout flare associated with ULT initiation.²⁰

Pause and Ponder: What patient factors determine eligibility for urate lowering therapy (ULT)?

Table 2 provides recommendation on initiation of ULT based on patient-specific factors.

Table 2 - Indication for ULT 20
Patient factors	2020 ACR guideline recommendation	Comment
≥1 subcutaneous tophi	ACR guideline strongly recommends initiating ULT	Moderate or high certainty of evidence that benefits of ULT consistently outweigh the risks
Gout-attributable radiographic damage
≥2 gout flares per year
> 1 flare but < 2 flares per year	ACR guideline conditionally recommends initiating ULT	Low certainty of evidence or no data available and/or benefits and risks closely balanced
First flare and any of the following: ·        Chronic kidney disease (CKD) stage ≥ 3 ·        Serum uric acid > 9 mg/dL ·        Urolithiasis
First gout flare	ACR guideline conditionally recommends against initiating ULT
Asymptomatic hyperuricemia*

*Serum uric acid > 6.8 mg/dL

Pause and Ponder: Which urate-lowering agent is first-line therapy?

Table 3 summarizes urate-lowering medications.

Table 3 - Urate Lowering Medications 20,74-76
Pharmacological class	Mechanism of action	Medication	Comments
Xanthine Oxidase Inhibitors	Inhibition of xanthine oxidase resulting in decreased conversion of hypoxanthine to xanthine and xanthine to uric acid.	Allopurinol Febuxostat	·        Allopurinol is first-line agent. ·        Start allopurinol at ≤ 100 mg/day in normal kidney function and ≤ 50 mg/day in CKD stage ≥ 3 then titrate. ·        Start febuxostat at ≤ 40 mg/day then titrate.
Uricosuric Agents	Inhibition of urate reabsorption in the renal tubules resulting in increased excretion of uric acid in the urine.	Probenecid	·        ACR guideline strongly recommends XOI over probenecid for patients with CKD stage ≥ 3 ·        Start probenecid at 500 mg PO once or twice daily then titrate.
Urate Oxidase Enzyme	Catalysis of uric acid oxidation to water-soluble allantoin resulting in increased excretion of the allantoin in the urine.	Pegloticase	·        ACR guideline strongly recommends against use of pegloticase as a first-line agent ·        Administer pegloticase 8 mg IV infusion every 2 weeks along with methotrexate 15 mg PO once a week with a folic acid supplement. ·        Start weekly methotrexate and folic acid supplementation 4 weeks before initiating pegloticase and continue while on pegloticase.

 

Clinicians usually determine eligibility for ULT when patients present with an acute gout attack.²⁰ Some experts favor initiating ULT two to four weeks after the resolution of a gout attack.⁷⁷ One reason for this practice stems from the fear of gout attack worsening with ULT initiation. The other reason is the perception that during a gout attack, patients are in too much pain to process information regarding chronic therapy. However, the ACR guideline favors initiating ULT during a gout flare as patients may not return for a follow-up visit to initiate ULT after the flare resolves.²⁰

XANTHINE OXIDASE INHIBITORS (XOIs)

XOI include allopurinol and febuxostat.²⁰ XOI are first-line among urate-lowering agents, and the guideline recommends allopurinol as a first-line agent for all patients with gout, unless contraindicated.

Allopurinol

Allopurinol is associated with an increased risk of allopurinol hypersensitivity syndrome (AHS), a rare but severe, and potentially life-threatening adverse reaction.⁷⁸ AHS presents as fever, severe rash, eosinophilia, hepatitis, and acute kidney injury.⁷⁹ AHS is more common in patients who are African Americans or of Southeast Asian descent.⁷⁸ Pharmacogenetic studies show that these patients have a gene on their human leukocyte antigen (HLA) system that increases the risk of developing AHS. This gene is the HLA-B*5801 allele.⁸⁰ The interaction of allopurinol with the HLA-B*5801 allele triggers an immune reaction characterized by T-cell activation.⁸¹ Not all patients who are positive for HLA-B*5801 allele develop AHS.⁸² Risk of AHS increases in HLA-B*5801 allele positive patients who have elevated allopurinol serum level due to dose increase or renal dysfunction.⁸¹

In the US, testing for HLA-B*5801 in Caucasians or Hispanics is not cost-effective.⁸³ The 2020 ACR guideline recommends genetic testing for the HLA-B*5801 allele before starting allopurinol for patients who are African Americans or of Southeast Asian descent.²⁰ The guideline recommends starting allopurinol at a low dose of 100 mg daily for normal renal function and a lower dose in case of renal dysfunction.

The prescribing information recommends protecting allopurinol from light.⁷⁴ ISMP lists the brand name of allopurinol, Zyloprim, on the look-alike sound-alike (LASA) list due to potential for confusion with zolpidem.⁴²

 

SIDEBAR: DID YOU KNOW THAT THE DISCOVERY OF ALLOPURINOL LED TO A NOBEL PRIZE AWARD?

Gertrude Elion, who earned a master’s degree in chemistry from New York University in 1941, worked as a lab assistant for George Hitchings. Up until the 1950s, scientists produced medications by screening and modifying naturally existing substances.⁸⁴ However, Elion and Hitchings’ contribution to medicine was groundbreaking to drug development as they introduced drug therapy that was targeted to specific cells. In 1963, Elion and Hutchings discovered that allopurinol blocked the synthesis of uric acid. In 1988, the Nobel Prize Committee awarded Gertrude Elion and George Hitchings the Nobel Prize in Physiology or Medicine for the discovery of allopurinol and other medications.⁸⁵

 

Febuxostat

Febuxostat carries a boxed warning for increased risk of CV death in patients with cardiovascular disease (CVD), when compared to allopurinol.⁸⁶ Therefore, the 2020 ACR guideline recommends selecting another ULT medication in patients with established CVD.²⁰ For patients who experience a CV event while on febuxostat, the ACR guideline recommends switching to a different ULT medication.²⁰ The FDA requires pharmacies to distribute a medication guide when dispensing febuxostat to patients.⁸⁶

URICOSURICS

Probenecid

Probenecid is the only uricosuric drug approved in the United States.^87,88 Probenecid may cause nephrolithiasis (uric acid stones in the kidneys).⁸⁹ These uric acid stones form as the uric acid crystallizes in an acidic urine. The prescribing information for probenecid recommends adequate hydration and adjunct urine alkalinizing agents (example: sodium bicarbonate or potassium citrate).⁸⁹ However, the 2020 ACR guideline determined insufficient evidence to recommend the routine use of alkalinizing agents with probenecid.²⁰ Probenecid is usually an add-on therapy in patients with partial response to an XOI. Remember to counsel patients on adequate hydration to decrease the risk of nephrolithiasis.

ISMP lists probenecid on the LASA list due to potential for confusion with Procanbid, the brand name for procainamide, an antiarrhythmic drug.⁴² Probenecid also has some interesting abuse potential (see the SIDEBAR).

 

SIDEBAR: CAN PROBENECID HELP ATHLETES IMPROVE PERFORMANCE?

Random drug testing in sports led athletes to misuse probenecid to mask the unlawful use of performance-enhancing drugs such as anabolic-androgenic steroids.⁹⁰ Probenecid inhibits the tubular secretion of anabolic-androgenic steroids in the kidneys, thus inhibiting their excretion in the urine. As a result, urine drug testing will not detect the use of these illegal substance, and athletes can pass the random drug testing successfully. In 1986, a doping control officer traveled from Norway and collected 6 urine samples from 6 Norwegian athletes who were training in the US. The athletes showed up at least 1.5 hours late probably to allow time for onset of action of the masking agent. Five of the samples showed an unusually dilute urine with low specific gravity. In addition, the concentration of endogenous androgenic-anabolic steroids in the urine samples was at least 100 times below normal.⁹⁰ These unusual findings along with suspicious behaviors projected by the athletes during the testing process, triggered further analysis of the urine samples. The lab identified a “new masking agent”, probenecid and its metabolite, in these urine samples. Today, probenecid appears on the World Anti Doping Agency (WADA) prohibited list.⁹¹ The WADA list serves as a standard for identifying substances that athletes may illegally use to enhance performance in sports.⁹¹

 

URATE OXIDASE ENZYME

Pegloticase

The FDA approved pegloticase for adults with chronic gout refractory to conventional therapy.⁹² The 2020 ACR guidelines recommends switching to pegloticase when XOIs, probenecid, and other interventions fail.²⁰ In clinical trials, administering methotrexate with pegloticase increased the chance of tophi resolution by 22.8% compared to pegloticase monotherapy.⁷⁶ Therefore, pegloticase’s prescribing information recommends co-administration with methotrexate, unless contraindicated. Folic acid supplementation decreases the risk of hepatotoxicity and GI side effects associated with methotrexate.⁹³ Pharmacists should counsel patients about the importance of adherence to folic acid while on methotrexate.

The manufacturer recommends storing pegloticase in the refrigerator and protecting it from light before dispensing.⁷⁶ After diluting pegloticase for IV infusion in an institutional setting, healthcare workers should protect the solution from light.

 

Pause and Ponder: When does the guideline recommend switching urate-lowering agents?

The 2020 ACR guideline recommends using the maximum tolerated or recommended dose of a ULT.²⁰  Figure 1 outlines the management of patients taking a XOI requiring adjustment to therapy:

Figure 1. Switching ULT

Jim’s medication profile reveals that he has been taking allopurinol for little over a year now.

 

DURATION OF THERAPY

For patients tolerating ULT, the 2020 ACR guideline recommends indefinite therapy to avoid worsening gout and its associated complications.²⁰ Patients may not adhere to therapy due to cost, pill burden, and low health literacy.⁹⁴ Remember to counsel patient on adherence and goals of ULT as patients may think they do not need to take ULT if they have no symptoms.

PREVENTING GOUT FLARE UPON INITIATION OF ULT

Initiation of ULT may trigger a gout flare due to activation of crystals precipitated in joints.^{95, 96} The risk of gout flare increases with higher reduction in serum uric acid levels. Studies suggest that gout attacks associated with ULT may decrease patient adherence to ULT.⁹⁷ Prophylaxis with anti-inflammatory medications decreases the risk of gout flare upon ULT initiation. The 2020 ACR guideline recommends prophylactic therapy upon initiating ULT and for at least three to six months. Patients who continue to experience flares may require a longer duration of prophylactic therapy.²⁰ Experts recommend colchicine or NSAIDs as first-line prophylactic therapy.⁹⁸ Table 4 summarizes prophylactic medications and recommendations.

Table 4 – Medications that Prevent Gout Attack with ULT Initiation
Medication	Recommendation
Low-dose colchicine	Use 0.6 mg once or twice daily
Low-dose NSAIDs	Use naproxen 250 mg or equivalent dose of different NSAID Add proton pump inhibitor if indicated
Low-dose prednisone or prednisolone	Use less than or equal to 10 mg per day Reserve corticosteroids for patients who cannot tolerate colchicine and NSAIDs

 

NONPHARMACOLOGIC THERAPY AND LIFESTYLE MODIFICATIONS

Serum uric acid levels decrease only slightly with dietary modifications.²⁰ In addition, certain diets may trigger a gout flare. To decrease the risk of flares, the 2020 ACR guideline conditionally recommends the following approaches:

• Limiting alcohol intake
• Limiting purine intake. Some examples of high-purine foods include seafood like sardines, tuna, haddock, and meats like bacon, turkey, veal, and liver.^{99, 100}
• Limiting high-fructose corn syrup intake
• Following a weight loss program if the patient is overweight or obese

Jim projected an alcohol breath when speaking. Jim may be consuming excessive amounts of alcohol. He may be consuming a non-gout friendly diet.

DIGITAL HEALTH AND GOUT MANAGEMENT

Digitalization of health care is rapidly evolving and involves the use of technology to manage health conditions, ameliorate modifiable risk factors, and promote health and wellness.¹⁰¹ Wearable devices such as fitness trackers, patient portals, and mobile apps are only few examples of digital health tools. Investigators suggest that gout mobile health apps may improve patient perception of the disease, clarify beliefs, and benefit self-care.¹⁰² However, further studies are essential to prove these mobile applications beneficial. As of this writing, several gout-related mobile health applications are available. Target users for these applications can be clinicians or patients. For example, a physician developed a mobile application called Gout Diagnosis. The application includes an evidence-based algorithm to facilitate an accurate diagnosis of gout.¹⁰³ On the other hand, patients can download from a variety of existing gout mobile applications at little or no cost.¹⁰⁴ The National Kidney Foundation developed a mobile application called Gout Central. This application comes from a reputable foundation and provides patient education on symptoms and risk factors for gout, nonpharmacologic recommendations such as diet and lifestyle modifications, and medications to treat gout and prevent flares.¹⁰⁴ The FDA does not regulate mobile medical applications.¹⁰⁵ Therefore, the choice of mobile health application depends on patient preference such as cost, ease of use, compatibility, security, and type of content.¹⁰⁶

A mobile application may help Jim learn about foods and drinks that may trigger gout attacks.

PHARMACY TEAM IMPACT ON GOUT MANAGEMENT

Pharmacists are the most accessible healthcare professionals. Patients with a gout flare may seek pharmacists for recommendations on pain management. When patients without a previous gout diagnosis present to the pharmacy, pharmacists may recognize signs of gout and refer them to their primary care clinician. Pharmacists can educate patients who have a diagnosis for gout about the phases and goals of gout therapy, including the likelihood that ULT will be a lifelong therapy.

Pharmacists are well-positioned to assess adherence to ULT and educate patients about the importance of ULT.¹⁰⁷ Pharmacists can assess patient understanding of various therapies and remind them that anti-inflammatory medications treat acute gout attack or prevent gout flare upon initiating ULT. Pharmacists should empower patients to request from their clinician a medication-in-pocket prescription. Pharmacists should counsel patients on the proper use of medication-in-pocket by reminding them to take the anti-inflammatory medication as soon as possible, ideally within 12 hours of onset of a gout attack.¹⁰⁸ In addition, patients may need a reminder about continuing their ULT while taking the medication-in-pocket for acute flares.¹⁰⁹

Pharmacy technicians can ensure that patients have refills on their medication-in-pocket prescription to facilitate early initiation. Updating the patient’s records in the pharmacy software with the gout diagnosis can facilitate this continuity of care. The pharmacy team should encourage patients to fill all their prescriptions at the same pharmacy. Through access to all the patient’s medications, pharmacists and pharmacy technicians can play a crucial role in optimizing gout management by identifying medications that increase serum uric acid levels.¹¹⁰

In addition, the pharmacy team can identify potential drug-drug interactions. This is particularly important with colchicine as it is a substrate for CYP3A4 and P-gp and has a narrow therapeutic window.¹¹¹ In addition, some medications are known to increase serum uric acid levels.²⁰ Advising patients to check with the pharmacy team before purchasing an over-the-counter (OTC) medication can decrease the use of inappropriate medications. When completing transactions at the register, pharmacy technicians are well positioned to identify OTC products that can worsen gout, such as vitamin A or niacin.¹¹² On the other hand, frequent purchase of OTC anti-inflammatory medications like naproxen or ibuprofen may imply uncontrolled gout.

Patients can find educational videos on YouTube to learn more about gout therapy and appropriate diet.¹¹³ Additional resources are available to patients on goutalliance.org. These include videos, podcasts, guides, and awareness events.¹¹⁴ Some patients may like to learn about their condition using gout-related mobile applications.

Pharmacy interns may benefit in hearing from patients about their experience with gout, especially the debilitating pain. This may help future pharmacists empathize and develop better relationships with patients, which can improve patient outcomes.¹¹⁵

The entire pharmacy team could engage in alleviating misconceptions about gout. Some patients with gout have reported stigma regarding their condition from friends, family members, and healthcare workers.¹¹⁶ Some patients with gout have even reported an internalized stigma. Stigmatization may be due to the misbelief that gout is benign, preventable, or self-inflicted.

Did you know that May 22 is National Gout Awareness Day?

Jim states that he feels embarrassed about wearing slippers that expose his swollen toe. The pain is so intense that he is unable to tolerate a close-toe shoe.

Table 5 summarizes some medications that may increase serum uric acid level.

Table 5 – Managing Medications that Increase Serum Uric Acid Level and Risk of Gout Attack20,110,117-119
Medication	Mechanism	Recommendation
Loop and thiazide diuretics Use: hypertension, edema	Decrease urate excretion	The guideline recommends switching to a different antihypertensive and suggests losartan when feasible.
Aspirin (low-dose, 81 mg) Use: prevention of CVD	Increases uric acid renal reabsorption and decreases secretion	The guideline conditionally recommends against discontinuing low-dose aspirin with appropriate indication.
Niacin Use: dietary supplement	Inhibits the enzyme uricase, thus inhibiting the oxidation of uric acid, or decreases uric acid excretion	The guideline does not provide a specific recommendation for niacin-induced hyperuricemia. Experts recommend adequate hydration.

 

After looking into Jim’s medication profile and inquiring about his OTC products, the pharmacist does not identify any medication that may be increasing his serum uric acid level.

CONCLUSION

Gout is the most common type of inflammatory arthritis. Untreated gout can lead to complications such as degenerative arthritis, urate nephropathy, infections, renal stones, joint fractures, and nerve or spinal cord impingement. ULT is indicated for chronic gout management. Allopurinol is the first-line urate-lowering agent. Colchicine, NSAIDs, and corticosteroids are indicated for acute flares, and, in lower doses, for gout flare prophylaxis upon initiating ULT. Diet and lifestyle modifications complement the pharmacologic therapy. The pharmacy team plays a crucial role in identifying drug-induced hyperuricemia and educating patients about the importance of adherence to ULT. Gout flares are painful and debilitating. Pharmacists can recommend initiation of anti-inflammatory therapy for acute gout flares. Pharmacy technicians can ensure patients have refills for their anti-inflammatory medication to facilitate the medication-in-pocket approach.

Jim’s uncontrolled gout may be due to various reasons that pharmacy team can investigate. Inquiring about Jim’s drinking habits and educating him about the negative impact of alcohol on gout management is a necessary first step in his therapy. If an adequate trial of dietary changes does not control his symptoms, then switching to a different XOI or adding probenecid, depending on what he has tried so far, would be appropriate.

 

 

Download CE Activity

INTRODUCTION

A drug information (DI) request is a medication-related question posed by any interested party, but usually a healthcare professional or a patient. As the healthcare team’s drug expert, one of a pharmacist’s main duties is answering these queries effectively and providing an answer that is appropriate for the inquirer’s level of expertise. Pharmacy technicians and pharmacy interns also answer some drug information questions (see TECH TALK SIDEBAR). This continuing education activity outlines various drug information questions that pharmacy staff field most often and describes a methodical approach to ensure pharmacy staff answer requests effectively and accurately.¹

 

 

TECH TALK SIDEBAR: Questions within the Pharmacy Technician’s Scope of Practice?^2,3

Pharmacy technicians and interns can answer general questions that are within the bounds of their education and training. That vague statement requires some interpretation. If the answer is common knowledge (not specialized pharmaceutical knowledge), technicians can answer. In addition to working with supervising pharmacists to interpret the statement, pharmacy technicians and interns need to know state law governing their scope of practice.

 

Pharmacy technicians and interns are often the first point of contact for customers who want over-the-counter (OTC) medications. Technicians can answer general questions about ingredients if the information is on the label. Some examples include

• Does this product contain acetaminophen? What brands of acetaminophen do you stock?
• Where are the medicines for pain?
• Is there a less expensive generic or store brand for this product?
• Do you have any [insert name of prescription medication] in stock?
• Do I need to refrigerate this liquid antibiotic?
• What does “analgesic” mean?
• What does “sustained release” mean?
• Is this prescription for a controlled substance?
• Why can’t I refill this prescription today?

 

Pharmacy technicians and interns can also convey information from the pharmacist but should be careful. A PRO TIP is that if technicians or interns don’t understand what the pharmacist says, they should ask the pharmacist to make the information clearer. And if the answer is long or complicated, they should write it down and recite it back to the pharmacist before transmitting it to the person with the question.

 

Helping customers find specific medications or classes of medications is within the technician’s scope of practice. When patients have questions about their medications, doses, and how best to administer them, technicians may hesitate to answer. If the information is clearly printed on the prescription label, on the auxiliary labels, or contained in an FDA-approved Medication Guide, the technician or intern can answer.

 

Technicians and interns need to work with the supervising pharmacist to determine if they can answer other questions. When in doubt, technicians should consult with or refer the question to the pharmacist. Technicians and interns must refer questions about potential adverse effects, administration problems, possible alternative medications, and clinical issues to the pharmacist. Before referring the patient, they can collect some baseline information. They cannot counsel or give advice, even if the medication is OTC.

 

 

Depending on the practice setting, the nature and complexity of DI requests can vary. Being able to answer DI requests is every pharmacy employee’s responsibility (although the type of information varies and at a certain level, the response is the pharmacist’s primary responsibility). Having an organized approach to answering DI questions is highly relevant when working within the community and hospital settings.⁴

 

Pharmacy employees who work primarily within a community setting can expect to receive DI requests from patients and from practitioners. These requests can range from asking about drug storage requirements (which a technician can usually answer) to consequences of taking an OTC medication in combination with prescription drugs, to requests regarding the safety of a medication for an uncommon or off-label indication. Pharmacists who work in hospital settings can expect to receive most DI requests from colleagues within the care team. For instance, a DI request could come from a prescriber asking about medication absorption and distribution in a patient with comorbid conditions, or from a nurse asking if a medication can be crushed. Pharmacists who work in industry settings, however, may receive medication information requests that vary greatly from those received in clinical settings.⁴

 

All DI requests require referencing reliable materials and sometimes, various internal policy or research documents. While DI requests are diverse, they all require similar analysis of sources and communication to provide a quality answer. Because pharmacy employees at different levels of responsibility can answer DI questions, this continuing education activity will call the person asking the question the requestor and the person finding the answer the respondent.

 

SCREENING THE REQUEST

One of the most confounding situations in the pharmacy occurs when someone asks a question, the respondent spends times finding an answer, and then the requestor says, “Oh, that’s not what I needed to know!” Sometimes, requestors don’t really know how to ask questions effectively. This is a problem that all customer service fields encounter, and answering DI requests is both a clinical function and a customer service. It’s why when you call many customer service lines, the customer service representative will say, “OK, what I hear you asking is….” and then rephrase the question.⁵

 

To answer DI requests effectively, the respondent must thoroughly understand the question.⁵ Very specific questions tend to be easily answerable, while others are more general or vague. In both instances, respondents need to ensure they understand the question. They can rephrase the question in their own words and say, “Let me make sure I understand. Do you mean….”, or they can use open ended questions (questions that cannot be answered with a yes or a no) to ask the requestor to provide more information. This avoids answering a question that wasn’t asked or intended or was poorly formulated.

 

Often, requestors don’t know how to ask a question that will provide the information they need. The hallmark of this type of question is that the requestor may use jargon inappropriately or words that don’t seem to make sense. Respondents can say, “Excuse me, I’m not sure I understood entirely. Can you rephrase the question?” or “Pardon me, but I didn’t quite understand the question. Can you tell me a little more about what you want to know and why?” That final word—WHY—provides the impetus for the requestor to provide necessary information.

 

Once the question has coalesced and both parties agree on its intent, the respondent can solicit important details from the requester and, if applicable, the patient, before delving into a search. At this point, the respondent needs to spend time actively listening to the requestor’s explanations.

 

This can be difficult if the requestor is long-winded, difficult to understand, or cognitively impaired, so it requires patience. Here’s a PRO TIP for listening: it’s called the traffic-light-rule.⁶ During the first 30 seconds (which seems like a short period of time, but is actually relatively long), the requestor’s “talking light” is green. Pharmacy staff should let them talk. In the next 30 seconds, the requestor’s light is yellow: pharmacy staff probably have enough information and should make note of comments or questions. After one minute, the requestor’s talking light is red: pharmacy staff should be comfortable stopping the requestor politely or asking questions.⁶

 

Before continuing, review the following DI requests. How would you proceed? Later  in this activity, we’ll provide a description of the ideal process.

 

Pharmacist DI request #1: TN, 35-year-old obese female (BMI = 32.4 kg/m²) with uncontrolled type 2 diabetes will start on an atypical antipsychotic today to manage schizophrenia. TN’s psychiatric nurse practitioner (NP) calls with questions about drug selection. The NP mentions that TN’s drug formulary lists aripiprazole, haloperidol, olanzapine, and quetiapine as tier 1 preferred options. The NP wants your opinion as to which atypical antipsychotic may be most appropriate to prescribe for TN. What do you suggest?

 

Pharmacist DI Request #2: You work at a tertiary care internal medicine center. MS, an 80-year-old female, was recently admitted to the medicine floor. She had fallen when she was trying to use the restroom at her nursing home and presented to the emergency department with a wrist fracture. She suffers from insomnia and other comorbidities. Her medication list includes lisinopril 20 mg daily, metformin 500 mg twice daily, rosuvastatin 20 mg daily, and lorazepam 0.5 mg PRN anxiety and sleep. The nursing home staff states that MS received more doses of lorazepam in recent weeks. The medical resident believes that the increased lorazepam use could have contributed to the fall and wants to know if trazodone would be a safer replacement for MS’s insomnia. How do you respond?

 

Technician DI Request #1: I left this medication in my bathroom for four days, and then I noticed it says, “Keep in the refrigerator.” My house is cold, and the bottle didn’t feel warm. Is this still good, and if it isn’t, what should I do?

 

Technician DI Request #2: My child is having trouble swallowing her medication and refuses to take it. Are there any easier ways I could give it to her?

 

Identify Critical Information

Although it may seem counterintuitive, beginning with the end in mind is critical and the person gathering information must determine the requestor’s preferred response format. This means asking how the requester wants to receive the response. The respondent will need to adjust the answer according to the requestor’s preferences. Some requestors will want to wait for an answer. If the information is to be communicated through email or an electronic medical record, respondents may use their organization’s required format (a SOAP note or similar formats; see Table 1), but formats used in medical records may not be the most efficient approach in person or over phone. In person or on the phone, respondents need to use a more conversational tone. Furthermore, the respondent will need to determine the requestor’s level of medical competency and tailor the response accordingly. If the requestor is a patient, it is more appropriate to use simple language than if a provider asked the same or  similar question. Respondents will have to evaluate these factors critically to provide a sound and comprehensive answer.⁷

Table 1. Formats for Communicating Critical Information^8,9

Communication Format	Parts of the format	Uses
SOAP	S: Subjective information This section includes descriptive information about a patient’s symptoms, feelings and experiences.   O: Objective information This section includes pertinent lab values, imaging, or diagnostic tests.   A: Assessment In this section the subjective and objective information are taken into consideration to make an assessment regarding the patient's disease states.   P: Plan/ Follow Up This section outlines a detailed plan regarding the patient's treatment and the follow-up and monitoring required.	This format is a widely-used written format in healthcare. It helps organize pertinent patient information and efficiently present an answer. This format is especially useful when the respondent must consider multiple pieces of information.
ISBAR	I: Introduction Introduction of the pharmacist and the respondent, and the pharmacist’s role and location.   S: Situation What are the current events regarding the patient?   B: Background What has happened in the past with the patient?   A: Assessment Identify the problem at hand and make assessments regarding the patient's disease state.   R: Recommendation Outline the next steps and your plan.	This format is beneficial for verbal communication. It helps the presenter explain the problem at hand and the solution in a time efficient way.
TITRS	T: Title Introduction of who you are and your purpose in helping the patient.   I: Introduction Present the patient and the problems that the patient needs help with.   T: Text State subjective and objective information that is necessary to support any recommendations.   R: Recommendation Outline the treatment plan in a clear, complete, and concise manner.   S: Signature Include name, title, and phone number.	This format is beneficial when a brief and concise formal consult is needed to communicate a progress note towards a medical team.

 

Assess the Urgency of the Response

While it is critical to provide an appropriate response for the question, doing so in a timely manner is just as critical. Asking the requestor is the simplest way to determine the expected response time. However, many times the requestor isn’t present or cannot be reached, and it is up to the respondent to determine which questions require immediate responses and which may not. Clinically critical topics include

• Medication safety: does the DI request ask if a certain therapy could cause or have caused harm to the patient?
• Time sensitivity of the treatment: how important is timeliness to the treatment and disease progression?
• How much of a concern is the problem to the requestor: does it seem that the requestor needs an immediate response?

 

Sometimes, respondents don’t know the answer to the question immediately.^10,11 Pharmacy staff will never be able to answer every question, but they can handle every question gracefully and provide a complete, accurate answer within a reasonable time. When they don’t know the whole answer, they should answer what they can immediately and tell the respondent that they need to do a little more research to answer the remainder. A PRO TIP is to tell the requestor when to expect an answer (and to be sure to follow through).^10-12

 

Obtain Sufficient Background Information

In simple words, this step is about getting to know the patient or problem or establishing a strong understanding of the patient’s relevant characteristics by obtaining background information. Since some patients have low health literacy, obtaining this information can be a challenge. However, narrowing the search to only include relevant information and filtering unnecessary information can make the process more efficient. This could be achieved by⁷

• Asking targeted questions to patients. For example, instead of asking patients if they take their medication regularly (a closed-ended question that can be answered with yes or no), asking when they last took their medications provides a more precise answer.
• Identifying avenues that can provide accurate information. For example, instead of asking patients what other medications they take, checking the local profile and/or contacting their community or specialty pharmacist to receive a medication list can be more accurate.
• Reviewing any available records like medical charts or dispensing records.

 

Identify Extraneous Information

Obtaining complete information is important but ensuring that the information is pertinent to the question being asked is just as important.

 

Many times, DI requests are in-depth and require researching two or more sources before arriving at an answer. While conducting this search, ensure that the sources are relevant to the problem at hand. For example, if a study suggests that a medication is contraindicated in a patient, determine if the patient’s characteristics are similar to the study’s population. Furthermore, extraneous information could come from data gathering as well. For example, a patient may have multiple diseases, but they may not all impact the problem at hand. Making this distinction is important to provide a thorough and accurate answer.⁷

 

Answers to Pause and Ponder

Pharmacist DI request #1: Haloperidol is not an atypical antipsychotic; therefore, it would be eliminated immediately and the remaining atypical antipsychotics would be reviewed as outlined below:

Screen Request	Pertinent patient information: past medical conditions (uncontrolled diabetes, schizophrenia). Medications on tier 1 of patient's formulary: quetiapine, olanzapine, haloperidol, aripiprazole.
Reformulate Request	This is a therapeutics drug information request because the provider is looking for the best medication to treat the patient's schizophrenia without adding any contraindications to the patient's current medication list or concomitant medical conditions.
Formulate Response	The provider made the request in writing, so a written response is most appropriate. The SBAR format would succinctly and effectively convey the message. First, we conducted a Google search and a tertiary source search (PubMed) including the pertinent patient information and request. Our search read "effects of antipsychotics on obesity and diabetes." Through this, we determined that some antipsychotics lead to changes in metabolic activity. Because the patient has diabetes that is exacerbated by weight gain, the best choice is an antipsychotic that does not have a significant effect on the metabolism. After conducting a more thorough primary source search on the metabolic effects of antipsychotics, we found that the best drug would be aripiprazole. Additionally, monitoring the BMI and efficacy would be appropriate.
Assess Understanding	Provide the response in a professional and timely manner. Document the request to display accountability and in case there is a similar question in the future. Follow up with the requestor to access the outcomes and ensure that there are no lingering questions or concerns.

 

Pharmacist DI request #2:  Off-label use of low-dose (25 to 100 mg) trazodone, a decades-old antidepressant with drowsiness as a side effect, is common.¹³ In fact, off-label usage for insomnia has surpassed its use for depression.¹⁴ The American Academy of Sleep Medicine does not recommend trazodone because of limited supporting data. A 2018 Cochrane review found equivocal evidence supporting its short-term use for insomnia, but little data on long‐term safety and efficacy exists.¹⁵ The Beers Criteria doesn’t highlight trazodone as a potentially inappropriate medication in older adults, not because of evidence demonstrating safety, but because of lack of studies demonstrating harm. However, a retrospective cohort study found low-dose trazodone was no safer with respect to fall-related injury risk than benzodiazepines among 15,582 nursing home residents aged 66 years and older. Future studies need to confirm trazodone’s safety with respect to other risks such as dependence, withdrawal, and cognitive impairment.¹⁶

 

Technician DI request #1:

It would depend on the medication. Some medications, like amoxicillin, are refrigerated to preserve the taste while most others, such as insulin, are refrigerated to preserve the compound. The technician should ask what medication the patient is referring to and then look up the specific storage requirements for that medication. Some places where this information is available include Drugs.com (https://www.drugs.com/medical-answers/drugs-that-require-cold-storage-166784/) and (https://www.iehp.org/en/members/helpful-information-and-resources?target=emergency-safety). If the medication is not listed in these resources or the medication’s stability has possibly been compromised (such as exposure to extreme heat), the technician should consult the pharmacist.

 

Technician DI request #2:

It would vary depending on the medication. Some medications have specific coating that needs to stay intact to ensure proper drug delivery, and such medications should not be crushed. Other medications do not have such restrictions and can be crushed, split in half, sprinkled in foods like applesauce, or have a liquid formulation that can be considered as an alternative with a doctor’s approval. The technicians should ask, “What medication is your child taking so that I can look it up?” Information regarding which medications can be crushed can be found in the following website https://pharmacist.therapeuticresearch.com/Content/Segments/PRL/2014/Aug/Meds-That-Should-Not-Be-Crushed-7309. If the medication or the specific dosage form is not available on the list, the technician should ask the pharmacist to review the medication.

 

Recognize when to ask for additional support or information. While drug information requests can be challenging, involving other healthcare professionals to hear about their experiences with similar clinical situations can offer a new perspective. Some benefits of consulting with experts include formulating a patient-specific answer to the question whereas a study may be irrelevant. When the request requires analysis beyond the scope of a drug information search, it is appropriate to reach out to a professional. While this may take additional time, arriving at the correct answer is more important than to harm the patient unknowingly. And a PRO TIP is that if reaching out will mean you cannot answer the question in the time frame promised, contact the requestor and say you need more time and why.

 

REFORMULATING THE REQUEST 

To ensure the core request is clear, the respondent will need to ask many questions, especially if requesters don’t know what question they need to ask. Before starting to research the answer, respondents need to gather information needed from the requestor. In addition, it’s prudent to identify resources the requestor has already consulted (and their reliability in case information needs to be corrected).

 

Categorize the Request

Requests can be based on complex patient specific cases, for educational purposes, or geared towards a decision-making process in medication therapy for a specific patient demographic. To fully optimize patient care and provide evidence-based recommendations, it is helpful to ask specific questions and consider all factors pertinent to the specific DI request. Categorizing the request can help stay on track, address all concerns, and point the respondent to the appropriate resources. Table 2 lists common categories and the questions that can clarify the request.

 

Table 2. Common DI Categories and Related Questions¹

DI Category	Related Questions
Allergy/Cross-reactivity	Does the patient have any documented allergies? What caused or is suspected to have caused the allergic reaction? When did the patient take the medication, and when did the reaction occur? What type of allergic reaction occurred? Is this a class or drug specific effect?
Alternative, or Complementary Medicine	Where did the patient obtain the medication? Why is the requestor taking or interested in taking the medication? What other medications or treatments are available?
ADR/Safety	What are the possible side effects? What monitoring parameters need to be considered?
Compatibility (Y-site, syringe, IV)	What solution will medication be used in? If applicable, how will the medications be administered?
Dosage/Route/Administration	What is the route of administration? What is the recommended therapeutic dose for pediatrics, adults, and geriatrics? How should the medication be taken (with/without food, with water, etc)
Drug Identification	What was the source of the medication (e.g., domestic or foreign)? What is the generic and brand name? Where did the medication come from?
Ingredients/Stability	What physical conditions exist? (Temperature, light protectant, storage duration, diluents) Are there IV admixture compatibility/non-admixture stability data available?
Interactions	What are the possible interactions between: ●      Drug-drug ●      Drug-food ●      Drug-lab ●      Drug allergy
Kinetics	What is the onset/half-life/duration? What are the serum levels? Is dialysis a consideration? What is the medication’s bioavailability?
Pharmacoeconomics	Are there other competitors on the market? Are there cheaper alternatives with the same therapeutic effects? What is the AWP pricing?
Pharmaceutics	What is the drug route of administration and drug dosage? What patient factors will affect the drug? Age, weight, gender, organ function, current medications
Pharmacology	What factors will affect drug metabolism and bioavailability?
Pregnancy/Lactation	What health conditions does the mother have? What medications is the mother currently taking? What is the current trimester? How long has the mother been taking the medication or expected to take this medication? Will the drug be present in breast milk? How will the drug affect the infant? What is the infant's age? What health conditions do the mother and infant have? Was the infant a full term or premature delivery?
Vaccinations	Is the vaccination appropriate for the patient? What are some side effects to monitor? When should the patient get the vaccination?
Therapeutics	What is the desired effect? Is the goal cure or prophylaxis? What previous medications and doses has the patient used? Is this medication being used for an FDA approved or off-label use?
Toxicity	What are possible sequelae? What management strategies are available?

Abbreviations: ADR = adverse drug reaction; AWP = Average Wholesale Price; FDA = Food Drug Administration; IV = Intravenous

 

Finding Reliable Sources

Being able to locate sources efficiently and correctly for a DI request is very important. Three main types of sources are available: primary, secondary, and tertiary.

• A primary source is any original research found in journals. Examples of primary sources are trial results found in the New England Journal of Medicine (NEJM) or similar journals in which researchers use a trial design to answer a specific question. (Note that NEJM and similar journals also publish secondary source materials, too.) This is the strongest Limitations of using this evidence include lack of access to journals that require paid subscriptions and lack of good search skills to find relevant papers.
• Secondary sources analyze, interpret, present, or restate information from primary sources. Textbooks, books and review articles, commentaries, guidelines, and Medline are examples of secondary sources.
• Tertiary sources compile information from other sources and organize it. Lexicomp , Micromedex, and DynaMed are common tertiary sources for DI requests as they use information from Food and Drug Administration-approved complete prescribing information (package inserts) and clinical studies. One limitation to be aware of is these sources are not updated rapidly therefore the information could be old and outdated.

 

Determine the Best Source

When evaluating DI requests, in most cases the best course of action is to start with tertiary sources, such as textbooks or DI databases, when possible.¹ These platforms provide a starting point and often suggest a basic idea for the answer. For many DI requests such as dosage, half-life, or adverse effects, the tertiary resource may provide a sound answer. Requests asking to compare two medications’ efficacy or assess the appropriateness of an uncommon or off-label medication use may require further research. Databases that identify off-label use include Micromedex.  In such cases, a primary source is the best resource. References sections of databases like DynaMed and Micromedex can be a great start for finding appropriate primary sources. Using search engines such as MEDLINE, PubMed or Google Scholar (scholargoogle.com) can provide access to relevant primary literature as well.¹ Reviewing two to three sources is good practice for most drug information requests. Respondents must determine the relevance of the studies by evaluating if the trial size was large enough to be statistically reliable, if its findings were clinically significant, and if the patient population is similar to the patient.

 

Use General Search Engines Appropriately

Using general search engines like Google, and Microsoft Edge can be an acceptable starting point for a search. A metasearch engine is usually better. A metasearch engine is a platform that aggregates the results from multiple search engines and organizes them based on their relevance. Examples of metasearch engines include Dogpile, ixquick, and Metacrawler which aggregate information from sources like Google and Yahoo as well as videos posted on various platforms.

Researchers must consider the following factors when determining a source’s credibility¹⁷:

• Is the information’s original source listed and reliable?
• Does the funding for the site come from a sound source such as a university (.edu), an established patient advocacy organization or a professional society (.org), or a government-funded organization (.gov)?
• How is the information presented and how is it supported?
• Who wrote the article on the webpage? Is the author a credible healthcare provider or a journalist writing about a medical topic?
• Is the information updated and verifiable with other sources?

 

Table 3 matches types of information and reliable sources to find information.

 

Table 3. Finding Reliable Sources for Drug Information Requests

Type of Request		Source
Alternative or Complementary medicine		Natural Medicine Comprehensive Database
ADR/Safety		Lexicomp*, UpToDate*, Micromedex*, Package Inserts
Compatibility		FDA-approved prescribing information, Trissel’s Stability of Compounded Formulations*
Dosage/Route/Administration		Complete prescribing information, Lexicomp*, Micromedex*, etc.
Drug Identification		Lexicomp* (Drug I.D) Drugs.com, WebMD Pill identifier, RxResouce.org (pill identification tool)
Ingredients/Stability		Complete prescribing information, Lexicomp*
Interactions	CYP	Complete prescribing information, Lexicomp*
	HIV	HIV Drug Interactions Clinicalinfo Drug Database
Kinetics		Complete prescribing information, Lexicomp*
Pharmacoeconomics		Studies published in pharmacoeconomics journals
Pharmaceutics		PubMed* and primary sources
Pharmacology		Lexicomp*, Micromedex* and could require further research with primary sources
Pregnancy/Lactation		LactMed
Regulatory		The Pharmacy Practice Act, Pharmacist's Manual
Therapeutics		Dynamed*, UpToDate*, DiPiro’s textbook
Toxicity		MSDS, PubChem, Micromedex*
Vaccinations		CDC vaccine and immunization schedule, Lexicomp
Veterinary Information		Plumb’s Veterinary Drug Handbook

*=sources requiring a subscription or payment

Abbreviations: ADR = Adverse Drug Reactions; CDC = Center for Disease Control and Prevention; CYP = Cytochrome P450; FDA = Food and Drug Administration; MSDS = Material Safety Data Sheet;  HIV = Human immunodeficiency virus

 

Another relevant option that many healthcare professionals are considering for answering drug information requests is artificial intelligence (AI) platforms such as ChatGPT. While these seem to be able to provide responses that are based on data and research, the issue that users run into is the AI is not able to approach/appraise situations critically. While AI can provide information that may be or seem accurate, it is cannot assess the data that it uses to ensure that it is relevant to the situation or specific patient. Additionally, AI doesn’t cite its sources, meaning that it can be difficult to assess the appropriateness of the source. Last, it is important to realize that AI has sometimes provided wrong answers that could lead to patient harm and therefore need to be checked against reliable sources.

 

Figure 2 summarizes a typical drug information process.

Figure 2. The Drug Information Process

FORMULATE THE RESPONSE 

Verbal responses tend to be easier for most people than written responses, but respondents should document every request. One simple rule should guide the response: Use principles of clear communication. Clear communication reduces risks of misinterpretation and increases the requestor’s understanding. It optimizes patient care. Clear, concise sentences that are short (fewer than 25 to 32 words) and straightforward create an ideal response.¹⁸ It is best to be comprehensive with adequate information and complete sentences that leave no confusion. Each statement should have a clear purpose with no extraneous information or unnecessary words. Respondents must paraphrase important information from accumulated data taken from reliable sources, while avoiding copying and pasting from other outside sources. The response must focus on the audience (the requestor) and the requestor’s background, remembering that different types of professionals have different education and focus.¹⁸

 

Organize and Evaluate Information 

Organizing information makes research and presentation straightforward and simple for the audience to understand quickly. Templates are available to help keep information organized and formulated, but they have advantages and disadvantages.

 

• Pros: Templates provide consistency that makes it easier for requesters to follow. (Saving your responses to DI requests is a PRO TIP, discussed in the SIDEBAR) Templates also provide an idea about how the completed presentation will look and reduce the time associated with creating the response. Some organizations provide templates for their employees. Lacking an approved template, respondents can find customizable templates from their workplace or university. Example templates found in the appendices show how useful templates can be. Templates can act as checklists to remember what should be included in a drug information response.
• Cons: Many templates limit the amount of allowable customization or text, and respondents must be knowledgeable about editing templates. Templates may also limit the approach to the topic and limit the information to standard or predictable fields; this is a problem when the question is unique or unusual. It is important to understand that templates are guides in answering requests and are not restrictions.

 

Templates that can be used while answering drug information questions have different strengths and limitations. The choice of template can be dependent on the pharmacist’s preference as well as the type of drug information request. We reviewed the templates in the addendum and assessed their utility. Take a minute to look at them. How do your assessments compare to ours?

 

Template 1 located in Appendix 1:

Pros: Extensive prompts for what should be included in a drug information response. This format is very detailed which could be useful for less experienced users.

Cons: Could be too detailed to be used for a wide range of requests. It lacks space, so users will have to use it against a document that they have already created.

 

Template 2 located in Appendix 2:

Pros: This format displays the drug information request topic quickly, organizes patient information and the response, and includes references to use for evidence-based literature support. It is broad enough to be used for multiple types of requests. It could be especially helpful for pharmacists who receive a wide variety of requests as it allows them to focus and tailor responses appropriately.

Cons: Insufficient prompts or guidance responders, making it more suitable for experienced pharmacy staff. This would too broad for beginners or pharmacy students because it does not outline various aspects of drug information responses.

 

SIDEBAR: Saving FAQs for Future Use: The FAQ File^19,20

Pharmacy staff often notice that they receive the same or similar questions repeatedly. Each time a requestor asks the question, the respondent must answer again. When employees in the pharmacy discuss questions they receive, they may find that although each of them has only answered a specific question once or twice, collectively they are answering the same question often. A frequently asked question (FAQ) file has numerous advantages. It can

• Save time for everyone including the requestor
• Standardize the answer so that it is consistent each time staff answer the specific question
• Provide the answer in clear language
• Create an answer that technicians and students can give to requestors without asking the pharmacist to intervene
• Refer requestors to web sites or documents for additional information

 

To develop a reliable FAQ file, pharmacy staff should take several steps:

• Identify the questions that are asked frequently.
• Develop a simple format for all FAQs. Usually, the actual question appears at the top of the documents, with the answer below.
• Start small and ask one employee to draft the FAQ.
• Have two or three people review the FAQ, including a pharmacist and at least one or two support personnel. Encourage reviewers to provide constructive criticism. If the FAQ usually comes from a colleague or patient, involve colleagues and patients in the review.
• A good process for reviewing FAQs is to ask a reviewer to read to a certain point and then stop. The project coordinator should ask, “Can you tell me in your own words what you just read?” If the reviewer explains and the information is incorrect, the project coordinator should not correct the reviewer; rather, the project coordinator should make a note that the section needs work and why.
• The project reviewer should ask additional, open-ended questions including
  • What’s your general reaction to this draft FAQ?
  • What did you like about this draft FAQ?
  • What did you dislike about this draft FAQ?
  • Is anything in this draft FAQ confusing?
  • What would you do if you got this document?
  • What do you think the writer was trying to do with this document?
  • And here’s a PRO TIP: Often, people will not answer directly because they do not want to appear uneducated or picky. A way to circumvent this issue is to ask, “Thinking of other people you know who might get this document…”
    • What about the document might work well for them?
    • What about the document might cause them problems?
  • Once the FAQ completes the process and is ready for “prime time,” save it in a format that cannot be edited (i.e. a PDF that is locked for editing) and upload it to a shared file or drive where all employees can access the document and print or clip it to an email when needed.

 

Finally, drugs and drug information change over time. Organizations that use FAQ files must schedule routine review (at least annually and more often if necessary) to ensure that the content in FAQ files remains current and correct.

 

Proofing and Editing Drafts 

Proofing and editing written drafts entails first fact-checking the narrative and the sources used, and then reviewing the text to ensure it is clear and professional. The respondent must re-assess and re-evaluate each source and the information gathered. Asking other healthcare professionals who have expertise to contribute to or proofread the draft is smart. Collaborating with colleagues can be beneficial, especially in healthcare. The recent emphasis on interdisciplinary approaches reminds us that healthcare professionals from multiple backgrounds need to collaborate and exchange information more often than not. Colleagues can also help confirm or modify any information, while also giving feedback to learn how to better future drug information requests.

Once the data is confirmed as accurate, the last step is to double check for spelling and grammar errors and ensure the response is clear and concise. A skilled pharmacy technician is often an exceptional collaborator in this step.

 

Document, Document, Document

Documentation is helpful when pharmacy employees have to refer back to that specific topic on a similar drug information question or when colleagues have a similar request in the future. Documenting the response will aid as a reference point and could help clinicians in the future make decisions regarding patient care.²¹ Documentation will also display accountability and the respondent’s value to the organization and the interdisciplinary team. Many healthcare organizations have policies and procedures for documenting DI requests, and all staff should follow them if they exist.

 

ASSESS REQUESTOR’S UNDERSTANDING AND SATISFACTION 

Following up after responding to a DI request is a professional action. The respondent should follow up with the requestor in a timely manner and assess the outcomes. If the requestor is not completely satisfied, the respondent can adjust the answer and recommendations appropriately.⁷ Follow-up will also reveal if the requestor has implemented the recommendation (and if it worked), provide feedback for potential modifications in future DI requests, and show professionalism and dedication to patient care. A PRO TIP is to document the follow-up and outcomes.

 

CONCLUSION

Pharmacy teams have serious responsibilities related to DI requests, which can cover a broad spectrum of topics and specialties. Pharmacists, pharmacy technicians, and pharmacy students should use a methodical approach, followed by documentation. As the ever-changing landscape of healthcare, medicine, and technology continues to advance, the providing drug information will remain an integral part of the pharmacist’s responsibilities.

 

Table 4 provides additional resources.

 

Table 4. Additional Resources

Systematic Approach to Answering Drug Information Requests   This resource helps characterize the various types of drug information requests	https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/preceptor-toolkit/sicp-busy-day-systematic-approach-answering-drug-info-requests.ashx?la=en&hash=7C8B36648FAB999DE761D3AE37BFE48A847B8551
7 Tips on Improving Communication in Your Pharmacy   This resource provides guidance on how best to speak with patients	https://www.pbahealth.com/elements/7-tips-on-improving-communication-in-your-pharmacy/
Formulating an Effective Response: A Structured Approach   This resource provides strategies to answer formulated drug information requests.	https://accesspharmacy.mhmedical.com/content.aspx?bookid=2275&sectionid=177197497 :
ASHP Guidelines on the Pharmacist’s Role in Providing Drug Information   This resource provides suggestions on how to answer a formulated drug information request.	https://www.ashp.org/-/media/assets/policy-guidelines/docs/guidelines/pharmacists-role-providing-drug-information.pdf
How To Evaluate Health Information on the Internet: Questions and Answers   This resource provides approaches on how to find credible sources to answer drug information requests.	https://ods.od.nih.gov/HealthInformation/How_To_Evaluate_Health_Information_on_the_Internet_Questions_and_Answers.aspx

 

 

Templates:

Requirements checklist for drug information Response1 - UBC Blogs. Accessed July 3, 2023. https://blogs.ubc.ca/oeetoolbox/files/2019/01/Requirements-Checklist-for-Drug-Information-Response.pdf.

Drug Information Request and Response Form.; 2017. Accessed July 3, 2023.

https://blogs.ubc.ca/oeetoolbox/files/2019/01/DIR-Example.pdf

PHRM Handbook. Accessed July 3, 2023.

https://blogs.ubc.ca/oeetoolbox/files/2019/01/Drug-Information-Request-and-Response-Fillable-Form-.pdf

Download CE Activity

INTRODUCTION

Hepatorenal syndrome (HRS), a type of kidney injury unique to patients with advanced liver disease, carries a grim prognosis. Therapies such as volume resuscitation (e.g., crystalloids or albumin) and vasoconstrictors (e.g., norepinephrine or terlipressin) focus on restoring blood flow to the kidneys before they are irreparably injured. Pharmacists and pharmacy technicians can play a crucial role in helping select and monitor therapies for treatment of this syndrome, and perhaps more importantly, by helping patients avoid developing HRS in the first place. By educating patients to avoid certain over the counter (OTC) medications that can worsen the condition (e.g., non-steroidal anti-inflammatory drugs [NSAIDs]), and teaching patients to monitor their diuretic use by weighing themselves daily and monitoring their blood pressure, engaged pharmacists and pharmacy technicians can make a large difference in their patients’ clinical outcomes.

 

HRS: A Complication of Cirrhosis

Cirrhosis, an advanced state of liver disease, is increasingly common and an important cause of mortality.¹ Globally, in 2017 the estimated incidence of people living with compensated cirrhosis was 112 million. In 2019, cirrhosis was associated with 2.4% of deaths worldwide.² Classically, cirrhosis in developed countries is most commonly due to hepatitis C infection and alcohol misuse.¹ However, over the past decade, the incidence of non-alcoholic fatty liver disease (NAFLD) has increased dramatically with improvement in diagnostic criteria and screening. At the same time, treatment improvements for hepatitis B and C infections have decreased viral hepatitis-related deaths in some areas of the world. The COVID-19 pandemic has also had significant impact, with data collected from multiple countries showing a substantial increase in alcohol consumption, and an increase in alcohol-associated cirrhosis deaths.^2,3 Testing and treatment rates for hepatitis B and C declined internationally between January 2019 and December 2020,⁴ and treatment delays are predicted to lead to excess liver-related deaths.^2,5

PAUSE AND PONDER: How will the new hepatitis C direct-acting antivirals (e.g., elbasvir, glecaprevir, ledipasvir, pibrentasvir, sofosbuvir, velpatasvir, and voxilaprevir) change the landscape of HRS?

Although the causes of cirrhosis may be shifting, the transition from chronic liver disease to cirrhosis is generally the same. Chronic inflammation of the liver leads to fibrosis and scarring, causing structural and hemodynamic changes within the liver (Figure 1). One of the main consequences is development of portal hypertension. Portal hypertension results because the scarring of the liver makes it more difficult for blood to flow through it, leading to increased blood pressure in the portal vein as blood is delivered from the splanchnic organs (stomach, small intestine, colon, pancreas, and spleen) (Figure 2). The obstruction of blood flow through the portal vein additionally results in dilation of the splanchnic circulation as a compensatory mechanism aimed at restoring blood flow. In turn, increased blood flow to the splanchnic circulation worsens portal hypertension.¹  

Figure 1. Stages of Liver Disease.

 

Figure 2. The splanchnic circulation. The splanchnic circulation describes blood flow to the abdominal organs. Blood from these “splanchnic” organs is delivered to the portal vein, and accounts for the majority of the blood flow to be processed by the liver.

 

Pathophysiology of HRS

Portal hypertension and the changes in blood flow that result are the main drivers of several consequences of cirrhosis. These complications include the development of ascites, espophageal varices, and HRS.

 

Ascites is fluid accumulation in the peritoneal cavity that commonly appears as abdominal swelling or bloat. A patient with significant ascites will often test positive for a “fluid wave.” That is, when a patient is lying flat and someone applies pressure to the abdominal midline, a clinician can tap one flank sharply, and an impulse or “shock wave” will travel through the fluid in the abdomen. The clinician will be able to be feel the tap on the other side.

 

Esophageal varices are enlarged veins in the esophagus that can lead to bleeding that commonly presents as “coffee ground” looking emesis (or vomitus) that is a result of the blood being digested in the stomach then regurgitated through the esophagus. In the case of HRS, the portal hypertension and splanchnic vessel dilation mean that blood tends to pool in the splanchnic circulation, decreasing effective arterial volume (i.e., a decreased amount of blood effectively perfusing organ tissue, including the kidneys). Additionally, the body activates various compensatory mechanisms aimed at increasing blood volume (e.g., the renin-angiotensin system and the sympathetic nervous system). This action is an attempt to restore effective blood volume, which leads to vasoconstriction of the kidney arterioles and further hypoperfusion of the kidney (Figure 3).⁶

Figure 3. Changes in blood flow with cirrhosis. The image on the left represents normal splanchnic and portal blood flow. The image on the right shows blood flow to a cirrhotic liver. Blood from the splanchnic organs meets increased resistance in the portal vein, leading to portal hypertension. The splanchnic arteries vasodilate which worsens portal hypertension and leads to decreased blood flow to the kidneys.

ABBREVIATIONS: ADH: antidiuretic hormone, IMA: inferior mesenteric artery, RAAS: renal angiotensin aldosterone system, RBF: renal blood flow, GFR: glomerular filtration rate, SMA: superior mesenteric artery

Prevalence and Prognosis

HRS is a type of acute kidney injury (AKI) that is unique to patients with decompensated cirrhosis. HRS occurs in the absence of hypovolemia or any structural changes to the kidney—in fact, the kidneys often function normally following liver transplantation.⁷ HRS is common in patients with cirrhosis, and risk of development increases as the severity of cirrhosis and the duration with which the patient has had it increase. In one study of patients with cirrhosis and ascites, the incidence of HRS increased from 18% at one year to 39% after five years.⁸ The development of HRS is unfortunately associated with a very poor prognosis, and often the only way to reverse the kidney failure is to receive a liver transplant.⁷

 

Classification and Diagnosis

Two distinct forms of HRS have been described. According to the American Association for the Study of Liver Diseases (AASLD) guidelines⁹

• Type 1 HRS is a rapid increase in creatinine (0.3 mg/dL or greater) within 48 hours or an increase in serum creatinine to levels that are at least 50% higher than the most recent baseline value measured within three months. It often has a precipitating factor, such as a bacterial infection, gastrointestinal bleeding, or over-diuresis. This type of HRS is more common and more severe, making up 75% of cases and having a median survival of one month.
• Type 2 HRS takes a longer time to develop and is defined as an estimated glomerular filtration rate of less than 60 mL/minute/1.73m² for three months or more in the absence of other (structural) causes. This is the same definition used for all patients with chronic kidney disease (CKD). Type 2 HRS often co-occurs with other complications of cirrhosis (i.e., refractory ascites) and has a median survival of about seven months.⁸

 

In recent years the nomenclature has been updated so that type 1 HRS is referred to as HRS-AKI and type 2 is called HRS-CKD.^6,9

 

Sometimes it is hard to know that a patient with end-stage liver disease is in kidney failure. These patients may have decreased muscle mass, are prone to malnutrition, and may take diuretics to control volume status. All three of those factors make serum creatinine an unreliable surrogate measure of kidney function.¹⁰

In patients with cirrhosis and ascites who meet the criteria for AKI, the diagnosis of HRS-AKI becomes one of exclusion. Clinicians must attempt to rule out hypovolemia, shock, medication-induced AKI, and structural kidney injury. In the absence of these alternative causes for AKI, a diagnosis of HRS-AKI can be made, and treatment commenced as soon as possible, as early intervention is key to decreasing mortality.⁹

 

Sidebar: Why is serum creatinine unreliable in advanced liver disease?

In clinical practice, clinicians often estimate kidney function by measuring a patient’s serum creatinine and inputting the value into a kidney function estimating equation. Creatinine is a byproduct of creatine, an amino acid produced by the liver and released into the circulation to reach target tissues, such as muscle. Creatinine is released during normal muscle metabolism. It is used in kidney function estimates because the glomerulus filters it freely, and so theoretically the rate at which the kidneys clear creatinine should be similar to the glomerular filtration rate itself.

 

However, a patient’s serum creatinine value is not affected by glomerular filtration rate alone. A malfunctioning liver may produce lower amounts of creatinine’s precursor, creatine. Additionally, patients with cirrhosis may have decreased oral intake due to nausea, ascites, and/or ongoing alcohol use. This means they consume less creatine is consumed from the diet as well. Finally, since creatinine is a product of muscle tissue breakdown and patients with cirrhosis tend to have significantly reduced muscle mass, they may generate less creatinine from the creatine. The end result is a serum creatinine that is normal or even lower than that seen in healthy individuals.

 

Hence, kidney function estimates that rely on creatinine tend to overestimate kidney function in these patients and even small absolute increases in creatinine could represent an acute kidney injury.

PAUSE AND PONDER: Is there a better way to measure true kidney function in patients with end-stage liver disease?

 

Current and Emerging Therapies for HRS

Therapies used to treat HRS aim at removing the precipitating factor and increasing blood flow to the kidneys. First, clinicians must identify and treat the potential etiology leading to the decline in kidney function (e.g., antibiotic therapy in the treatment of an infection of ascites fluid called spontaneous bacterial peritonitis [SBP], proton pump inhibitors, and endoscopic intervention to stop a gastrointestinal bleed). Removing the cause is one of the most important factors in ensuring that the change in kidney function is not permanent.

 

Fundamentally the kidney receives insufficient blood flow secondary to a decrease in effective arterial blood flow, so initial therapy’s main goal is to improve the patient’s mean arterial pressure as soon as possible. The most common goal cited is to increase the patient’s mean arterial pressure (MAP) to greater than 65 mmHg to improve perfusion to target end organs, specifically the kidney.^11,12 The goal is to improve kidney function and give the patient additional time to secure a liver transplant or stabilize the end stage disease and decrease mortality. This continuing education activity will review the agents used to improve kidney function in the setting of HRS. Table 1 summarizes guideline recommendations for initial management of patients with HRS-AKI.

 

Table 1. Summary of Society Guidelines for Initial Management of HRS-AKI in the ICU9,22,23,32,33
Society	HRS-AKI Definition	Volume expander	Vasopressor of choice	Target
American Association for the Surgery of Trauma 2022	Increase in SCr > 0.3 mg/dL within 48 hours or > 50% increase in SCr in preceding 7 days in patients with cirrhosis/ascites without another cause	Lactate ringers or Plasmalyte over Normal Saline; albumin 20-25% 1 gm/kg/day x 48 hours	Norepinephrine, Terlipressin	MAP > 65 mmHg, increased urine output
American Association for the Study of Liver Disease 2021	Increase in SCr > 0.3 mg/dL within 48 hours or > 50% increase in SCr in preceding 7 days in patients with cirrhosis/ascites without another cause; use SCr values for the last 3 months prior to event to evaluate baseline	Albumin 1 gm/kg on day 1, then 40 to 50 gm daily while receiving vasopressor therapy	Terlipressin,* Norepinephrine 0.5 mg/h ; max 3 mg/h	Increase MAP by at least 10 mmHg above pre-treatment baseline or urine output >200 mL over 4 hours; albumin to maintain CVP between 4-10 mmHg; Continue treatment until SCr back to baseline up to 14 days; if SCr remains at or above pre-treatment values after 96 hours stop vasopressor therapy
European Association for the Study of the Liver 2010	Kidney failure in the setting of liver disease unexplained by another cause	Albumin 1 gm/kg/day (max 100 gm/day)	Terlipressin 1 mg every 4 to 6 hours in combination with albumin, if SCr does not improve by at least 30% in 72 hours increase dose to 2 mg every 4 hours	Increase in MAP by at least 5 mmHg by day 3
American Gastroenterological Association 2022	Increase in SCr > 0.3 mg/dL within 48 hours or > 50% from baseline or urine output is <0.5 mL/kg/hr for > 6 hours	Albumin 1 gm/kg/day x 48 hours, if no improvement continue 1 gm/kg x 1 day then 20 to 40 gm daily while receiving vasopressor therapy	Terlipressin 1 mg every 4 to 6 hours; increase to 2 mg every 4 to 6 hours if reduction in SCr < 25% by day 3 if available up to 14 days, alternative norepinephrine or midodrine/octreotide	Increase MAP by at least 10 mmHg or urine output by at least 50 mL/h for at least 2 hours, maintain priority for liver transplant if survive
*not approved in US at the time of guideline construction
ABBREVIATIONS: CVP = central venous pressure; MAP = mean arterial pressure; SCr = serum creatinine

 

 

 

PAUSE AND PONDER: When might these interventions be considered “too late?” What would you do then?

 

Crystalloids

Initial evaluation of patients includes an assessment of their effective arterial blood volume status. Early cessation of home medications that impact blood pressure or volume status, such as diuretics (e.g., spironolactone, furosemide) will allow a more accurate determination. If the patient’s effective arterial blood volume is not optimized, inadequate blood flow to the kidney can precipitate acute kidney injury in the setting of cirrhosis.

 

Crystalloids, such as normal saline and Lactated Ringer’s, stay within the intravascular space and provide appropriate initial fluid replacement. However, clinicians must provide fluid replacement (also referred to in this case as fluid resuscitation) carefully and with appropriate monitoring as patients can become volume overloaded. Patients with end stage liver disease have low albumin levels and tend to lack the oncotic pressure (a type of osmotic pressure induced by plasma proteins, especially albumin) required to keep crystalloids within the intravascular space. Even minimal resuscitation can produce significant peripheral edema and pulmonary edema, and worsen ascites.¹³

Pharmacists should provide support in appropriate monitoring of volume status and ensuring serum electrolytes are frequently obtained. Fluids may need to be stopped abruptly in response to volume overload to prevent hypervolemic hyponatremia (low sodium levels).¹⁴ Appropriate understanding of the patient’s intravascular volume status will determine if using albumin during resuscitation is appropriate.

 

Albumin

Patients with end-stage liver disease typically have reduced or low albumin levels because the liver is no longer able to manufacture these proteins. Reduced albumin decreases the circulating oncotic pressure which yields fluid leakage from blood vessels into other areas of the body (e.g., peritoneal space), reducing the arterial blood volume going to the kidney. This becomes especially apparent when a precipitating event such as a hemorrhage or infection occurs, which further decreases circulating blood volume. Clinicians often administer concentrated albumin (e.g., 25% or 25 grams/100 mL) every six to eight hours to increase the intravascular circulating blood volume. Albumin allows fluid to move from the interstitial spaces back into the blood stream and keeps exogenously administered crystalloids in the vessels, thereby increasing blood flow to the kidneys.¹² Clinicians should reserve concentrated albumin for patients with baseline low serum albumin (e.g., less than 3 mg/dL) who are also volume overloaded and limit them to just the amount that restores hemodynamic stability.¹⁵

 

Patients who have inadequate total body volume or those who have capillary leak (e.g., septic shock) may benefit from less concentrated (e.g., 5%) albumin infusions. A recent single center open-label, randomized study evaluated hypotensive patients with end-stage liver disease and compared volume replacement with albumin to normal saline.¹⁶ The primary outcome was to determine which approach could reverse a mean arterial pressure less than 65 mmHg more effectively within the first hours of resuscitation. Of note this trial excluded patients who needed immediate interventions, such as variceal bleed or vasopressor agents.¹⁷ The researchers randomized patients to receive 250 mL of 5% albumin over 30 minutes followed by 50 mL/hr for three hours or normal saline 30 mL/kg over 15 to 30 minutes followed by 100 mL/h over three hours. Albumin was more effective than normal saline in improving mean arterial pressure above 65 mmHg in the first hour (25.3% albumin vs 14.9% normal saline, p = 0.03) of resuscitation. The benefit continued over the next three hours (p < 0.001) and survival was also better in patients resuscitated with albumin than those treated with saline (43.5% vs 38.3%).^16,18 The researchers note that results are predicated on appropriate management of the underlying causes of hypotension (i.e., sepsis).

 

Albumin is expensive, can be and has been subject to shortages. It should be used with stewardship in end stage liver disease and HRS; however, the evidence for benefit is robust especially when combined with other modalities.¹⁶ It is important to understand the patient’s volume status and hemodynamic goals to select the appropriate concentration and frequency.^19,20 The AASLD Guidelines for the Diagnosis, Evaluation and Management of Ascites, Spontaneous Bacterial Peritonitis and HRS suggest that patients who present with HRS should receive 1 gram/kg albumin on day 1 and then 40 to 50 grams per day until kidney function improves and other therapies are no longer needed.^9,15 The daily dose may be reduced (e.g., 20 to 40 grams/day) if given in combination with vasopressor agents with a goal to maintain adequate volume. Clinicians sometimes use a surrogate measure of volume using a central venous catheter to measure central venous pressure (CVP), which reflects the amount of blood in the patient’s anterior vena cava and venous tone. In this case, a CVP goal between 10 and 15 mmHg is targeted.^10,21 Unfortunately CVP can be unreliable when ascites is present and clinicians may need to employ other invasive methods along with close monitoring for the development of pulmonary edema.^9,22,23

 

Ensuring albumin is available for patients with HRS is necessary. Some ways to aid centers in managing their supplies when shortages occur include limiting scheduled orders to 24 hours (e.g., 1 gram of 25% every 8 hours for 24 hours). Limiting “evergreen” orders to 24 hours will ensure clinicians assess patients appropriately before administering additional albumin and may prevent unappreciated volume overload. Also, standardized order sets will prevent use of partial vials, larger than needed vials (e.g., 250 mL or 500 mL) and inappropriate ordering of the incorrect concentration (e.g., 5% versus 25%). Teaching hospitals may also benefit from limiting albumin orders to certain clinical situations or diagnoses to avoid ubiquitous use for volume resuscitation in patients (e.g., trauma) who can be resuscitated with crystalloid.

 

Vasopressors

Vasopressors are given in combination with resuscitation, specifically albumin. The exogenous albumin facilitates adequate oncotic pressure to keep fluid in the vasculature, allowing vasopressors to constrict the vessels, increase mean arterial pressure, and supply fluid to the kidney. Vasopressors will be ineffective and can make kidney function worse if fluid in the vasculature is insufficient. Therefore, prescribers should only institute vasopressors along with or after volume resuscitation. The main adverse effects associated with any vasopressor therapy are related to ischemia (poor blood flow) in the peripheral limbs/tissues (e.g., fingertips, skin), gastrointestinal tract, or heart.⁹ Limited head-to-head trials exist to identify which agent or combination is the most effective in reversing HRS beyond early implementation of therapy in combination with albumin volume expansion. Table 2 summarizes the pros, cons, and considerations related to vasopressor agents used in the treatment of HRS.

 

Table 2. Vasopressor Agents Pros, Cons and Considerations
Medication	Pros	Cons	Considerations
Norepinephrine	Frequently used in the ICU setting, team comfort with monitoring for adverse effects and ease/experience with titration	May be less effective in hypothermia, pH dysregulation, continuous infusion	May require ICU setting, especially for acute titration; may require a central line
Terlipressin	Does not require a central line, or continuous infusion	Requires additional monitoring for ischemia which may require ICU level care to ensure safety	Requires monitoring for ischemic events
Octreotide	Can be given outside the ICU	Slow response, IV or subcutaneous administration	May be continued as an outpatient
Midodrine	Available as an oral agent, can be given outside the ICU	Slow response, only available as an oral agent; frequency of dosing	May be provided on discharge to help maintain blood pressure in the setting of hypotension

ABBREVIATIONS: ICU = intensive care unit; IV = intravenous

 

Norepinephrine

Norepinephrine is an exogenous catecholamine that targets alpha-1-adrenergic receptors which helps improve peripheral vascular resistance.²⁴ Norepinephrine has been used consistently in the United States (U.S.) for many years and has been the agent of choice until the recent approval of terlipressin. Norepinephrine’s limitation is that it can be less effective, as are other catecholamines, if patients have temperature or pH dysregulation. Appropriate resuscitation and correction of these variables can improve norepinephrine’s efficacy. A meta-analysis comparing the effectiveness of norepinephrine and terlipressin suggests that norepinephrine is as effective in increasing mean arterial pressure and reversal of kidney dysfunction.²⁴ The most frequent doses of norepinephrine cited in terlipressin head-to-head trials were between 0.5 to 3 mg/hour and/or 0.05 to 0.7 mcg/kg/minute titrated to increase mean arterial pressure 10 mmHg above baseline or increasing urine output to more than 200 mL/hour.²⁴ Clinicians must monitor norepinephrine administration carefully to prevent complications of vasoconstriction, such as cardiac or digital ischemia and therefore it is often restricted to the intensive care unit (ICU).²⁴

 

Terlipressin

Terlipressin is a prohormone of lysine-vasopressin, causing extended release of lysine-vasopressin and activation of V1 and V2 receptors allowing intermittent administration.²⁴ V1 receptors are predominantly located in the smooth muscles of the arterial vasculature in the splanchnic region. Activating V1 receptors constricts the splanchnic vessels (reducing delivery of blood flow to the portal vein, lowering portal pressure) which subsequently may improve blood flow to kidneys. Additionally, activation of the V2 receptors causes reabsorption of water in the kidney.^24,25 Terlipressin has been evaluated in several prospective, placebo-controlled clinical trials evaluating its efficacy in improving kidney function in HRS.¹⁸ Specifically, a recent prospective, randomized, double-blind controlled trial evaluated the effectiveness of terlipressin against placebo in combination with albumin in reversing HRS-AKI.²⁵ Terlipressin was more effective than placebo in reversing HRS (32% vs 17%, p < 0.006), but did yield more respiratory failure.²⁵ This trial was an impetus for U.S. Food and Drug Administration (FDA) approval of terlipressin in 2023.

 

The FDA approved terlipressin for rapid reduction in kidney function in the setting of cirrhosis with no other etiology, or reversal of HRS at a dose of 1 mg administered by intravenous bolus every six hours.¹⁰ If the patient’s serum creatinine fails to improve or increases within the first 96 hours then prescribers should discontinue terlipressin. If improvement is marginal (e.g., less than 30% from baseline) the dose can be increased to 2 mg every six hours.¹⁰ Therapy should be continued until the patient’s serum creatinine is 1.5 mg/dL or less for two days or a maximum of 14 days. Prescribers should use terlipressin with caution in patients with a history of ischemic conditions (e.g., cardiac, mesenteric).¹⁰ Terlipressin should not be used in patients who have a serum creatinine exceeding 5 mg/dL, in patients who are hypoxic (SpO₂ less than 90%), or in patients who develop ischemia.^10,23

 

Terlipressin is often given outside the ICU and does not need continuous cardiac monitoring, which may make it desirable for longer term administration.¹⁰ Initial clinical trials compared norepinephrine continuous infusion (1 mcg/kg/minute increased every four hours to increase MAP by 10 mmHg) to terlipressin (1 mg every four hours; increased to 2 mg every four hours after three days) combined with albumin to maintain a CVP between 10 and 15 mmHg. These trials defined a complete response as an improvement in serum creatinine by at least 30% from baseline within 14 days of therapy. There was no difference in responders between norepinephrine and terlipressin (70% and 83%).^21,26,27 Therefore terlipressin’s benefit may lie in its intermittent dosing and ability to be administered outside the ICU.

 

Terlipressin’s most common adverse reactions (≥10%) include abdominal pain, nausea, respiratory failure, diarrhea, and dyspnea. Terlipressin does have some additional considerations. It also has a boxed warning for possible serious or fatal respiratory failure, and clinicians need to monitor patients’ oxygen saturation carefully.²⁸

 

Terlipressin is supplied as a single dose 0.85 mg vial that must be stored under refrigeration and protected from light. Vials are reconstituted with 5 mL of sodium chloride and if not used, must be refrigerated and expire after 48 hours. The initial dose based on the approved labeling is one vial (0.85 mg) every six hours; which can be increased to two vials (1.7 mg) every six hours.²⁸

 

Midodrine and Octreotide

Midodrine and octreotide in combination have been a staple in the treatment of acute HRS for the last two decades in the U.S. Midodrine, an oral tablet, is like norepinephrine and produces vasoconstriction through alpha-1-adrenergic receptors.²⁴ Octreotide injection is a somatostatin analogue that decreases the release of vasodilatory substances and glucagon leading to vasoconstriction of the splanchnic circulation.²⁴ Because norepinephrine must be administered in the ICU, some healthcare facilities favor the combination of midodrine and octreotide. They also use midodrine/octreotide if they have not added terlipressin to their formularies.²³ Unfortunately, patients tend to respond slowly to the combination and the combination requires an extended duration for full benefit.²³ Octreotide cannot be given without midodrine but midodrine may be continued long-term (e.g., post-discharge) to maintain blood pressure in patients who are persistently hypotensive.^23,29

 

Researchers recently published a single center experience with standardizing administration of midodrine and octreotide for treatment of HRS at their center.²⁹ They wanted to standardize the use and dosing of albumin in combination with midodrine dosed at 2.5 to 10 mg three times daily and octreotide 50 to 100 mcg subcutaneously three times daily for 14 days and compare it to previous unstandardized prescribing. The goal was to obtain a full response: a serum creatinine within 0.3 mg/dL of baseline within seven to 14 days. Use of the standardized protocol was more effective in producing a full response than the historical unstandardized practice (25% vs 10%, p = 0.07).²⁹ Additionally, the researchers also found that fewer patients in the protocol group required kidney replacement therapy. Guidelines suggest initiating midodrine at a dose of 7.5 mg three times daily and titrating it to 12.5 mg three times daily in combination with octreotide.²³ The combination may still be in favor because it is a cost-effective alternative to terlipressin outside the ICU.

 

Midodrine is supplied in three tablet strengths which include 2.5 mg, 5 mg and 10 mg.³⁰ This allows outpatient tapering or adjustment if the patient experiences tachycardia. Unfortunately, it is short acting and requires three times daily dosing initially. In practice, dropping the middle of the day dose without reducing the strength allows improved adherence once the patient’s blood pressure is stable. Midodrine’s labeling includes a boxed warning for possible marked elevation of supine blood pressure, and clinicians should monitor supine and standing blood pressure regularly.³⁰

 

Octreotide is supplied in single dose ampules or multidose vials that must be stored in the refrigerator and protected from light; multidose vials must be discarded within 14 days. Octreotide is stable for 14 days at room temperature.³¹ Doses of 50 mcg to 100 mcg are administered every eight hours around the clock during the inpatient stay. If patients continue on octreotide as outpatients, the hospital pharmacy often needs to supply the doses. Patients and caregivers need appropriate education on subcutaneous injections and disposal of injection materials. In practice, the dose used in the hospital with success is often continued and not reduced to allow for the shortest duration possible. Octreotide subcutaneous injections on the outpatient side typically require additional insurance approval and preparation so discharge planning early is important.³¹

 

The Role of Pharmacists and Pharmacy Technicians in the Treatment of HRS

Pharmacists and pharmacy technicians can play an integral role in improving outcomes for patients presenting with or who have a history of HRS. Prevention is the key! Patients with end-stage liver disease should avoid medications that can precipitate HRS such as non-steroidal anti-inflammatory drugs and will require appropriate adjustment or discontinuation (if possible) of potential nephrotoxic agents (e.g., certain antimicrobials).

 

Ensuring patients with a history of spontaneous bacterial peritonitis (SBP) are on appropriate antibiotic prophylaxis can prevent subsequent SBP events that decrease blood flow to the kidneys. In the ambulatory setting, careful blood pressure monitoring and adjustment of blood pressure medications commonly used to treat portal hypertension (e.g., carvedilol), can ward off hypotensive events that can precipitate HRS.

 

Table 3 summarizes some lifestyle counseling tips that can help empower patients to play an active role in optimizing their care and preventing HRS episodes. Additionally, general management of concurrent disease states, such as heart failure and diabetes, can aid in maintaining optimal hemodynamics.

Table 3. Lifestyle Counseling Points for Patients with Cirrhosis at risk for HRS35-37
Avoid alcohol	Even if the cause of liver damage isn’t drinking, alcohol use can increase the amount of damage. Patients who cease alcohol can experience dramatic improvements in some of the complications of cirrhosis.
Low sodium diet (especially in patients with ascites)	Limit sodium intake. This can be quite difficult, but if it can be done will help quite a bit with volume management. Patients with ascites are often asked to target ≤2 g/day. (For reference, 1 teaspoon of salt contains 2.3 g!)
Weight loss in patients who are overweight	Even a small amount of weight loss (e.g., a few pounds) can have a beneficial effect in patients with NAFLD or chronic HCV.
Protect yourself from infections	Patients need to stay up to date on vaccinations, wash their hands frequently, and avoid people who are sick.
Organize medication schedule	Patients with liver impairment can take seven to 10 medications a day—some administered multiple times a day. Investing in a strong adherence-enhancing system with alarm reminders or reminders from caregivers can be key.
Use OTC medications carefully	NSAIDs, such as ibuprofen and naproxen, can precipitate acute kidney injury.
Monitor weight daily (if on diuretic treatment)	Patients need to weigh themselves first thing in the morning after urinating. They should report significant weight changes to their providers (e.g., losing 1 pound or more a day or gaining more than 5 pounds in a week).

 

 

SIDEBAR: Did you know…acetaminophen can be a great choice for patient with HRS?³⁴

Imagine a situation where a medical intern is cross-covering in the medical intensive care unit and receives a call from a nurse about a patient with HRS. The patient is experiencing some mild pain and the nurse would like an as-needed medication to help.

 

Or…

 

You are working in the pharmacy and receive an order for oxycodone 5 mg every six hours as needed for mild pain. You are very concerned that this patient has both kidney and liver insufficiency and oxycodone is not a good choice but what else can you recommend?

 

What about acetaminophen?!?

 

Acetaminophen tends to have a bad rap mainly because it is in so many prescription and OTC products. It’s often in the news for causing liver toxicity. Oftentimes patients and providers do not think about the total acetaminophen exposure (the total daily dose of acetaminophen) and that is where the danger can come in. When the amount of acetaminophen’s toxic intermediary N-acetyl-p-benzoquinone imine (NAPQI) exceeds the liver’s glutathione stores, NAPQI starts to stick to hepatocytes (the liver’s main structural component). NAPQI acts like an antigen and stimulates the immune system to attack the liver.

 

Fortunately, it takes a significant amount administered at one time or consistently over several days to expend the glutathione stores. Doses up to 2,000 mg per day are safe and effective in most patients with severe liver insufficiency. (The maximum daily dose in healthy adults is 3900 mg.) Pharmacists and pharmacy technicians can ensure providers and patients with liver disease know they have alternative options. They can also help patients avoid reaching for a NSAID, especially if the patient has had a recent bout of HRS or if the patient is taking other medications that would suggest the presence of liver insufficiency (e.g., lactulose, rifaximin, norfloxacin). Remember prevention of HRS is the key!

 

When a hospital admits a patient, healthcare providers need to understand what the patient was taking at home and stop or continue the appropriate medications at the right doses. For example, prescribers should discontinue medications that could be reducing blood pressure (e.g., beta blockers and alpha beta blockers) on admission.^11,16 They need to consider adjusting home medications for kidney dysfunction and restarting medications needed to manage other complications of end-stage liver disease (e.g., lactulose for encephalopathy).

 

When prompt administration of resuscitation with albumin is needed, the team may need help selecting the appropriate concentration. Patients who are significantly volume overloaded but have fluid in the extravascular space (e.g., in the abdominal cavity) would likely benefit from concentrated (25%) albumin. With the multidisciplinary team, the pharmacy team needs to understand the patient’s volume status and goals of therapy. Helping teams develop protocols to treat HRS can aid in goal-directed therapy and allow quick implementation of pharmacologic interventions to improve blood flow to the kidneys.

 

At discharge pharmacists and pharmacy technicians must ensure that medications are appropriately adjusted for the patient’s current kidney and liver function after the acute event has resolved or stabilized. The pharmacy team should be involved in educating patients on how to organize their new medication regimens, how to monitor their responses to therapy and recognize common adverse effects, and how appropriate lifestyle changes can increase the effectiveness of therapy and help avoid the advanced complications of liver disease.

 

CONCLUSION

HRS is a common complication for patients with advanced liver disease and ascites. Patients are in a state of decreased effective arterial blood flow to the kidneys and other end organs, and kidney injury is easily precipitated by nephrotoxic agents, over-diuresis, or bacterial infection. Acute treatment is aimed at restoring blood flow to the kidneys with the use of volume resuscitation and splanchnic vasoconstrictors. Pharmacists and pharmacy technicians can identify medications that may worsen kidney function, and assist in the appropriate prescribing, monitoring, and stewardship of these agents. Additionally, appropriate patient education—empowering patients to monitor their fluid/blood pressure status and avoiding OTC medications that can worsen their condition or precipitate HRS—is key in optimizing patient outcomes.

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INTRODUCTION

The feeling of grit under the eyelids is uncomfortable, annoying, and frustrating and can pose a serious health issue. This feeling, often accompanied by burning, itching, redness, and visual disturbances, is a symptom of keratoconjunctivitis sicca, otherwise known as dry eye disease (DED). At its simplest, DED is inflammation of the cornea and conjunctiva from tear hyperosmolarity (higher concentration of solutes like salts, sugars, or other dissolved particles) and tissue dryness. Left untreated, DED may result in severe eye inflammation, corneal ulcers, and vision loss.¹

 

DED affects approximately 16.4 million people, or 6.8% of the United States (U.S.) adult population.^2,3 DED is likely underreported and underdiagnosed, with estimates as high as 22.9 million adults experiencing symptoms.² Researchers estimate DED’s global prevalence is as high as 50%.⁴

 

Despite this prevalence, experts began to recognize DED as a disease state only about 30 years ago.^5,6 Initially described as a component of Sjogren’s syndrome (an autoimmune disease involving tear and saliva glands), DED emerged as a separate condition as ocular surface study progressed. The National Eye Institute first defined DED in 1995.¹

 

The Tear Film and Ocular Surface Society (TFOS) is a non-profit organization focused on eye health research and education.⁵ In 2015, the Dry Eye Workshop II (DEWS II), organized by TFOS, examined multiple aspects of DED. The workshop updated the definition, diagnosis, and classification of DED, the disease’s impact, therapeutic management options, and clinical trial design.⁵

 

TFOS DEWS II defines DED as "… a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles."⁵ In simpler terms, DED occurs when the tear film, which keeps the eyes moist, becomes imbalanced, leading to problems like tear film instability, high concentration of substances in the tears, inflammation and damage on eye surface, and abnormal nerve sensations.

 

Many risk factors contribute to DED development (Table 1). Women are two to three times more likely to develop DED than men.^3,4 Risk of developing DED increases with age. Adults aged 50 or older are three times more likely to develop symptoms than those 18 to 49 years old.^2,3 However, DED’s incidence is rising steadily in the younger population, possibly due to increased disease awareness.³ Digital device use may also contribute. Studies show that using digital devices decreases blink rate and increases incomplete blinks, leading to ocular surface dryness and, ultimately, DED.^4.7

 

Table 1. Dry Eye Disease Risk Factors^1,4,5

Modifiable	Non-modifiable
Androgen deficiency Computer use Contact lens wear Environment Medications	Age ≥ 50 years Asian race Connective tissue diseases (e.g., rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus) Diabetes Female sex Meibomian gland dysfunction

 

 

DED impacts the American economy significantly. Several factors contribute to DED burden: direct costs of medical care, the impact of lost productivity, and the associated quality of life burden. In the U.S., estimates of direct medical costs exceed $3.84 billion, fueled by healthcare professional visits, pharmacologic therapies, and surgical procedures.^4,8 The cost of lost productivity (i.e., time spent seeking and receiving treatment, avoidance of aggravating work environments, and inability to perform work due to visual changes) is even more substantial. One study estimates that these indirect costs total $11,302 per patient annually.⁸ If more than 16 million people have DED, that totals more than $150 billion annually.^4,8

 

Beyond monetary costs associated with DED, the disease also affects vision-related quality of life (VR-QoL). As DED progresses, visual quality decreases. Individuals with DED are three times more likely to report visual difficulties than those without.⁴ This impacts many daily activities such as reading, driving, watching television, and smartphone use.⁴ DED-associated pain and discomfort, along with difficulty in activities of daily living, impact mental health negatively.⁸ A 2021 study examined self-reported health status and psychological burden in patients with DED. The study associated DED with having a negative self-perception of health status and experiencing increased psychological stress.⁹

 

A Deeper Look at DED

A better understanding of DED requires review of the surface anatomy of a healthy eye (see Figure 1). The eye's surface consists of the ocular surface and ocular adnexa (accessory anatomical parts).¹⁰ The ocular surface includes the cornea, conjunctiva (including goblet cells), and tear film. The ocular adnexa includes the eyelids, lacrimal and meibomian glands, tear ducts, and the connecting muscles and nerves.¹⁰

 

Figure 1. Eye Surface Anatomy and Tear Film Formation

 

Tears lubricate the eye, and the tear film—which provides nutrients and moisture, removes microbes, and smooths the ocular surface—has three layers^10,11:

• Outermost lipid layer, produced by meibomian glands
• Aqueous layer, produced by the lacrimal gland
• Innermost mucin layer, produced by goblet cells

 

Tear film instability, primarily increased tear osmolarity, leads to ocular surface damage in DED.⁷ DED's categorization is based on the mechanism leading to tear hyperosmolarity. In aqueous deficient dry eye disease (ADDE), decreased tear secretion increases tear film osmolarity. Increased evaporation of tears leads to hyperosmolarity in (you guessed it) evaporative dry eye disease (EDE).⁵

 

ADDE is further categorized based on the underlying cause: Sjogren’s Syndrome or non-Sjogren’s syndrome. As mentioned, Sjogren’s syndrome is an autoimmune disease attacking the salivary and lacrimal glands resulting in dry mouth and eyes. Non-Sjogren’s syndrome ADDE has various causes, including lacrimal deficiency, lacrimal gland duct obstruction, and systemic drugs. These mechanisms decrease tear secretion, resulting in tear hyperosmolarity.^5,10

 

Meibomian gland dysfunction (MGD) is the primary cause of EDE.^12,13 Meibomian glands line the inside of the upper and lower eyelid. Lipid secretion by meibomian glands forms a coating on the aqueous layer, impeding tear evaporation and providing protection against environmental irritants. Risk factors for MGD include aging, hormonal changes, contact lens wear, diet, and systemic and topical medications.¹³

 

Separation of DED into ADDE and EDE implies mutual exclusivity, but many patients presenting with DED exhibit characteristics of both. Recent evidence indicates the two classifications co-exist, with more patients presenting with EDE due to MGD. ^6,14,15 Regardless of the subtype or mechanism, the result is a vicious, self-perpetuating cycle of inflammation.^6,16 Tear film hyperosmolarity triggers an innate inflammatory immune response, activating CD4+ T-cells. This leads to conjunctival and corneal cell death and impaired lacrimal gland function, further decreasing tear production.^16,17 This further increases tear hyperosmolarity, which continues the cycle.

 

Diagnosing DED is problematic due to its multi-factorial nature and inconsistent symptom presentation. Exploring differential diagnoses using triaging questions is crucial to exclude diseases that mimic DED, including allergic, bacterial, or viral conjunctivitis; blepharitis; and rheumatic disorders.^5,18 A thorough patient history screens for risk factors such as smoking, contact lens wear, and certain systemic and topical medications. Several questionnaires also exist to help clinicians screen for DED. The Dry Eye Disease Questionnaire (DEQ-5) contains five items asking patients to rate the frequency of eye discomfort, eye dryness, and watery eyes during a typical day.¹⁸ The Ocular Surface Disease Index (OSDI) is another popular questionnaire. The OSDI questionnaire asks a series of 12 questions assessing eye symptoms, vision issues (e.g., reading, driving), and environmental conditions.¹⁸

 

Patients with positive questionnaire results should progress to a more detailed tear film and ocular surface examination. A positive result in any of the following tests is diagnostic of DED¹⁸:

• Tear breakup time (TBUT): There are two methods for measuring TBUT, using fluorescein dye or illumination of the cornea. Both measure how long it takes for tears to break up after a blink. Lower TBUT scores indicate tear instability.
• Osmolarity: Clinicians use a device with a test strip to gain a sample of the tear film from both eyes to check tear osmolarity. An osmolarity of 308 mOsm/L or greater in either eye or a difference of more than 8 mOsm/L between the eyes is diagnostic of DED.
• Ocular surface staining: After applying dye to the lower eyelid’s inner lining, clinicians examine the ocular surface for missing or damaged epithelial cells. Positive scores range from five to nine spots depending on the dye used.

 

Clinicians also commonly deploy the Schirmer test to evaluate the eye’s ability to produce tears. A notched paper strip placed over the lower eyelid stimulates tear production during the test. After five minutes, a length of wetting greater than 10 mm indicates normal tear function. Values less than 5 mm signify tear insufficiency.¹⁸

Pause and ponder: How would vision loss affect your everyday life?

 

Treatment Goals

Treatment goals for DED are to decrease ocular inflammation and restore ocular surface homeostasis (balance). DED's complexity and heterogeneous presentation necessitate an individualized approach. TFOS DEWS II recommendations emphasize identifying the disease’s root cause to determine an appropriate management approach.¹⁴ From there, the report outlines a stepwise, flexible approach to guide treatment based on patient-specific disease etiology and severity.¹⁴ Table 2 briefly summarizes recommended management steps.

 

Table 2. Treatment Steps in DED Management¹⁴

Step 1: ·       Education ·       Environmental modifications ·       Lifestyle modifications ·       Dietary supplementation ·       Eyelid hygiene ·       Medication review ·       Artificial Tears	Step 2: ·       Preservative-free artificial tears ·       Prescription therapy ·       Tear Conservation ·       Overnight treatments ·       In-office treatments
Step 3: ·       Tear stimulation ·       Biological tear substitutes ·       Therapeutic contact lenses	Step 4: ·       Prescription therapy ·       Surgical intervention

 

 

NON-PHARMACOLOGIC TREATMENT

One of the first steps, patient education, is essential for successful disease management.¹⁴ Patient education starts with thoroughly explaining DED’s chronic nature, including the ongoing, often long-term nature of therapeutic management. Discussing the patient’s home and work environment during the session may identify contributing factors.¹⁴ The environment affects overall health and well-being. Air pollution, low humidity, high altitude, and wind contribute to DED development.¹⁴ Adding an air humidifier inside or using protective eyeglasses outside can help mitigate DED symptoms. Other strategies include minimizing exposure to digital screens, cigarette smoke, and air conditioning.¹⁹

 

Proper lid hygiene is important in managing many eye conditions, including DED.¹⁴ Patients can use a cotton swab to scrub the eyelid with a dilute solution of baby shampoo to keep the area free of crusty build-up and environmental contaminants. Warm eye compresses also promote good lid hygiene and help alleviate DED symptoms. Unfortunately, lid hygiene adherence is poor, with estimates of just over 50% adherence at six weeks.¹⁴ Reinforcing the importance of lid hygiene with patients is an important component of DED patient counseling.

 

Identifying medications that may contribute to DED is an important task for pharmacy staff. Many medication classes produce drying effects on the body, intentionally or as an adverse effect.^14,19 Table 3 lists examples of medications that may worsen DED. Pharmacists and pharmacy technicians should review patient profiles to identify drying medications, including ophthalmic formulations, as medications for glaucoma (an eye condition causing progressive vision loss) may contribute to DED.¹⁴ Mitigating options to consider include changing the route of administration from oral to topical, substituting with a therapeutic alternative, and adjusting doses.¹⁴

Table 3. Examples of Medications that Worsen Dry Eye Disease^14,19

Drug Class	Examples
Antihistamines and decongestants	Chlorpheniramine Diphenhydramine Fexofenadine Loratadine Pseudoephedrine
Antidepressants ·       TCA ·       SSRI ·       SNRI	Amitriptyline Citalopram Duloxetine Fluoxetine Sertraline Venlafaxine
Anti-Parkinson’s	Levodopa
Antipsychotics	Aripiprazole Perphenazine Quetiapine
Beta-blockers	Atenolol Carvedilol Metoprolol Propranolol
Diuretics	Furosemide Hydrochlorothiazide
Proton pump inhibitors	Omeprazole Pantoprazole
Hormone therapy	Estrogen

DED = dry eye disease; TCA = tricyclic antidepressants; SSRI = serotonin-selective reuptake inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor

 

Diet and Nutrition

An emerging body of evidence suggests that certain diet changes and nutritional supplementation may play a role in DED treatment. Dehydration increases tear osmolarity, so maintaining adequate hydration is important to disease control.¹⁴ Lactoferrin is an anti-inflammatory glycoprotein found in natural tears. Studies have found decreased lactoferrin levels in patients with DED leading researchers to the explore lactoferrin topical application and oral supplementation as treatment for the condition. One study found improved dry eye symptoms and tear film stability in patients taking an oral lactoferrin supplement.²⁰ Oral lactoferrin is available as a supplement in many retail locations.

 

Supplementation with omega-3 fatty acids also shows potential in DED. Omega-3 fatty acids block proinflammatory substances and are essential for ocular surface homeostasis.¹⁴ Some studies have found that omega-3 fatty acid supplementation improves TBUT and Schirmer scores.^21,22 Conversely, The Dry Eye Assessment and Management (DREAM) trial reported no difference between groups receiving omega-3 fatty acids and placebo.²³ While oral omega-3 fatty acids show benefit for some patients, further study is necessary. These conflicting results prompted studies for alternative administration routes. Topical application of omega-3 fatty acids shows promise. A systematic review of 10 studies (five in animals and five in humans) showed overall improvement in ocular surface staining and TBUT.²⁴ Further study is necessary to evaluate long-term efficacy and optimize dosage and delivery formulations.

 

Artificial Tears

Patients often attempt self-treatment before seeking healthcare professional assistance. Tear replacement with artificial tear (AT) formulations is essential for patient comfort and a mainstay of initial and ongoing therapy. Global sales of AT reached $2.64 billion in 2019, and experts predict this to reach $4.30 billion by 2027.²⁵ Many AT products line the pharmacy shelves, all touting their ability to lubricate the eye. Faced with the confusing array of products, patients often employ a trial-and-error approach for AT selection, leading to high costs and frustration. Knowing the differences between ATs enhances the pharmacy team’s ability to counsel patients effectively.

 

AT supplementation is generally safe and well tolerated and associated adverse effects are mild, including blurred vision and ocular discomfort.¹⁴ Most ATs are water-based with viscosity-enhancing agents added for lubrication. Osmolarity, viscosity, and pH vary between products. Table 4 describes the components of AT products and their functions.

 

Table 4. Components of Artificial Tear Products^11,14,26

Component	Purpose	Examples
Viscosity-enhancing agents (lubricants)	Aid lubrication Increase tear film thickness Protect ocular surface Promote tear retention Improve goblet cell density	Carbomer 940 (polyacrylic acid) Carboxymethyl cellulose (CMC) Dextran Glycerin Hyaluronic acid (HA) Hydroxypropyl-guar (HP-guar) Hydroxypropyl methylcellulose (HPMC) Polyvinyl alcohol Polyvinylpyrrolidone Polyethylene glycol (PEG)
Lipids	Restore the lipid layer Increase lipid layer thickness Prevent evaporation	Mineral oil Castor oil Flaxseed oil
Osmoprotectants	Balance osmotic pressure	Trehalose Levocarnitine Erythritol Betaine
Preservatives	Prevent microbial growth in multi-dose formulations	Benzalkonium chloride (BAK) Sodium chlorite Sodium perborate
Buffers	Control pH	Sodium borate Sodium citrate Sodium phosphate
Electrolytes	Promote ocular surface homeostasis	Potassium Calcium Magnesium Phosphate

 

 

Viscosity-enhancing agents, or demulcents, are the most common ingredient in AT and typically listed as the active ingredient on product packaging. The higher the viscosity (i.e., the thicker the product), the longer the ocular surface retention time, but differences in viscosity can influence product choice. High viscosity can create visual disturbances and buildup on the eyelid leading to decreased adherence.²⁶ These products are best for nighttime use, and patients should use lower-viscosity products during the day.²⁶ Many products contain multiple viscosity-enhancing agents. Commonly paired agents include carboxymethyl cellulose (CMC) with hyaluronic acid (HA) and hydroxypropyl-guar (HP-guar) with HA.^14,26 Studies suggest that combining viscosity-enhancing components improves symptom control.¹⁴

 

There is significant interest in developing novel formulations to increase the spreading and retention time of applied drops.¹⁴ Lipid-containing eye drops are gaining in popularity as understanding of DED’s pathophysiology progresses.¹⁴ Lipids restore and thicken the lipid layer of the tear film and prevent tear evaporation. Formulated as oil-in-water emulsions, lipid-containing products contain macro-, micro-, or nano-particles. Particle size is important. Macro particles are associated with cloudy, blurred vision. As particle size decreases, blurring decreases.¹⁴

 

Osmoprotectants balance osmotic pressure, as the name implies, to protect and prevent corneal and conjunctival cell death.²⁶ Levocarnitine and erythritol protect cells from hyperosmolar stress and improve DED’s symptoms.²⁶ Clinical trials have shown that trehalose is more effective at improving ocular surface staining than saline.^14,26

 

Multi-dose products contain preservatives to prevent microbial growth, but these can also worsen symptoms in DED. Benzalkonium chloride (BAK), the most common preservative, may cause corneal damage and interfere with tear film stability.¹⁴ Newer “disappearing preservatives” (e.g., sodium chlorite, sodium perborate) have a lower impact on the ocular surface. Exposure to light or the ocular surface breaks down these compounds, minimizing toxicity.^14,27 Even newer preservatives carry risk, making preservative-free drops the best choice, especially in patients with severe DED. Preservative-free AT products are available in disposable single-use units but are generally more expensive.¹⁴

 

The pH of ATs affects product activity, stability, patient comfort, and safety.¹⁴ Adding electrolytes to reproduce the electrolyte profile of the tear film aids osmotic balance. Studies show that hypotonic solutions (i.e., having a lower osmotic pressure) decrease DED signs.²⁶

 

No large-scale, randomized clinical trials have evaluated all currently available AT formulations. Some clinical trials evaluate individual AT products, and a few head-to-head studies exist.^16,28 Several published systematic reviews have concluded that ATs treat DED safely and effectively. One systematic review of more than 60 studies published in 2022 drew the following conclusions²⁷:

• Combination formulations, including the following, may be more effective than single-ingredient products: CMC and HA, HA and trehalose, CMC and glycerin, and HA and coenzyme Q10.
• Formulations containing polyethylene glycol (PEG) may be more effective than those with CMC.
• Preservative-free formulations are preferable.
• Patients with EDE and/or MGD should use drops containing phospholipids.
• Patients should administer AT four times daily for one month to assess efficacy.
• Patience is key; sometimes, it may take up to four months of consistent use to see improvement.

 

Another literature review of 18 studies compared commercially available AT products and concluded that products containing CMC, hydroxypropyl methylcellulose (HPMC), or HA were the most beneficial in improving patient comfort level.²⁹ This study also determined that clinicians should recommend administration three to four times daily for two months to assess patient response before escalating therapy. The use of a preservative-free formulation is preferable.²⁹ If patients choose or clinicians recommend preservative-containing eye drops, administration should be limited to four to six times daily.²⁹ Researchers created a stepwise approach to selecting AT products²⁹:

• Step 1: Start with CMC, HPMC, or HA-based formulations
• Step 2: Move to formulations with PEG or PEG and glycerin
• Step 3: Consider gel or lipid formulations
• Step 4: Progress to ointments, liposomal sprays, or prescription inserts

 

Both studies reached similar conclusions. Adherence and persistence are key to successfully evaluating an individual product, a fact that pharmacy staff should reiterate to patients. While some trial and error may be necessary, following the above recommendations allows patients and providers an organized approach to AT selection. While AT are a mainstay of early symptomatic treatment of dry eye disease, they do not address DED’s underlying causes. Prescription therapies target the underlying inflammatory processes.

 

Hydroxypropyl cellulose ophthalmic insert (HCOI) is a prescription-only lubricant insert containing 5 mg of hydroxypropyl cellulose. The insert is preservative-free and designed to provide continuous lubrication throughout the day. Patients insert HCOI once daily using an applicator.³⁰ They rinse the applicator in hot water then use the grooved end to pick up the insert. Patients then place the insert in a pocket created by pulling out the outer corner of the eyelid. The HCOI softens and slowly dissolves, stabilizing and thickening the tear film, prolonging TBUT. One study comparing HCOI to using AT four or more times a day found increased TBUT and decreased foreign body sensation with HCOI compared to AT.^30,31 Reported adverse effects include blurred vision, eye irritation, eyelid matting, and light sensitivity.³⁰

 

Pause and Ponder: A patient approaches the pharmacy counter with a plastic bag full of bottles of different brands of artificial tears. Dumping them on the counter, she states, “None of these work! I don’t know what to do next.” What advice would you give her?

 

PRESCRIPTION THERAPIES

Available prescription therapies (outlined in Table 5) target the inflammatory cycle of DED through different mechanisms with varying degrees of success.

 

Table 5. Prescription Therapies to Treat Dry Eye Disease^28,32-36

Drug	Brand Name (Manufacturer)	Formulation(s)	Dosing	Supplied
Cyclosporine A	Restasis (Allergan)	0.05% emulsion	1 drop in each eye BID	Single-use vials
	Cequa (Sun Pharma)	0.09% solution	1 drop in each eye BID	Single-use vials
	Generic (Mylan)	0.05% solution	1 drop in each eye BID	Single-use vials
Lifitegrast	Xiidra (Novartis)	5% solution	1 drop in each eye BID	Single-use containers
Loteprednol	Eysuvis (Kala Pharma)	0.25% suspension	1-2 drops in each eye QID for up to 2 weeks	Multi-dose 10 mL bottle
Perfluorohexyloctane	Meibo (Bausch & Lomb)	100% solution	1 drop in each eye QID	Multi-dose 5 mL bottle
Varenicline	Tyrvaya (Oyster Point Pharma)	0.03 mg/0.05ml solution	1 spray in each nostril BID	Multi-dose nasal spray

ABBREVIATIONS: BID, twice daily; QID, four times daily

 

Cyclosporine A

Cyclosporine A (CsA) is an anti-inflammatory immune modulator approved for use in DED more than two decades ago.¹⁶ Calcineurin activates T-cells, increasing inflammatory cytokine production. CsA inhibits calcineurin to prevent T-cell activation, disrupting the inflammatory cycle in DED.¹⁶

 

Many clinical trials have evaluated CsA’s safety and efficacy in DED treatment.^1,5,14,37 Results consistently show that CsA improves Schirmer test scores, corneal staining results, and goblet cell density. Improvement often takes several months, making patient education key to adherence.^1,5,14,37 Topical CsA alleviates symptoms in approximately 50% of patients.¹ Patients using CsA experience decreases in blurred vision, ocular dryness, foreign body sensation, and watery eyes.^1,14 Treatment often causes stinging and irritation. Other adverse effects include blurred vision, ocular itching, eye redness, and foreign body sensation.³⁷ Pretreatment with an ophthalmic steroid such as loteprednol may decrease CsA’s adverse effects.^1,38

 

As a hydrophobic (water-fearing) substance, CsA is challenging to formulate into an ophthalmic topical formulation. Initially, products used castor oil and corn oil as vehicles, but poor bioavailability and adverse effects preclude their use.¹⁶ The first commercially available CsA product, a 0.05% emulsion, uses a castor oil-in-water emulsion, which reduces but does not eliminate adverse reactions.³⁷

 

Approval of CsA 0.09% nanomicellar solution introduced a novel formulation.^16,37 Clinical efficacy trials found a response as early as day 28.¹⁶At the end of 12 weeks, 17% of study participants receiving CsA 0.09% experienced increased tear production with a Schirmer score greater than 10 mm. Reported adverse effects included mild instillation site pain, eye irritation, blepharitis, and headache.³² Preliminary studies suggest CsA 0.09% is more effective and better tolerated than CsA 0.05%.¹⁶

 

Lifitegrast

Approved in 2016, the novel drug lifitegrast is a lymphocyte function-associated antigen-1 (LFA-1) antagonist.³³ LFA-1 binds to intracellular adhesion molecule-1 during inflammation, activating T-cell migration and resulting in ocular inflammation. Lifitegrast binds to LFA-1, preventing this interaction and decreasing T-cell-mediated inflammation.³³ The U.S. Food and Drug Administration (FDA) approved this drug based on four randomized, double-masked, 12-week efficacy and safety trials. ^33,39-41 All studies showed a reduction in patient-rated eye dryness scores at the end of 12 weeks. Patients in three of the four studies experienced reduced corneal staining scores.³³

 

The one-year multicenter, randomized, placebo-controlled SONATA study evaluated lifitegrast safety.⁴² Reported adverse effects included burning, reduced visual acuity, dry eye, and taste changes. Researchers observed no serious adverse events and discontinuation rates were 12.3% and 9% for lifitegrast and placebo, respectively.⁴² A 2021 retrospective review of 600 patient charts examined real-world experience with lifitegrast in DED.⁴³ Most patients continued treatment for six months and showed improvement in DED symptoms. Patients also experienced improved quality of life at three and 12 months of treatment.⁴³

 

Perfluorohexyloctane

Perfluorohexyloctane, formerly known as NOV3, reduces tear evaporation from the ocular surface.⁴⁴ The drug’s exact mechanism in DED is unclear. In May 2023, the FDA approved an ophthalmic formulation containing perfluorohexyloctane for treating DED in adults 18 and older based on data from two phase 3 clinical trials: GOBI and MOJAVE.^44,45

 

These trials evaluated efficacy and safety in more than 1,200 patients with DED meeting similar inclusion and exclusion criteria based on tear film break-up time, ocular surface disease scores, and MGD evaluations. Both trials were multi-center, randomized, double-masked, and saline-controlled.^44,45 GOBE and MOJAVE results also consistently showed statistically significant reductions in reported symptoms of DED. Reported adverse events occurred in less than 4% of study participants and included blurred vision, blepharitis, instillation site pain, and conjunctival redness.^44,46 Patients must remove contact lenses before and for at least 30 minutes after administration of perfluorohexyloctane drops.³⁴

 

Perfluorohexyloctane should be available in the second half of 2023.⁴⁴

 

Short-Term Corticosteroids

Corticosteroids are potent inhibitors of inflammatory mediators.¹⁴ Many clinical trials have demonstrated their efficacy in breaking the inflammatory cycle of DED. Unfortunately, long-term therapy is associated with increased intraocular pressure, cataracts, and risk of infection.¹⁴

 

Loteprednol is a synthetic corticosteroid derived from prednisolone. Its rapid breakdown into inactive metabolites reduces risk of adverse reactions.⁴⁷ A retrospective safety study concluded that loteprednol therapy carries a low risk of treatment-related elevated intraocular pressure compared to other steroids.⁴⁸ Several loteprednol ophthalmic formulations are available, but only the 0.25% suspension is FDA approved for the short-term treatment of DED. This formulation uses mucus-penetrating particle (MPP) technology to allow nanoparticle penetration through the mucin layer.^47,49

 

The FDA approved loteprednol 0.25% suspension based on the STRIDE series of trials.³⁶ These trials randomized patients with DED to the drug or a vehicle control four times daily in both eyes for two weeks. All trials reported significant improvements in eye redness and discomfort at the end of two weeks.³⁶

 

One role for topical steroids in DED is pre-treatment prior to topical CsA therapy. A 2014 study compared loteprednol versus AT during a two-week lead-in period to CsA.³⁸ Patients self-administered either loteprednol or AT four times daily for two weeks, followed by CsA twice daily plus either loteprednol or AT twice daily for an additional six weeks. Both groups showed improved ocular staining and OSDI and Schirmer scores. Loteprednol provided more rapid relief of DED symptoms and resulted in a lower CsA discontinuation rate than AT.³⁸

 

Patients with moderate-to-severe DED with adequate long-term control may still experience periodic symptom exacerbation. Short-term pulse steroid therapy (using steroids of a week or two, then tapering and resuming if necessary) can be useful for patients with symptom exacerbations.¹⁴

 

Varenicline Nasal Spray

Pharmacy staff may recognize varenicline as a treatment for smoking cessation, but a newer nasal spray formulation shows utility for treating DED. Tear film production results from stimulating afferent nerves in the cornea and conjunctiva and parasympathetic nerves in the lacrimal gland, meibomian glands, and goblet cells.^50,51 This neural pathway is accessible through central nervous system or peripherally through the nasal cavity. While the drug’s mechanism in DED is not fully understood, experts theorize that varenicline, a cholinergic agonist, activates this pathway to stimulate tear production.^50,51

 

The randomized, double-masked, vehicle-controlled, 28-day ONSET-1 and ONSET-2 trials evaluated varenicline nasal spray’s safety and efficacy.^50,51 Participants self-administered one spray of varenicline solution or vehicle in each nostril twice daily. Both studies found a significant improvement in tear production measured by Schirmer scores. The most common patient-reported adverse effects included sneezing, cough, throat irritation, and nasal irritation.^50,51 The 2021 MYSTIC study examined varenicline nasal spray's long-term safety and efficacy compared to placebo over a 12-week period.⁵² Patients reported no severe or serious adverse events during the study; sneezing was the most common adverse reaction, occurring in 82% of patients.⁵²

 

Varenicline packaging includes two glass bottles, each containing a 15-day drug supply. Patients must initially prime the bottle by pumping seven sprays into the air away from the face. Re-priming by pumping one spray into the air is necessary after five days of nonuse.³⁵

 

Steps for administration of varenicline nasal spray³⁵:

• Blow nose if needed to clear nostrils
• Remove the cap and clip from the bottle
• Hold the bottle upright, placing one finger on each side of the applicator and thumb on the bottom of the bottle
• Tilt head back slightly
• Insert the applicator tip into one nostril, pointing it toward the ear on the same side of the nostril, leaving space between the tip and the wall of the nostril
• Place tongue on roof of mouth and breath gently while pumping one spray into the nostril
• Repeat in other nostril
• Wipe the applicator with a clean tissue and replace the cap and clip

 

Antibiotics

Clinicians sometimes use oral or topical antibiotics with anti-inflammatory effects off-label to treat DED due to MGD.¹⁴ Many patients experience MGD due to overgrowth of eyelid flora, so reduction of eyelid flora and inflammation improves patient-reported symptoms.⁵³ Oral administration of doxycycline and minocycline in small doses (40 to 400 mg of doxycycline and 50 to 100 mg of minocycline) to treat MGD improves patient-reported symptoms.^1,53 Unfortunately, gastrointestinal adverse effects limit the use of these medications. One study found that azithromycin 1% eyedrops improved eyelid inflammation and tear film lipid layer stability.⁵⁴

 

EMERGING THERAPIES

New and novel therapies are also in the pipeline for DED treatment. Pharmacy staff should be aware of their potential place in therapy and prepared to incorporate them upon approval.

 

Reproxalap

Exploring another causative mechanism in DED, reproxalap is a reactive aldehyde species (RASP) inhibitor. RASP molecules are found at the top of the inflammatory cascade and are elevated in many inflammatory diseases. They bind to and disrupt the function of enzymes and ion channels, which activates pro-inflammatory mediators. RASP inhibition, therefore, decreases pro-inflammatory substances associated with DED.^55,56

 

A randomized, double-masked, phase 2a trial evaluated the efficacy of three formulations of reproxalap: 0.1% and 0.5% solutions and a 0.5% lipid solution.⁵⁵ Participants used the products four times daily for 28 days. The study found a significant improvement in four questionnaire scores, Schirmer test values, tear osmolarity, and tear staining scores. Within one week, patients reported symptom improvement. Researchers concluded that reproxalap could potentially alleviate DED symptoms.⁵⁵

 

A separate randomized, double-masked, phase 2b trial compared reproxalap 0.01% and 0.25% to a control vehicle solution.⁵⁶ Patients self-administered drops four times daily for a total of 12 weeks. The study found statistically significant improvements in ocular dryness and staining over 12 weeks.⁵⁶

 

A 2021 tolerability study compared ocular adverse effects between two formulations of reproxalap 0.25% (one solution, one lipid-based) and lifitegrast 5% solution.⁵⁷ Over seven days, study participants received one dose of each solution with a 3-day washout period between administrations. Researchers assessed adverse effects after 1 hour. Reproxalap formulations were similar to one another and superior to lifitegrast in ocular discomfort, blurry vision, and dysgeusia.⁵⁷

 

Reproxalap offers a novel approach to treating the underlying inflammatory process involved in DED. Preliminary study results show improvements in DED symptoms and better patient tolerability, potentially leading to lower discontinuation rates and improved patient outcomes.

 

Cationic Cyclosporine

A cationic (positively charged) 0.1% CsA nanoemulsion is available in Europe to treat DED.⁵⁸ Experts theorize that a cationic emulsion increases the surface time of CsA on ocular tissues. All FDA-approved products are anionic (negatively charged). Clinical trials are evaluating CsA 0.1% nanoemulsion for FDA approval.⁵⁸

 

PHARMACY TEAMS: FRONT-LINE SUPPORT

Pharmacists and pharmacy technicians are among the most accessible healthcare providers. People routinely turn to neighborhood pharmacies for advice on many health topics. Most people self-treat dry eye symptoms long before seeking professional help. These facts make the pharmacy team essential in supporting people suffering from DED. The SIDEBAR provides basic counseling information about eye products.

 

SIDEBAR: Counseling Tips for Eyedrop and Eye Ointment Administration^59,60

Proper administration of ophthalmic formulations is key to their success. Administration is awkward, and many patients struggle with it. Advising patients on proper technique is a key role for the pharmacy team. General tips for all ophthalmic products include

• Confirm you have the correct product
• Check expiration date
• Read the directions
• Wash your hands
• If using both eyedrops and eye ointment, wait five to ten minutes between drops, and administer the eyedrops at least 10 minutes before the ointment
• Using a mirror may make it easier to see what you are doing

 

Eyedrops:

1. Gently shake the bottle

1. Be sure the eye dropper is clean, and do not let it touch any surface
2. Tilt your head back and look up

4. Pressing your finger gently on the skin just beneath the lower eyelid, pull your lower eyelid down and away from your eyeball to make a “pocket” for the drops
5. With the other hand, hold the eye drop bottle upside down with the tip just above the pocket
6. Squeeze the prescribed number of eye drops into the pocket
7. If you think you did not get the drop of medicine into your eye properly, use another drop
8. Blink a few times so that the medicine spreads across your eye
9. For at least 1 minute, close your eye and press your finger lightly on your tear duct (small hole in the inner corner of your eye) to keep the eye drop from draining into your nose

1. Wash your hands

11. Wait at least 10 minutes before you use other eye products, especially ointments, gels, or other thick eye drops

 

Eye ointment:

1. Be sure the top of the ointment tube is clean, and don’t let it touch any surface, including the eye, eyelid, or lashes. (If it does, call your pharmacy and arrange to get another tube of eye ointment.)
2. Tilt your head back and look up
3. With one hand, pull the lower eyelid down with one or two fingers to create a small pouch
4. With the other hand, position the medicine above your eye
5. Put a thin line of ointment in the pouch. Close the eye for 30 to 60 seconds to let the ointment absorb
6. Wash your hands
7. Eye ointments can cause some temporary blurring of vision

 

Knowledge of risk factors, including precipitating medications (revisit Table 3 for a refresher), aids in identifying patients at risk for developing DED. Technicians are often the first point of contact at the pharmacy counter, routinely fielding questions. Actively listening and asking open-ended questions help gather necessary information. Patients reporting dry eye symptoms or buying AT products may need counseling or a referral to a pharmacist or an eye care professional.

 

Educating patients about avoiding certain environmental factors is important. Remind patients that minimizing exposure to wind or smoke, taking a break from digital screens, and using a humidifier may help alleviate symptoms. Adherence to therapeutic interventions is key in DED treatment. Some interventions, such as lid hygiene, are time-consuming, and many patients stop after only a few days.  Reinforcing the importance of lid hygiene with patients is an important component of DED patient counseling.

 

 

Advising patients on selecting an appropriate AT product decreases frustration and increases overall patient satisfaction. Proper administration of ophthalmic preparations can be difficult for some patients, particularly older individuals. Taking the time to counsel on proper technique sets patients up for successful administration and improved outcomes.

 

Patients with severe refractory DED may not benefit enough from lifestyle modifications and pharmacologic therapy. Many other interventions exist including¹⁴

• Punctal plugs blocking the tear ducts to promote tear conservation
• Pulsed light therapy delivered in office with a handheld flash gun
• Tear stimulation utilizing topical and systemic secretagogues
• Biological tear substitutes utilizing patient-derived serum
• Use of therapeutic contact lenses made of silicone hydrogel
• Surgery to correct any causative physiological abnormalities

Pharmacy staff should recognize when patients with worsening DED symptoms may require escalation of therapy and refer them to an eye care provider when appropriate.

 

Pause and Ponder: Consider your home and work environment. Could you take steps to minimize conditions contributing to developing dry eye?

 

CONCLUSION

You may have noticed a recurring theme throughout this activity: education. Helping patients understand the chronic nature of DED and navigate treatment options improves patient care and outcomes. Education must include the entire pharmacy team. Understanding the roles of each treatment allows for effective management and counseling. Educated pharmacy teams can assist patients with product selection, counsel on the timing and administration of treatments, improve safety, and provide referrals when appropriate.

 

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