INTRODUCTION

Acne vulgaris is a chronic skin condition characterized by open or closed comedones (bumps) and the development of inflammatory papules, pustules, or nodules.¹ Papules are small, raised bumps; pustules are small, pus-filled bumps; and nodules are larger, solid lesions that extend into the deeper layers of the skin. Acne is among one of the most common skin disorders, frequently affecting adolescents and young adults. In the 2013 Global Burden of Disease study, acne vulgaris ranked second most burdensome skin disease among all skin diseases as measured by disability-adjusted life years.² Experts estimate acne’s prevalence in young adults to be between 35% to more than 90%, with males affected more often than females in this age category.³ Acne’s incidence generally declines with increasing age, and tends to exhibit a female predominance following adolescence, affecting up to 15% of women.⁴

 

While acne is not associated with mortality, several complications may arise such as hyperpigmentation, scarring, and negative psychosocial effects.³ A variety of treatment options are available for acne vulgaris, both over-the-counter (OTC) and prescription; product selection depends on lesion severity and patient-specific factors. Topical therapies are for milder cases, while systemic therapies are employed in more severe cases, typically in conjunction with topical treatments.

 

Pathogenesis of Acne

Acne vulgaris is a complex inflammatory disorder affecting the pilosebaceous unit of the skin, which is composed of the hair follicle and sebaceous gland (glands that secrete sebum, an oily substance that keeps skin from drying out).³ Acne’s pathogenesis involves several different host factors that lead to lesion formation. The four main contributing factors associated with acne development include hyperkeratinization of follicles, increased sebum production, Cutibacterium acnes bacteria, and inflammation.³

 

Increased sebum secretion from sebaceous glands, often stimulated by androgens, serves as a growth medium for C. acnes bacteria. This bacterium has the propensity to activate an immune response that subsequently triggers an inflammatory response. The inflammatory response results in the formation of inflammatory papules and pustules.

 

Acne vulgaris may have other etiologies aside from the four main biologic factors. Cutaneous lesions can occur by way of mechanical injury or skin trauma because of scrubbing, squeezing, or friction, referred to as acne mechanica.⁵ Additionally, an association exists between psychologic stress and increased acne severity. Genetics is another factor that may contribute to the development of acne. Studies have shown that individuals with close family members who have acne are at increased risk of developing the condition.³

 

Insulin resistance is also implicated in the formation of acne as it can stimulate androgen production and lead to increased serum levels of insulin-like growth factor-1 (IGF-1). Increased IGF-1 levels are linked to increased facial sebum excretion, which ultimately facilitates acne formation. Androgens contribute significantly in the development of acne as they stimulate the growth and secretory function of sebaceous glands, further increasing sebum production.³

 

Several dietary elements have been associated with acne, although the evidence is not robust. A reduced glycemic index or a glycemic load diet (i.e., a low carbohydrate diet with reduced intake of processed meats, added sugar, and refined grains) may reduce the quantity and severity of acne lesions by reducing free androgens and IGF-1 levels.⁶ Additionally, omega-3 fatty acids can decrease IGF-1 and inhibit pro-inflammatory leukotriene B₄, which potentially lessens the number of lesions. Conversely, milk and dairy products have been associated with an increase in acne lesions, likely due to their opposite effects on IGF-1 levels.³

 

In addition to dietary intake, the gut microbiome can impact acne development.⁶ A randomized, placebo-controlled double-blind study of 20 adult patients with acne showed promising results in acne improvements with probiotic supplementation over a 12-week period.⁷ While this preliminary data supports the use of probiotics for acne, more robust data is needed to confirm these findings.

 

Despite these dietary correlations, the relationship between acne and weight or body mass index (BMI) is uncertain. A large population-based study of about 600,000 adolescents in Israel found that obesity was inversely related to the development of acne.⁸ Conversely, a smaller scale case-control study of adolescents with moderate to severe acne found a correlation between lower BMI and lower incidence of acne.⁹ As studies have yielded mixed results, a connection is unclear at this time.

 

Pretreatment Assessment

Prior to establishing a treatment plan, thorough assessment of the types of acne lesions and severity of those lesions is essential. Additionally, clinicians should consider potential contributing factors such as comedogenic skincare products (i.e., products that have a high likelihood of clogging pores), medications, or endocrine disorders. They should also consider the presence of complications such as scarring, hyperpigmentation, or presence and extent of psychologic distress when establishing treatment regimens and setting treatment goals.¹⁰ Anatomic location of the lesions is important to note as well.¹

 

Acne vulgaris lesions are either comedonal or papulopustular³:

• Comedonal lesions are milder in severity and characterized by closed comedones, also known as “whiteheads,” or open comedones, also known as “blackheads.” Comedonal lesions are non-inflammatory and typically smaller than 5 mm in size, or smaller than the size of a pencil top eraser.
• Papulopustular acne has a more inflamed presentation with relatively superficial papules or pustules, although still typically smaller than 5 mm in size.
• Nodular acne is a more severe variation of papulopustular acne with deep-seated, inflamed and often tender, large papules or nodules.

 

While no universally accepted method of assessing acne grade or severity exists, several characteristics may differentiate between mild acne and more severe variants. Mild acne typically has limited skin involvement with scattered, small (less than 5 mm in size) comedonal lesions or inflamed papules. Mild acne also has an absence of near confluent skin involvement (defined as lesions that flow together) and no scarring or large nodules. Many visually prominent comedonal or inflammatory papulopustular lesions are characteristic of moderate to severe acne. Other features indicative of moderate to severe acne include the presence of large nodules, scarring, and involvement of multiple body areas.¹⁰

 

PAUSE AND PONDER: Since several treatments for acne are available over-the-counter (OTC), what is a reasonable regimen for mild acne using only OTC drugs?

 

Treatment for Mild Acne

The American Academy of Dermatology published guidelines for the management of acne vulgaris in 2016, and on January 30, 2024, the academy published an update to these guidelines in the form of a systematic review.^1,11 The updated guidelines offer evidence-based recommendations and several good practice statements for the management of acne vulgaris. The guidelines classify recommendations as strong, where the benefits clearly outweigh the risks, or conditional, where the benefits are closely balanced with risks and burden. Conditional recommendations apply to most patients, but the most appropriate action may differ depending on patient or other stakeholder values.¹¹

 

Topical medications—as monotherapy or in combination—are typically the initial treatment of choice for mild acne.¹¹ For mild comedonal acne without inflammatory lesions, treatment with a topical retinoid is an appropriate choice.¹ Mild papulopustular and mixed acne may benefit from either a combination of a topical retinoid and topical antimicrobial or benzoyl peroxide and a topical antibiotic. Combining topical antibiotic treatment with benzoyl peroxide decreases the development of antibiotic resistance to C. acnes and improves treatment outcomes.¹⁰ The 2024 guidelines strongly recommend the following topical therapies for patients with acne based on moderate evidence: benzoyl peroxide, topical retinoids, and topical antibiotics (although not as monotherapy).¹¹

 

Topical Retinoids

Topical retinoids are routinely the initial treatment choice for mild comedonal acne. As vitamin A (retinol) derivatives, retinoids are important regulators of cell reproduction, proliferation (self-multiplication), and differentiation (specialization into specific cell types).¹² In comedonal acne, retinoids normalize follicular hyperkeratosis (excessive development of keratin in hair follicles which result in papules) and prevent formation of the microcomedo, the primary lesion of acne.¹⁰ Table 1 lists the four currently available topical retinoid therapies for acne vulgaris: adapalene, tazarotene, tretinoin, and trifarotene.

 

Table 1. Topical Retinoids for Acne Vulgaris^10,13

Medication	Usual Dosage	Available Dosage Forms	Common Adverse Effects
Adapalene	Apply to acne lesions once daily in the evening or before bedtime	Cream: 0.1% Gel: 0.1% (OTC), 0.3% Lotion: 0.1%	Local skin irritation: erythema (redness), skin scaling, xerosis (dryness), burning, and pruritus (itching); photosensitivity (light sensitivity)
Tazarotene		Cream: 0.05%, 0.1% Gel: 0.05%, 0.1% Foam: 0.1% Lotion: 0.045%	Local skin irritation: burning and stinging, contact dermatitis, erythema, pruritus, skin discoloration, skin inflammation, application site pain, and xerosis; photosensitivity
Tretinoin		Cream: 0.025% to 0.1% Gel: 0.01% to 0.05% Lotion: 0.05% Microsphere gel: 0.04% to 0.1%	Local skin irritation: peeling, xerosis, burning, stinging, erythema, and pruritus; photosensitivity
Trifarotene		Cream: 0.005%	Application site pruritus, skin irritation, and photosensitivity

OTC, over the counter.

 

Tretinoin, when used topically, reduces the likelihood of follicular epithelial cells from sticking together, and decreases microcomedone formation. Additionally, it can increase turnover of follicular epithelial cells and stimulates mitotic activity or cell division thereby causing expulsion of comedones.¹⁴ Tretinoin is available in various dosage forms including creams, gels, and lotions. Newer formulations of tretinoin such as microsphere gels release the medication more slowly and are generally less irritating.¹⁰

 

Patients should apply tretinoin to the affected area once daily at bedtime, 20 minutes following washing and drying of the face. Newer formulations are more stable, allowing patients to use them immediately following cleansing.¹⁴ Adverse effects of topical tretinoin, listed in Table 1, are typically most pronounced in the first month of therapy. Pharmacy teams should instruct patients to apply sunscreen in the morning to minimize photosensitivity (sensitivity to light), and guidelines recommend using sunscreen throughout the course of treatment with topical retinoids.¹

 

Adapalene is a retinoid-like drug that functions as a modulator of cell differentiation, keratinization (i.e., when the epithelial cells develop a hardened horn-like character), and inflammatory processes.¹⁵ Adapalene is available as a cream, gel, and lotion applied topically at bedtime after cleansing. It is the only retinoid available without a prescription. Adapalene has demonstrated similar efficacy and superior tolerability compared to other retinoids.¹⁶

 

Tazarotene is a retinoid prodrug (i.e., inactive compound that turns into an active drug once metabolized) that reduces the number of inflammatory and non-inflammatory lesions in acne vulgaris.¹⁷ Patients apply tazarotene (a cream, gel, foam, or lotion) to the affected area once daily at bedtime after cleansing. The adverse effect profile is similar to that of other retinoids. While topical retinoid therapy is generally not recommended in pregnancy, this topical acne medication is contraindicated in pregnancy.

 

Trifarotene is a retinoic acid receptor (RAR) agonist with specific activity at the gamma subtype of RAR. RAR activation causes transcription of several genes that are responsible for cell differentiation and mediation of inflammation.¹⁸ It is the first topical retinoid specifically studied in both facial and truncal acne, yielding favorable safety, tolerability, and efficacy data in patients with moderate acne.¹⁹ Trifarotene is available as a cream applied once daily in the evening or before bedtime.

 

Benzoyl Peroxide

Benzoyl peroxide is a topical oxidizing drug which kills the bacteria on the skin, halts the production of sebum, and breaks down the outermost layer of the skin. It has potential to improve both inflammatory and non-inflammatory acne lesions.²⁰ Benzoyl peroxide is available in a variety of dosage forms including creams, gels, washes, and foams and in several concentrations ranging from 2.5% to 10%, most of which are available OTC. Concentration-dependent irritation, staining, and bleaching of fabric and hair is a limiting factor in treatment with benzoyl peroxide. Pharmacists and technicians should inform patients that staining of towels and pillowcases is common when using this medication.

 

Irritation from benzoyl peroxide manifests as erythema, scaling, xerosis, or stinging, tightening, or burning sensations.¹⁰ Generally, lower concentrations (i.e., 2.5% to 5%), water-based, and wash-off products have better tolerability, particularly in patients with sensitive skin.¹ Presently, C. acnes shows no resistance to benzoyl peroxide, so addition of this medication to other regimens may further minimize development of antibiotic resistance.

 

Benzoyl peroxide is optimal for mild papulopustular acne with or without comedonal lesions. Patients may use benzoyl peroxide in conjunction with a retinoid or topical antibiotic, and several combination products are available by prescription only (described in Table 2). If using benzoyl peroxide in combination with tretinoin, patients should apply the medications at different times of the day to avoid oxidation or degradation of the tretinoin product (i.e., use benzoyl peroxide in the morning and tretinoin in the evening). Benzoyl peroxide application timing does not matter when co-administered with the tretinoin microsphere formulation or other retinoids.¹ The guidelines recommend using benzoyl peroxide one to three times daily, however, an increase in adverse effects such as dryness can occur with increased frequency of use. Usually, visible improvement occurs after about three weeks of benzoyl peroxide use, and maximal improvement is apparent after eight to 12 weeks.¹⁰

 

Table 2. Topical Combination Medications for Acne Vulgaris ^10,13

Category	Medication	Usual Dosage
Benzoyl Peroxide and Topical Antibiotic	Benzoyl peroxide 5% / clindamycin 1% gel	Apply twice daily
	Benzoyl peroxide 5% / clindamycin 1.2% gel	Apply once daily in the evening
	Benzoyl peroxide 2.5% / clindamycin 1.2% gel	Apply once daily in the evening
	Benzoyl peroxide 3.75% / clindamycin 1.2% gel	Apply once daily in the evening
	Benzoyl peroxide 5% / erythromycin 3% gel	Apply twice daily
Antimicrobial and Retinoid	Clindamycin 1.2% / tretinoin 0.025% gel	Apply once daily in the evening
	Benzoyl peroxide 2.5% / adapalene 0.1% gel	Apply once daily in the evening
	Benzoyl peroxide 2.5% / adapalene 0.3% gel	Apply once daily in the evening
	Benzoyl peroxide 3% / tretinoin 0.1% cream	Apply once daily in the evening
Antimicrobial, Antibiotic and Retinoid	Benzoyl peroxide 3.1% / clindamycin 1.2% / adapalene 0.15% gel	Apply once daily

 

Topical Clindamycin

Clindamycin is an antibiotic used topically for acne vulgaris, most often in combination with benzoyl peroxide. The guidelines discourage monotherapy with topical antibiotics due to concerns for antibiotic resistance.¹¹ Clindamycin is available in numerous topical dosage forms including gels, solutions, lotions, foam, and pledgets (small cotton rounds with medication embedded) and comes co-formulated with several retinoid medications.

 

A meta-analysis comparing different topical treatments for acne demonstrated that gels containing benzoyl peroxide and clindamycin in combination were modestly more effective than benzoyl peroxide alone for the treatment of inflammatory acne lesions, superior to clindamycin alone, and resulted in faster improvement.²¹ Clindamycin is generally well tolerated when used topically, but irritation may occur as with any topical acne medication. Patients apply clindamycin to the affected area twice daily. Topical erythromycin is an alternative to clindamycin; however, reduced efficacy due to antibiotic resistance has limited its use.¹

 

Salicylic Acid and Azelaic Acid

Several alternative topical medications are available for patients with acne who are unable to tolerate retinoid therapy. Topical salicylic acid is a comedolytic medication (product which resolves papules and prevents formation of new ones) with mild anti-inflammatory properties that works by causing desquamation (shedding) of the horny layer of skin.²² It is available OTC in a variety of different gels, washes, pads, masks, lotions, and solutions. The guidelines conditionally recommend salicylic acid for patients with acne based on low certainty of evidence.¹¹ Salicylic acid is typically dosed once daily, however patients may increase to two or three times daily if needed, as tolerated. Skin dryness and peeling may occur from using this medication, especially when used in excess.²³ For patients seeking an OTC resolution for acne, pharmacists can suggest salicylic acid in combination with benzoyl peroxide.

 

Azelaic acid is an effective treatment for acne due to its antimicrobial and antikeratinizing effects on the follicular epidermis and carries a conditional recommendation based on the guidelines.^24,11 Azelaic acid possesses mild anti-inflammatory properties and can improve acne-induced, post-inflammatory hyperpigmentation.¹⁰ Patients apply this medication to the affected area twice daily, and it comes formulated as a cream, gel, and foam. Studies have shown that azelaic acid’s efficacy is comparable to other topical acne treatments, and it is generally well tolerated. Azelaic acid’s most common adverse effect, as with other topical acne medications, is local skin irritation.^25,26

 

Alternative Therapies for Resistant Disease

In patients who report insufficient improvement with first line treatments, providers may consider several additional topical options before starting systemic therapy. For comedonal acne, providers may try an alternative concentration of the retinoid therapy if there is room to increase, or switch to another retinoid drug if the current medication is already maximally dosed. For papulopustular acne, providers may change the retinoid medication or add concomitant benzoyl peroxide and/or a topical antibiotic, if desired. Alternative approaches to managing papulopustular acne involve the addition of topical dapsone, clascoterone, or topical minocycline.¹⁰ Table 3 lists antimicrobial therapies and additional alternative topical medications available for the treatment of acne vulgaris.

 

Table 3. Antimicrobial Therapies and Alternative Topical Medications used for Acne Vulgaris ^10,13

Category	Medication	Usual Dosage	Available Dosage Forms	Common Adverse Effects
Antimicrobial	Benzoyl Peroxide	Apply one to three times daily	2.5 to 10% gels, lotions, creams, pads, masks, cleansers, foam (most are OTC)	Local skin irritation
	Clindamycin	Apply twice daily	1% gel, lotion, pledget, solution, foam	Generally well tolerated, skin irritation may occur
	Dapsone	Apply once daily	Gel: 5%, 7,5%	Application site dryness and pruritus
	Erythromycin	Apply twice daily	2% gel, solution, pledget	Generally well tolerated, skin irritation may occur
	Minocycline	Apply once daily 1 hour prior to bed	Foam: 4%	Headache
Topical Androgen Receptor Inhibitor	Clascoterone	Apply twice daily	Cream: 1%	Scaling, dryness, edema, or irritation of skin; HPA axis suppression
Other	Azelaic acid	Apply twice daily	Cream: 20%	Local skin irritation
			Gel: 15%
			Foam: 15%
	Salicylic acid	Apply one to three times daily	0.5 to 2% creams, gels, pads, cleansers, solutions, soaps, pledget, foam (most are OTC)	Local skin irritation including transient stinging, burning, or pruritus; potential for salicylate absorption

HPA, hypothalamic-pituitary-adrenal; OTC, over the counter.

 

PAUSE AND PONDER: What factors could contribute to the higher prevalence of acne in males during adolescence?

 

Topical dapsone is an antimicrobial agent that shows modest to moderate efficacy, particularly in the reduction of inflammatory acne lesions in clinical trials.^27,28 While dapsone’s mechanism of action is poorly understood, it is thought to possess both anti-inflammatory and antimicrobial properties. Additionally, dapsone has demonstrated superior efficacy in females as opposed to males.²⁹ Dapsone may be used in combination with benzoyl peroxide, however due to the potential for oxidation, patients must apply the medications at different times. Temporary yellow or orange discoloration of the skin and hair may occur if patients apply dapsone and benzoyl peroxide simultaneously. Patients apply dapsone to the affected area once daily and generally tolerate it well. Unlike with oral dapsone therapy, testing for glucose-6-phosphate dehydrogenase is unnecessary.¹

 

Clascoterone is a first-in-class topical androgen receptor inhibitor indicated for the treatment of acne vulgaris in individuals aged 12 years and older.³⁰ This medication competes with dihydrotestosterone (DHT) for androgen receptors to block DHT from binding to these receptors. This in turn reduces the transcription of androgen-responsive genes that modulate inflammation and sebum production.³⁰ Two phase 3 randomized clinical trials demonstrated that clascoterone has a similar safety profile to placebo without any downstream systemic androgenic effects.³¹ Patients apply clascoterone to the affected area twice daily. Clascoterone’s most common adverse effects include scaling, dryness, edema, or irritation of skin. Another, more serious potential adverse effect is hypothalamic-pituitary-adrenal axis suppression (i.e., inadequate cortisol production leading to impaired stress response).¹⁰ Currently, clascoterone carries a conditional recommendation for the treatment of acne; this is based on a high certainty of evidence, however, also considers cost and access to treatment.¹¹

 

Treatment for Moderate to Severe Acne

Patients with moderate to severe acne may benefit from topical therapy, but this disease severity often necessitates the addition of systemic medications to achieve optimal outcomes. The guidelines recommend several different oral medications for acne vulgaris including antibiotics, isotretinoin, and hormonal medications, listed in Table 4.¹ Prescribers usually employ systemic therapy in combination with topical medications, but they use oral isotretinoin as monotherapy. Drug selection is based on lesion severity and consideration of patient-specific factors.

 

Table 4. Systemic Therapies for Acne Vulgaris^10,13

Category	Medication	Usual Dosage	Common Adverse Effects
Tetracycline Antibiotics	Doxycycline	Immediate Release: 50 to 100 mg twice daily or 100 mg once daily Delayed Release: 100 mg every 12 hours for 1 day, then 100 mg once daily Sub-antimicrobial dosing: Immediate Release: 20 mg twice daily Delayed Release: 40 mg once daily	Photosensitivity, GI distress, pseudotumor cerebri; contraindicated in pregnancy and children < 8 years of age
	Minocycline	Immediate Release: 50 or 100 mg daily or twice daily Extended Release: 1 mg/kg/day (round to nearest available strength)	Dizziness, vertigo, serum sickness, drug-induced lupus, skin discoloration, pseudotumor cerebri; contraindicated in pregnancy and children <8 years of age
	Sarecycline	33 to 54 kg: 60 mg once daily 55 to 84 kg: 100 mg once daily 85 to 136 kg: 150 mg once daily	Photosensitivity, GI distress; contraindicated in pregnancy and children <8 years of age
Macrolide Antibiotics	Azithromycin	Pulse dosing due to long drug half-life; 500 mg 1–3 times per week or 4 times monthly was studied, optimal regimen unknown	GI distress
	Erythromycin	250 to 500 mg twice daily initially, then decrease to once daily
Aldosterone Receptor Antagonists	Spironolactone	50 to 100 mg/day in 1 or 2 equally divided doses	Menstrual irregularity, breast tenderness, minor GI symptoms, orthostatic hypotension, hyperkalemia, dizziness, headaches, fatigue; contraindicated in pregnancy
Oral Retinoids	Isotretinoin	0.5 mg/kg/day, increasing to 1 mg/kg/day in 1 or 2 equally divided doses; total dose 120 to 150 mg/kg over 20 weeks	Dry skin and mucous membranes, visual changes, myalgia, hypertriglyceridemia, elevation of hepatic enzymes; teratogenic (absolutely contraindicated in pregnancy)
Combination Oral Contraceptives	Various estrogen/progestin combinations	One tablet once daily	Nausea, breast tenderness, weight gain, thromboembolic events

GI, gastrointestinal.

 

Oral Antibiotics

Systemic antibiotics are indicated for moderate to severe inflammatory acne.¹ Antibiotics reduce inflammation by inhibiting the growth of C. acnes bacteria, with some antibiotics also exhibiting direct anti-inflammatory properties. When initiating oral antibiotic therapy for acne, prescribers should limit the duration of treatment to the shortest necessary interval to minimize antibiotic resistance; continuous therapy for three or four months is typically sufficient.³² The guidelines recommend simultaneous use of a topical retinoid with the oral antibiotic. Addition of topical benzoyl peroxide will further limit occurrence of antibiotic resistance.³²

 

Tetracycline antibiotics are first-line medications for the treatment of acne vulgaris.¹ While other antibiotics may be used when treatment fails or is not tolerated, treatment with non-antibiotic systemic medications (e.g., isotretinoin) is typically considered first.³² Tetracycline antibiotics inhibit protein synthesis by binding the 30S subunit of the bacterial ribosome, and they also possess anti-inflammatory properties.¹ Children younger than eight years old and patients who are pregnant cannot use tetracyclines due to the potential for discoloration of developing permanent teeth. Doxycycline, minocycline, and sarecycline are the main tetracyclines used for acne in the United States (U.S.). Providers no longer use tetracycline itself for acne due to tolerability issues, antibiotic resistance, and limited availability.

 

The guidelines strongly recommend doxycycline for acne vulgaris based on moderate evidence.¹¹ The typical recommended dose of doxycycline for acne is 100 mg twice daily. Patients take delayed release tablets once daily after the initial loading dose.³³ Several studies have also shown that sub-antimicrobial dosing of doxycycline—either 20 mg twice daily or 40 mg once daily of the delayed-release formulation—is an effective strategy for acne vulgaris management.^34-36 This dosing strategy eliminates the drug’s antibacterial action while maintaining its anti-inflammatory effects. Data shows that once daily 40 mg delayed-release doxycycline reduced inflammatory lesions and was better tolerated than doxycycline 100 mg once daily.³⁴ Doxycycline’s most common adverse effects are gastrointestinal complaints, which patients can mitigate by taking the medication with food. Photosensitivity and benign increased intracranial pressure (pseudotumor cerebri) have also been associated with the use of tetracyclines, including doxycycline.³³

 

Minocycline is a tetracycline antibiotic that the guidelines conditionally recommended for the treatment of acne vulgaris based on moderate evidence.¹¹ Although minocycline is effective, it has been associated with greater toxicity than doxycycline, so it is not usually used first.³⁷ Typical minocycline dosing is 50 mg to 100 mg twice daily, or 1 mg/kg/day of the extended-release formulation. Minocycline may produce vestibular adverse effects such as headache, dizziness and vertigo, serum sickness, and pseudotumor cerebri. According to a systematic review, minocycline is the only tetracycline associated with the development of lupus erythematosus, although the risk is small.³⁷ Photosensitivity may also occur with minocycline but typically to a lesser extent than with doxycycline.³²

 

Sarecycline is a newer, narrow-spectrum tetracycline antibiotic indicated for inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older.³⁸ The guidelines conditionally recommended this medication based on high certainty evidence.¹¹ A narrow-spectrum antibiotic targets specific types of bacteria, while a broad-spectrum antibiotic is effective against a wide range of bacteria. Using this narrow-spectrum drug reduces the potential for antibiotic resistance and gut microbiome disruption.³² Sarecycline dosing is weight-based ranging from 60 mg to 150 mg once daily.³⁸ Importantly, studies have not established sarecycline’s efficacy beyond 12 weeks or safety beyond 12 months. Sarecycline’s most common adverse effect in clinical trials was nausea.³⁸

 

Alternative antibiotics for acne vulgaris are reserved for patients who cannot tolerate or don’t respond well to tetracyclines and are not candidates for other systemic therapies.³² Clinical trials have evaluated macrolides—including erythromycin and azithromycin—for acne. A meta-analysis comparing the efficacy of azithromycin to doxycycline demonstrated that azithromycin pulse therapy (i.e., 500 mg one to three times per week or four times monthly) is equivalent to doxycycline 100 mg once or twice daily at 12 weeks in moderate to severe acne vulgaris.³⁹ While some data supports their efficacy, macrolides are rarely used for this indication due to concerns for antibiotic resistance.⁴⁰ Additionally, erythromycin is very poorly tolerated due to significant gastrointestinal adverse effects.

 

Other antibiotic regimens that may be effective for acne in adults are trimethoprim-sulfamethoxazole 160 mg/800 mg once to twice daily and cephalexin 500 mg twice daily, but data supporting their use is limited.⁴¹ The guidelines discourage using these antibiotics for acne due to increased risk of antibiotic resistance.¹

 

Topical Antibioitcs

Providers may consider topical minocycline as an alternative topical antibiotic for acne vulgaris in moderate to severe cases. Topical minocycline comes as a 4% foam and is indicated for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older.⁴² Three large clinical trials have shown topical minocycline foam consistently reduces inflammatory acne lesions.^43,44 Patients apply the medication to the affected area at the same time each day at least one hour before bedtime. Pharmacists should inform patients that minocycline foam is well tolerated, with headache being the most notable adverse effect.⁴²

 

Isotretinoin

Isotretinoin is an oral retinoid that tackles all four major factors in acne pathogenesis: sebum production, follicular hyperkeratinization, inflammation, and C. acnes bacteria. Isotretinoin is U.S. Food and Drug Administration (FDA) approved for the treatment of severe recalcitrant (refractory) nodular acne vulgaris.³² This medication is also a good option for moderate acne resistant to other treatments or for the management of acne that has produced physical scarring or psychosocial distress.¹ Oral isotretinoin is the only medication that can permanently alter the natural course of acne vulgaris, and has the potential to induce long-term remission.³² Most patients experience long-term improvement in acne severity after just one course of isotretinoin. Additionally, continued improvement may occur for several months following completion of the treatment course, so patients must wait at least five months before considering additional isotretinoin therapy.⁴⁵

 

Patients take isotretinoin as monotherapy over the course of several weeks. Dosing is weight-based starting at 0.5 mg/kg/day in two divided doses, then titrated up to 1 mg/kg/day after the first month. The typical treatment duration is 15 to 20 weeks or until the total nodule count decreases by more than 70%, whichever occurs first.⁴⁶ Taking the medication with food improves absorption (an important counseling point). Isotretinoin is contraindicated in pregnancy due to its teratogenicity (causes birth defects), but it is unclear whether teratogenic effects occur in sperm from males using isotretinoin.⁴⁷ All patients who are prescribed the medication, prescribing providers, and pharmacies who dispense isotretinoin must enroll in the iPLEDGE REMS to receive the medication. Pharmacy teams play an integral part in ensuring patients can safely obtain this medication. They must verify that both the patient and provider are enrolled, obtain a Risk Management Authorization (RMA) number prior to filling and dispensing each prescription, and that no more than a 30-day supply is dispensed. Additionally, upon authorization, the iPLEDGE REMS website provides a “do not dispense to patient after” date. It is calculated as 30 days after the office visit for patients who cannot get pregnant, and seven days from the documented negative pregnancy test for patients who can.

 

Isotretinoin is associated with several potential adverse effects including dry skin and mucous membranes, visual changes, and myalgia. Additionally, patients, particularly those with severe disease, may see an initial transient worsening of acne that requires adjustment to therapy.⁴⁵ Isotretinoin is known to cause hyperlipidemia and elevation of hepatic transaminases (liver enzymes) necessitating lab monitoring.³² Some research suggests a possible link between depression and suicidal ideation, but the data is inadequate to establish causality at this time.^48,49 Researchers have also suggested a link between isotretinoin and inflammatory bowel disease, but several large cohort studies have not confirmed this.^50-52

 

PAUSE AND PONDER: What would be the best course of action for a pregnant patient with acne?

 

Oral Hormonal Therapies

Combination oral contraceptives (COC) and/or spironolactone may be reasonable therapeutic options for patients with acne vulgaris assigned female sex at birth. Both therapies carry a conditional recommendation for use in acne based on moderate evidence.¹¹ These hormonal therapies work by reducing the androgenic effects on sebaceous glands, reducing sebum production. This can ultimately diminish comedone development and minimize C. acnes bacteria growth.³²

 

COCs containing an estrogen and progestin are effective therapies for acne vulgaris in female patients. Although most progestins in oral contraceptives have androgenic properties, all low-dose COCs are estrogen dominant and produce an overall antiandrogenic effect.³² The four COCs with an FDA approval for the treatment of acne vulgaris are

• drospirenone 3 mg/ethinyl estradiol 0.02 mg
• drospirenone 3 mg/ethinyl estradiol 0.02 mg/levomefolate calcium 0.451 mg
• norethindrone acetate/ethinyl estradiol/ferrous fumarate (triphasic formulation, meaning dose differs by the week)
• norgestimate/ethinyl estradiol (triphasic formulation)

These are all approved for patients with acne vulgaris who also desire contraception.¹³

 

COCs for acne are not for use in patients who are younger than 14 years of age or within the first two years of starting menses unless it is clinically warranted.¹ Other contraindications to COCs exist, including smokers aged 35 and older and patients with select cardiovascular and gastrointestinal comorbidities.¹¹ COCs may be used in combination with other oral acne medications, including the tetracyclines and spironolactone.¹ All COCs are associated with cardiovascular risks including thromboembolism and myocardial infarction, specifically in smokers. Additionally, they carry a potential risk of breast cancer and cervical cancer.¹³ Providers do not use progestin-only contraceptives for acne vulgaris as their androgenic properties may exacerbate acne.³²

 

Spironolactone is an aldosterone receptor antagonist with potent antiandrogen activity. It decreases testosterone production and competitively inhibits binding of testosterone and DHT to androgen receptors. Spironolactone may also inhibit 5-alpha-reductase (the enzyme that converts testosterone to DHT) and increase steroid hormone binding globulin (a protein that binds to estrogens and androgens).¹ While spironolactone is not FDA approved for acne, clinicians often use it off-label based on available evidence and expert opinion.^53-55 When used for acne, spironolactone is dosed at 50 mg to 100 mg in one or two equally divided doses. Patients generally tolerate it well, and the most common adverse effects include diuresis (increased urination), menstrual irregularities, breast tenderness, breast enlargement, fatigue, headache, and dizziness.¹ It is also important to note that spironolactone is a potassium-sparing diuretic and hyperkalemia (high potassium levels) may occur when given at high doses or in patients with comorbidities such as renal insufficiency or severe heart failure. Hyperkalemia can be serious, but young, healthy patients taking spironolactone for acne do not appear to be at significant risk for hyperkalemia and don’t require monitoring.^11,32

 

Rare, Severe Acne Variants

 

Acne Fulminans

Acne fulminans is a rare form of acne vulgaris characterized by the sudden development of large, inflammatory nodules and friable (fragile) plaques with erosions, ulcers, and hemorrhagic crusts. This may occur with or without systemic symptoms such as fever, malaise, bone pain, and arthralgias.³ These lesions typically present on the trunk; however, they may occur elsewhere. Isotretinoin can trigger acne fulminans, but some cases are idiopathic (no known cause). Acne fulminans typically occurs in adolescent males with preexisting acne vulgaris.³

 

Treatment for acne fulminans involves using oral corticosteroids, usually prednisone 0.5 mg to 1 mg/kg/day, in combination with isotretinoin. If isotretinoin precipitated acne fulminans, prescribers must stop this medication and proceed with corticosteroid monotherapy for four weeks in patients with systemic symptoms and for two weeks for patients without systemic symptoms. When acne fulminans resolves, patients may restart isotretinoin in conjunction with the oral corticosteroid for at least four weeks before gradually titrating isotretinoin up as tolerated and reducing the corticosteroid dose. Providers may consider combination therapy with oral corticosteroids and tetracyclines for acne fulminans, but it is less effective.³²

 

Acne Conglobata

Acne conglobata is a severe form of nodular acne that primarily affects males. Large draining lesions, sinus tracts (linear, burrowing lesions resulting when multiple nodules merge), and severe scarring are characteristic of acne conglobata. Unlike acne fulminans, acne conglobata is not associated with systemic symptoms.³ The recommended treatment is oral isotretinoin, but isotretinoin may also occasionally cause severe flares at the start of therapy. Similar to the treatment for acne fulminans, low initial doses of isotretinoin (0.5 mg/kg per day or less) with oral corticosteroids before or during isotretinoin therapy are usually required.³² Intralesional glucocorticoid injections with triamcinolone acetonide have demonstrated efficacy as an adjunct treatment for severe nodular acne lesions.^1,11 Additionally, tetracycline antibiotics have been used for severe nodular acne and may play a role in the treatment of acne conglobata, but they cannot be combined with isotretinoin due to the increased risk of pseudotumor cerebri.⁵⁶ Case reports supporting the use of tumor necrosis factor-alpha inhibitors (i.e., etanercept, adalimumab, and infliximab) have been documented, but more research is needed.^57-59

 

Physical Modalities and Complementary and Alternative Medicine

While various physical modalities have been employed to treat acne vulgaris, limited evidence supports these approaches in the peer-reviewed medical literature.¹ Comedeo extraction performed by a professional using pressure and excision when necessary to physically remove comedones may be beneficial in resistant cases and is often used in practice. Use of topical tretinoin cream for four to six weeks prior to extraction may be advantageous.²³

 

Several studies suggest that chemical peels may improve acne mildly, particularly in patients with non-inflammatory comedonal lesions.^60-62 However, more large-scale, high-quality double-blinded placebo-controlled trials are needed. Additionally, evidence suggests the need for multiple treatments, and the results may not be long-lasting.^23,60 Most chemical peels contain glycolic acid or salicylic acid.¹ Patients who are taking isotretinoin are not candidates for a chemical peel due to the increased potential for irritation. Pharmacists should counsel patients using topical retinoids to pause therapy for several days prior to receiving a chemical peel.²³

 

Microdermabrasion is a non-invasive superficial peeling modality in which abrasive crystals are propelled onto the skin and subsequently suctioned with a vacuum device, resulting in exfoliation of the outermost layer of the epidermis.²³ A pilot study conducted in a cohort of 24 patients supports the use of microdermabrasion for acne, but these patients continued to take other acne medications throughout the study.⁶³ High-quality evidence to support the effectiveness of microdermabrasion for acne is lacking.

 

Laser and light-based therapies have been used to treat acne, but additional studies are needed to evaluate their efficacy.⁶⁴ Dermatologists have used intense pulsed light, broad-spectrum continuous-wave visible light (i.e., blue light and red light), photodynamic therapy, photopneumatic technology, and laser sources such as potassium titanyl phosphate laser, pulsed dye laser, and infrared lasers.²³ The guidelines conditionally recommend against adding pneumatic broadband light to adapalene 0.3% gel based on low certainty evidence, however available evidence is insufficient to establish recommendations for other light-based therapies.¹¹

 

Photodynamic therapy shows the most promise compared to the other laser and light therapies.⁶⁵ With this modality, the dermatologist applies a photosensitizer, such as aminolevulinic acid, to the affected skin for 15 minutes to three hours.¹ The skin then absorbs the photosensitizer where sebocytes (sebum-producing epithelial cells) absorb it preferentially. Subsequently, a laser or light device activates the photosensitizer that generates singlet oxygen species, damaging the sebaceous glands and reducing C. acnes bacteria. While this treatment has great potential, additional research is necessary to determine the optimal photosensitizer, incubation time, and light source.¹

 

Complementary and Alternative Medicine

Tea tree oil, also known as melaleuca oil, is an essential oil produced by steaming the leaves of the Australian tea tree. Tea tree oil has been used for a variety of conditions and possesses both antimicrobial and anti-inflammatory properties.⁶⁶ Two clinical trials assessed tea tree oil’s effectiveness in acne vulgaris.^67,68 A placebo-controlled trial determined that topical 5% tea tree oil is effective for mild to moderate acne vulgaris.⁶⁷ A comparator trial compared tea tree oil to benzoyl peroxide for acne and demonstrated that tea tree oil is comparable to benzoyl peroxide with better tolerability but slower onset of action.⁶⁸ Pharmacists should note that tea tree oil may be a good option for patients seeking a more natural remedy for acne. While data supports its use, the guidelines state that available evidence is insufficient to develop a recommendation on the use of tea tree oil for acne.¹¹

 

Alpha hydroxy acids, such as glycolic acid and lactic acid, are weak organic acids that induce skin peeling to improve acne and hyperpigmentation among other dermatologic conditions. They are available over the counter in a variety of dosage forms (e.g., creams, washes, lotions) and are used in higher concentrations for in-office chemical peels.²³ Some preliminary evidence supports the use of alpha hydroxy acids for acne; however, they are thought to confer the most benefit when used synergistically as a component of a comprehensive acne regimen.⁶⁹

 

While conclusive studies supporting safety and efficacy are lacking, several marketed devices claim to improve acne using heat. These devices produce a pulse of heat directly to the lesion, which is thought to kill any C. acnes bacteria present and produce an anti-inflammatory effect. The FDA has cleared multiple devices for this purpose, meaning they have gone through a review process, but medical devices of this type do not undergo the rigorous FDA approval process that requires clinical trials.^{23, 70}

 

Conclusion

A variety of treatment options for acne vulgaris are available, and treatment selection is based on lesion severity and patient preference. Clinicians treat mild acne with topical medications, several of which are available OTC. Patients seeking OTC solutions may consider benzoyl peroxide, salicylic acid, or adapalene, and tea tree oil is an option for those seeking a more natural remedy. Topical therapies are often employed first for milder acne, however they are often beneficial as part of the treatment plan in more severe cases as well. Systemic medications such as antibiotics, hormonal medications, and isotretinoin treat moderate to severe acne. Pharmacy teams should ensure patients are aware of the potential for gastrointestinal symptoms with antibiotics and isotretinoin’s teratogenicity, among other potential adverse effects. Oral corticosteroids are appropriate for very severe cases involving relatively rare acne variants. Several other alternative therapies and physical modalities may be employed as part of the regimen for acne vulgaris, but more research is necessary to assess the safety and efficacy of these options.

 

 

 

Download CE Activity

INTRODUCTION

Self-care involves patients' ability to diagnose and treat their own illness without the help of a health care practitioner. Ninety-six percent of patients believe that over-the-counter (OTC) medications make it easy to care for these self-care conditions.¹ Patients save $56.8 billion annually when they use OTC/nonprescription medications instead of prescription medications.² Pharmacists and pharmacy technicians are frequently consulted about different self-care conditions and the appropriate choice of OTC medications and devices.

 

PAUSE AND PONDER: Would you be able to recognize the symptoms of an overdose?

 

Naloxone Nasal Spray

The Center for Disease Control and Prevention (CDC) reported that there were 106,363 opioid-related deaths during a 12-month period ending in July 2023.³ The Food and Drug Administration (FDA) originally approved Naloxone to reverse an opioid overdose in 2015 as prescription only.⁴ It moved to OTC/nonprescription status in March 2023 through the FDA’s Rx-to-OTC switch process.^5,6 The manufacturer drove this change to nonprescription status by providing data showing that the drug is safe and effective and that consumers could understand how to use the product based on the proposed labeling.⁵

 

Naloxone (Narcan, Emergent BioSolutions) was the first OTC medication approved to reverse opioid overdose in community settings. Patients (who use prescription or illegal opioids), caregivers, family members, or friends can now purchase naloxone in community pharmacies, grocery stores, and online without a prescription.^5,7 Based on Federal law, people of any age can purchase naloxone, but state laws may differ. ⁷ Table 1 describes symptoms of an opioid overdose. The overdose can result from use of fentanyl, heroin, morphine, oxycodone, and other opioids. Naloxone works by blocking the opiate receptors in the brain so that the opiate cannot exert its effects. If it is not an overdose situation, patients will experience no effect.⁵

 

 

Table 1. Opioid Overdose Symptoms5

·       Body aches ·       Diarrhea ·       Fever ·       Goose bumps ·       Increased blood pressure ·       Increased heart rate ·       Nausea or vomiting ·       Restlessness or irritability ·       Sweating

 

 

Naloxone nasal spray contains only one dose and is not reusable. It is available in a 4 mg dose. Observers or caregivers should administer naloxone as soon as possible when they suspect an overdose. The observer/caregiver should lay the patient down on his or her back with their neck supported and the head tilted back. The caregiver should remove the tab from the nasal spray. It does not need to be primed. Caregivers place their thumb on the bottom of the red plunger and the first and middle fingers around the nozzle. The caregiver then places the tip of the nasal spray inside the patient’s nose. They should press the red plunger to administer the medication. They can give additional doses every two to three minutes if needed. They should also call emergency services immediately.

 

During an overdose situation, the patient could experience withdrawal effects such as nausea, vomiting, sweating, tremors, shivering, or irritability.⁸ The cost is approximately $45 for two single doses.⁹

 

A Naloxone Nasal Spray Training Device is available for anyone that wants to learn how to administer the nasal spray. The kit contains instructions and two training devices. It does not contain active medication.¹⁰

 

In July 2023, the FDA approved a second OTC naloxone product. RiVive (Harm Reduction Therapeutics) contains 3 mg naloxone. This is also a Rx-to-OTC change supported by evidence demonstrating that the naloxone levels that reach the blood stream are similar in the prescription and nonprescription product.¹¹ The approximate cost is $36 for a twin pack.

 

PAUSE AND PONDER: How would you respond if a 13-year-old girl approached you and began asking questions about the norgestrel birth control? What questions would you ask?

 

Norgestrel 0.075 mg Tablets

In 2019, the CDC reported that 35.7% of pregnancies were unintended in women aged 15 to 44.¹² Unintended pregnancies may result in negative consequences due to a lack of early prenatal care and increased risk of preterm delivery.¹³ Having norgestrel available without a prescription may help to reduce unintended pregnancies.¹⁴

 

Opill (Perrigo) is the first nonprescription oral contraceptive. Opill tablets contain norgestrel 0.075 mg, which is a progestin, or a form of progesterone. It is only used to prevent pregnancy; it does not protect against sexually transmitted diseases such as HIV. The American College and Obstetricians and Gynecologists and the American Medical Medication Association have endorsed this product. Women of any age can purchase Opill in community pharmacies, grocery stores, and online.^14,15

 

Norgestrel thickens the mucus in the cervix, preventing sperm from reaching the egg. The progestin may also inhibit ovulation, but not in all cases. Each pack contains 28 tablets, 24 active tablets that contain progestin and four inactive tablets that do not contain progestin. Norgestrel will begin working two days after the patient starts a pack and patients must take one tablet at the same time daily to be effective.

 

Missing tablets or not taking the tablets at the same time every day may reduce the birth control’s effectiveness and increase the chance of pregnancy. If a patient fails to take the tablet by three hours or more of her scheduled time, she should take the next tablet as soon as possible. In this case, she and her partner should also use condoms (or another backup method of birth control) or avoid sex (vaginal) for the next two days.¹⁵ Once a pack is completed, patients should start the next pack without any break in between.¹⁶ With typical use, the pregnancy rate is 9 in 100 during the first year of progestin-only tablets and for perfect use (never forgetting to take a tablet and taking the same time every day), the pregnancy rate is 1 in 100 women.¹⁵

 

Patients may experience side effects such as headache, dizziness, nausea, fatigue, cramps, or bloating.¹⁶ Progestin-only medications are contraindicated in women who have a history of lupus or breast cancer. Opill will be available on store shelves in March 2024. The suggested cost is $19.99 for a one month supply.¹⁷

 

 

OTC Hearing Aids

Approximately 30 million adults in the United States have some type of hearing loss.¹⁸ OTC hearing aids are credited for improving the quality of life in patients, according to a study in the Journal of the American Medication Association.¹⁹ The study used a previously validated model (Decision model of the Burden of Hearing Loss Across the Lifespan: DeciBHAL-US) and simulated the projected probability of hearing loss and the use of traditional and OTC hearing aids in 40- and 50-year old males and females. Use of OTC hearing aids resulted in a $70 to $200 savings over a lifetime. Patients also began using OTC hearing aids earlier in life compared to traditional hearing aids (77.6 versus 78.9 years respectively).¹⁹ The OTC Hearing Aid Act provided the opportunity for patients to purchase OTC hearing aid devices without a medical examination or the necessity of being fitted by a hearing aid specialist.

 

OTC hearing aids are approved for adults 18 years of age and older and can be purchased online or in stores.¹⁸ OTC hearing aids are appropriate for patients with mild or moderate hearing loss. They are not appropriate for severe or profound hearing loss. OTC hearing devices have limits on the maximum output and would not treat severe hearing loss appropriately. Table 2 provides questions that a pharmacist might ask a patient regarding use of OTC hearing aids.

Table 2. Questions Pharmacists Should Ask Patient about OTC Hearing Aids 20

·       Are you 18 years or older? ·       Why do you think you need a hearing aid? ·       Have you had your hearing tested either by a professional or by using an online tool? ·       Do sounds appear muffled? ·       Do you have trouble hearing in a group or a noisy area? ·       Do you turn the television up to an excessively high level?

 

Patients wear OTC hearing aids behind or in the ear canal; implantation is not required. Sound is amplified in the ear canal and moved to the inner ear, where processing and transmission to the brain occurs.¹⁸

 

Patients should first test their hearing by using an online resource that is provided on the product’s website. Once the results are provided, patients can select the best product for their needs using online product selection tools, based on their brand name choice. Table 3 lists features of some OTC hearing devices.²¹

Table 3. Features of some OTC Hearing Devices 21

·       Advanced acoustics ·       Bluetooth streaming ·       Hands-free phone calling ·       Rechargeable ·       Water resistant

 

Brands include Jabra Enhance, Audicus, and MDHearing. Costs range from $200 to $1000 per pair.²² Some health insurance companies may provide coverage for OTC hearing devices based on specific brands.²³

 

 

Lidocaine 4% Patch

Lidocaine is a topical anesthetic and works by inhibiting nerve impulse conduction. It provides a numbing sensation and is used to treat minor pain. Areas that can be treated include the back, neck, shoulders, and knees/elbows.²⁴ Lidocaine patches are not appropriate for areas of inflammation.²⁵

 

Lidocaine patches can be used on patients 12 years of age and older. Patients apply the patch to the affected area of the skin every six to eight hours and should not exceed three applications per day.¹ The patch may fall off if exposed to water, so waiting until the patch is off is the best time to shower or swim. Patches should not be applied to damaged or broken skin. The patch should not be covered with a bandage or a heating pad because too much lidocaine may be absorbed through the skin.²⁵

 

After the patch is removed, it can be discarded in the trash after it’s folded in half (adhesive side in).²⁵ Common side effects include warmth or stinging.²⁶ This product should not be used longer than seven days.

 

Brand names include Salonpas (lidocaine 4%) Pain Relieving Gel Patch (approximate cost is $11 for 6 patches) and Aspercreme (lidocaine 4%) Lidocaine Pain Relief Patch (approximate cost is $10 for 3 patches).²⁴ Pharmacists and technicians should pay careful attention to brand name products with different ingredients. Salonpas Pain Relieving Patch contains camphor, methyl salicylate, and menthol.

 

Diclofenac Sodium 1% Gel

Diclofenac topical gel was also changed to nonprescription through the Rx-to-OTC switch process. The FDA approved it as a prescription in 2007 and approved the move to nonprescription status in 2020.²⁷

 

Voltaren (Haleon) is a nonsteroidal anti-inflammatory (NSAID) gel, which means that it reduces prostaglandins, which are often responsible for inflammation. It is approved for the treatment of arthritis pain in the hand, wrist, elbow, foot, ankle, or knee in adults older than 18 years. It is not approved for sprains, strains, or sport injuries.²⁷

 

Diclofenac relieves joint pain and stiffness.¹ Dosing is based on the area of application. Patients apply 2.25 inches to the upper body (hand, wrist, elbow) and apply 4.5 inches to the lower body (foot, ankle, knee). The dose is measured using an enclosed dosing card.

 

Diclofenac comes with an easy twist cap, which is helpful for patients with arthritis. The gel should be rubbed into the affected area up to four times a day for up to 21 days.²⁸ Voltaren does not feel greasy and has a clean scent, compared to other topical preparations used to treat joint pain and stiffness. Common side effects include mild skin irritation. Patients who are allergic to aspirin should not use diclofenac topical gel.²⁷ Diclofenac has limited systemic absorption and provides pain relief at the site of application.²⁹ Diclofenac topical gel does not work immediately. Patients may not notice relief for one week.²⁷

 

The cost is approximately $19 for a 3.5 oz tube.³⁰ 

 

PAUSE AND PONDER: What symptoms would patients experience if they thought they have atrial fibrillation?

 

KardiaMobile

KardiaMobile (Alivecor) is used as a personal electrocardiogram (ECG), which measures the electrical activity in the heart. It is FDA-cleared. KardiaMobile is a single-lead ECG used to detect common arrhythmias such as atrial fibrillation, bradycardia, and tachycardia in 30 seconds.³¹ More than 454,000 hospitalizations occur each year in the United States due to atrial fibrillation.³²

 

The KardiaMobile device is the size of a credit card and pairs or communicates with a smartphone. Patients open the Kardia app on their smartphone and press “Record now.” The patient should place the KardiaMobile device near the smartphone so that the two can connect. The patient places two fingers on each of the pads on the KardiaMobile device. After a few seconds, the results appear in the Kardia app. Patients can save the results or email them to a health care practitioner.³¹ Patients also have access for one year to KardiaCare, which is a service that includes ECG evaluations by cardiologists and monthly reports.³³

 

The sensitivity and specificity for atrial fibrillation are 92% and 95%, respectively, and 85% and 83% for normal sinus rhythm.³⁴

 

The Apple Watch also provides a similar service for the detection of heart arrhythmias. According to a study conducted in 2022, the Apple Watch and KardiaMobile can both detect rhythm and heart rate issues but the KardiaMobile had a nonsignificant trend toward better accuracy and rhythm detection.³²

 

The approximate cost for the KardiaMobile device is $79.³¹

 

Azelastine HCl 0.15% Nasal Spray

Azelastine (Astepro, Bayer) is approved for the temporary relief of nasal congestion, runny nose, and sneezing due to indoor and outdoor allergies. This is the first available OTC antihistamine nasal spray. It is steroid free and approved for adults and children 6 years of age and older.³⁵ About 25.7% of adults and 18.9% of children have seasonal allergies.³⁶

Azelastine is an H₁-receptor antagonist that prevents histamine from activating the histamine receptor and producing symptoms such as nasal congestion, runny nose, and sneezing. Patients should prime the spray before using it by pumping the spray until a fine mist comes out.³⁷ Before using the spray, they must blow their nose to clear the nostrils. The patient may then tilt their head downward and insert the tip ¼” to ½” into the nostril. Patients then press the pump once and sniff gently.³⁸

 

Children 6 to 11 years of age should use one spray in each nostril twice daily. Children 12 years of age and older and adults should use one or two sprays in each nostril once or twice daily. Common adverse effects include runny nose, headache, and bitter taste. If patients experience drowsiness, they can use the spray at bedtime (and this is a good counseling point). The labeling recommends avoiding azelastine with alcohol or sedatives. Patients should experience relief within the first three hours of the dose.¹

 

If the nozzle is clogged, the patient should unscrew the spray pump unit. The patient should fill a bowl or container with warm water, soak the nozzle, and pump the nozzle several times under water to clear the clog. Finally, the patient should let the nozzle dry before putting it back on the bottle. The product will need to be primed again before the next use.³⁸

 

The cost is approximately $24 for 120 metered sprays.³⁹

 

Olopatadine Hydrochloride 0.1%

Olopatadine (Pataday, Alcon) is used to treat itchy, red eyes caused by ragweed, grass, animal hair, and pollen allergies.⁴⁰ Forty percent of the population has experienced itchy, red eyes due to allergies.⁴¹ Olopatadine is a mast cell stabilizer, which prevents histamine from forming during the allergic cascade.²⁷ Patients 2 years of age and older can use this product. The dose is one drop in the affected eye twice daily every six to eight hours. Reminding patients to remove contacts before use and wait 10 minutes after using the drops before reinserting them is a key counseling point.⁴²

 

Patients should stop using the product if they experience changes in vision, increased eye redness, or eye pain.²⁷ The cost is approximately $20 for a 5 mL bottle.⁴² 

 

Pataday (olopatadine 0.2%) Once Daily Relief and Pataday (olopatadine 0.7%) Once Daily Relief Extra Strength are also available as nonprescription products.⁴³

 

Mometasone Furoate 50 mcg Nasal Spray

Mometasone furoate (Nasonex, Perrigo) is used to treat allergies, such as hay fever, that produces symptoms such as nasal congestion, runny and itchy nose, and sneezing.⁴⁴ Mometasone is a corticosteroid.⁴⁰ It blocks the release of substances that produce inflammation in the body. Nasonex can be used in patients 2 years of age and older. It is the first nonprescription nasal steroid and is full prescription strength.⁴⁰

 

As with many other nasal products, the steps for administration start with shaking mometasone furoate before each use and executing a priming spray before the first use. The patient should

• insert the tip of the bottle in the nostril using a finger to hold the other nostril closed
• breathe in and spray at the same time
• repeat the process in the other nostril
• avoid blowing their nose right after using the nasal spray.⁴⁴

 

Patients 2 to 11 years of age should use one spray in each nostril once daily and patients 2 years of age and older should use two sprays in each nostril once daily. Stinging of the nasal passages is a common side effect. The product must be discarded after 75 days from the first use, even if product remains in the bottle.⁴⁴ Pharmacists and pharmacy technicians can remind patients to note the day they start using the product and/or the day when it needs to be discarded on the label. The cost is approximately $15 for 60 sprays.⁴⁵

 

Ivermectin 0.5% Lotion

Approximately 6 to 12 million cases of head lice occur each year. Children between the ages of 3 and 11 years are most commonly affected.⁴⁶ Ivermectin was originally available by prescription only. In 2020, the manufacturer started the process to change the classification to nonprescription. Ivermectin lotion is no longer available as a prescription.⁴⁷

 

Head lice are parasites that survive by feeding on human blood. Lice are spread by person-to-person contact in close environments. Adult head lice are between 2 to 3 mm in length and move by crawling; they cannot hop or fly.⁴⁶ Commons symptoms of head lice include itching on the head and scratching behind the ears.⁴⁸

 

Ivermectin 0.5% lotion (Sklice, Azurity Pharmaceuticals) is used to treat head lice and nits and is approved for children 6 months of age and older. Sklice is applied to dry hair and the scalp. The entire scalp and the hair nearest the scalp should be completely covered before the person applying the lotion pulls it through to the end of the hair. Patients may require the entire tube of product. Sklice is left on the hair for 10 minutes and then rinsed with water only. Patients should wait 24 hours before applying shampoo. Side effects include ocular irritation and a feeling of burning skin. These effects are rare.

 

Lice eradication is possible with one treatment. Treatment is effective for 94.9% of patients.⁴⁹ The approximate cost is $293 for 177 grams, which is a single treatment.⁵⁰ Generic alternatives are also available. Other therapies for head lice include permethrin (approximate cost is $39)⁵¹ and pyrethrin/piperonyl butoxide (approximate cost is $14)⁵².

 

CONCLUSION

More than 700 products have been changed to OTC status through the Rx-to-OTC switch process.⁵³ More are sure to come. It is very important that pharmacists and pharmacy technicians stay up-to-date with not only products on the market from the Rx-to-OTC switch process but also with entirely new product entities. Continuing education programs, product websites, and package information are an appropriate way to become familiar with all new product releases.

 

 

Download CE Activity

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.

 

Download CE Activity

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