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

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

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

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

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.

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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

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.

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

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.

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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

*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

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}

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

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

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:

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.

A₁C, hemoglobin A1C; BUN, blood urea nitrogen.

John is taking the following medications:

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

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

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

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

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

CONCLUSION

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

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