Single maintenance and reliever therapy (SMART) is a new(er) treatment philosophy for asthma; it consists of using one medication that contains an inhaled corticosteroid and long-acting beta agonist (ICS-LABA) for maintenance and quick relief. An example is the budesonide-formoterol combination which gives the patient fast-acting relief if needed yet still addresses inflammation component of asthma. Formoterol is a quick-onset LABA, with effects seen <5 minutes after administration. Despite SMART therapy now being recommended as first line for many patients with moderate to severe asthma, many patients still may rely on or overuse their albuterol rescue inhaler.¹ While albuterol, a short-acting beta agonist, has a quick onset to provide immediate relief, it does not alleviate inflammation, which can lead to worsening symptoms and progression of asthma.

In 2022, the MANDALA study was published in the New England Journal of Medicine.² This study is the first to look at the use of fixed-dose combinations of albuterol and budesonide to see if it may reduce the risk of severe asthma exacerbations in comparison with albuterol alone. The MANDALA study was a multinational, phase 3, double-blind, randomized, event-driven trial that evaluated the efficacy and safety of the combination inhaler. The patients included those 4 years of age and older, who had at least one severe asthma exacerbation in the previous 12 months, defined as a clinical deterioration of asthma, with a worsening/new onset of symptoms leading to treatment with a systemic glucocorticoid for at least 3 days, or an emergency department/urgent care visit of <24 hours where systemic glucocorticoids were used to treat symptoms, or an inpatient hospitalization of 24 hours or more because of asthma. A forced expiratory volume in 1 second (FEV1) of 40-90% of the predicted normal value, FEV1 reversibility of at least 12% (as measured during a clinic visit), and a score on the Asthma Control Questionnaire-5 (ACQ-5, validated for persons 6 and older) of 1.5 or greater, which indicates poor asthma control were among the additional inclusion criteria. During the treatment phase, the patients could still receive their maintenance medications, such as a medium-high dose of inhaled glucocorticoids or a low-high dose of inhaled glucocorticoid-LABA combination with or without another controller. Patients with chronic obstructive pulmonary disease (COPD) or other lung disease, or who received a systemic glucocorticoid or biologic treatment within 3 months of screening were excluded.

Patients were randomized in a 1:1:1 ratio to one of three groups: a fixed dose combination of 180 micrograms of albuterol and 160 micrograms of budesonide (1 dose consisting of 2 actuations of 90 micrograms and 80 micrograms, respectively—the higher dose group); a fixed dose of 180 micrograms of albuterol and 80 micrograms of budesonide (each dose consisting of 2 actuations of 90 micrograms and 40 micrograms, respectively—the lower dose group); and 180 micrograms of albuterol alone (each dose was 2 actuations of 90 micrograms). Of note, children 4-11 were assigned only to the low-dose combination or albuterol alone group due to concerns of inhaled glucocorticoids in this population. Patients were instructed to use the medications in an “as needed” (PRN) manner in response to symptoms and could be used before exercise. Rescue use was limited to the trial medications; no additional fast-acting bronchodilators (including nebulizers) were allowed and changes in maintenance therapy were discouraged unless clinically indicated. The maximum daily dose was 12 inhalations (6 doses) for all trial arms.

The primary efficacy end point was the first event of severe asthma exacerbation in a time-to-event analysis. There were multiple secondary efficacy endpoints including: the annualized rate of severe asthma exacerbations, total systemic glucocorticoid exposure for asthma during the treatment period, and response on the ACQ-5 and either the Asthma Quality of Life Questionnaire (AQLQ+12; for those 12 and older) or the Pediatric Asthma Quality of Life Questionnaire (PAQLQ; for those 7-11). Patients 4-6 years old completed the PAQLQ with the help of a caregiver. Safety endpoints included adverse events and serious adverse events.

From December 27, 2018, to July 30, 2021, a total of 5620 patients enrolled in the trial; 3123 were assessed with respect to the efficacy endpoints and 3127 were assessed for safety endpoints. At baseline, the mean ACQ-5 score was 2.6 across the three trial groups. The primary endpoint, risk of a severe asthma exacerbation in a time-to-event analysis, was significantly lower, by 26%, in the high-dose combination group compared to albuterol alone (hazard ratio, 0.74; 95% confidence interval [CI] 0.62 to 0.89; P=0.01). When comparing the low-dose combination group to albuterol alone, the hazard ratio was 0.84 (95% CI, 0.71 to 1.00; P=0.052).

The secondary endpoints were also positive regarding the combination treatment versus albuterol alone. There were decreases in the annualized rate of severe asthma exacerbations and less systemic glucocorticoid exposure in the combination group compared to albuterol alone. This may be attributed to exacerbations and the steroid treatment for those in the albuterol alone group. At week 24, quality of life indicators, such as the ACQ-5 and AQLQ+12, showed improvements regarding asthma-related complications and functioning.

An assessment of safety was also evaluated. The incidence of any adverse event was similar among the three groups: 46.2% in the higher dose combination group, 47.1% in the lower dose combination group, and 46.4% in the albuterol alone group. Serious adverse events, including death, ranged from 5.2% in the higher dose combination group, 3.8% in the lower dose combination group, and 4.5% in the albuterol alone group. Of the patients who died (n=7), none were attributed to the study treatments. The most common adverse events were nasopharyngitis, headache, and upper respiratory tract infections.

For patients with moderate to severe uncontrolled asthma, the risk of severe asthma exacerbation was significantly lower in the high dose combination group compared to the albuterol alone group. Both doses of the combination treatment also demonstrated an acceptable safety profile. The adherence and usage were measured by patients or their caregivers and was similar across the three groups, with many patients reporting using 2 or less inhalations on most trial days. This study had several strengths: including its low dropout rate, with 93% of patients completing at least 24 weeks. It also allowed for the addition of maintenance therapies, which could include inhaled glucocorticoids, reflecting the real-world applicability. This study did allow pediatric patient involvement, which provides greater understanding and data to support its use in those 4 and older; however, a limitation may be that the average participant age across all treatment groups was 50 years of age.

Albuterol-budesonide (Airsupra) was approved by the Food and Drug Administration (FDA) on January 11,2023. It is indicated for those 18 and older for intermittent symptom relief and is not a controller or maintenance therapy. It is available as a metered dose inhaler with 90 micrograms of albuterol and 80 micrograms of budesonide, with a maximum daily dose of 12 inhalations. (No information is yet available on cost.)

References

1. Reddel HK, Bacharier LB, Bateman ED, et al. Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes. Eur Respir J. 2021;59(1):2102730. Published 2021 Dec 31. doi:10.1183/13993003.02730-2021
2. Papi A, Chipps BE, Beasley R, et al. Albuterol-Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma. N Engl J Med. 2022;386(22):2071-2083. doi:10.1056/NEJMoa2203163

Authors: Grace Kenley, PharmD/MPH Candidate 2024, Kim Benner PharmD 
Samford University McWhorter School of Pharmacy

With the rise in prevalence of food allergies, researchers look for options that could mitigate these allergic burdens. Historically, it had been thought that the exclusion of certain foods would prevent the development of IgE antibodies to peanuts. However, in 2008 it was determined that even with an elimination diet, allergies still developed. In 2019 the American Academy of Pediatrics (AAP) stated that the early introduction of peanuts may prevent allergy in high-risk infants.¹ However, only around 20% of children outgrow their peanut allergy and thus the number of adults with this allergy is projected to rise. To combat this, the Food Allergen Labeling and Consumer Protection Act passed in 2004 required the common and high-risk allergens to be visible on the packaging by manufacturers.² Although this was a step forward, there is still a risk for people with allergies.

In 2020, the FDA approved the first oral immunotherapy for the desensitization of peanut allergy in children. Peanut (Arachis hypogaea) Allergen Powder-dnfp (PAHAP) is approved for initiation in individuals aged 4 to 17 years old with a confirmed diagnosis of peanut allergy.³ The exact mechanism of PAHAP has not been determined but we know it is a complex biologic drug of peanut protein manufactured from defatted peanut flour with a well-defined allergen profile.⁴ As with other oral immunotherapies, PAHAP is ingested initially in very small quantities and is gradually increased using a 3-phase dosing approach. The safety and efficacy of PAHAP was tested in the PALISADE study, which was the largest phase 3, randomized, double-blind, placebo-controlled trial for peanut allergy.⁴ After the completion of the study, all participants completed a double-blind, placebo-controlled food challenge to mimic an accidental exposure to peanut and assess tolerability. The primary endpoint of the study was the percentage of participants who tolerated a single dose of 600 mg of peanut protein during the study without experiencing more than mild allergic symptoms after 6 months of maintenance treatment. For the patients aged 4 through 17, 67.2% met this endpoint compared to the 4% of the placebo group.⁴ Of note, 20.4% of the patient’s discontinued treatment during the study, with 12.4% withdrawing due to treatment-related adverse effects. The highest reported adverse effects in patients treated with PAHAP were the respiratory, gastrointestinal, and dermatologic manifestations typically seen with allergic reactions.⁴

The safety of PAHAP was tested in a second trial, RAMSES, which was a phase 3, multicenter, double-blind, placebo-containing randomized study, designed to gain experience with Palforzia in a real-world setting.⁴ The study lasted 6 months for the 506 highly peanut-sensitive participants and compared the safety and tolerability of Palforzia (n = 337) with placebo (n = 168). The primary endpoint focused on the frequency of treatment-emergent adverse events, including serious adverse events during the overall study period.⁵ Palforzia had consistent safety results across both studies.

The PALISADE and RAMSES trials were not the only studies to target peanut allergic children with oral immunotherapy. In the RAMSES study, 78% of its subjects demonstrated sustained unresponsiveness to peanut four weeks after stopping early oral immunotherapy and the reintroduction of peanut into the diet.⁶ In the same year, the POISED study found that oral immunotherapy (OIT) with peanut was able to desensitize people with peanut allergy to 4000 mg of peanut protein, but that discontinuation, or even a reduction to 300 mg daily, increased the likelihood of regaining clinical reactivity to peanut.⁷ Two years after the completion of these trials, the IMPACT trial concluded development of remission correlated with certain immunological biomarkers as well as a window of opportunity at a young age to induce desensitization. The IMPACT trial supported the effectiveness of OIT in young children (71% desensitized to peanut), but only if they had certain levels of specific immunological biomarkers and were reached within the window of opportunity.⁸ Important questions are still unanswered regarding the longevity of the treatment effects and the appropriate dosages.

PAHAP is available as 0.5 mg-100 mg oral capsules of peanut protein and a 300 mg of peanut protein sachet.^3,4,9 The capsule and sachets must be emptied into a few spoonsfuls of semisolid food such as applesauce or yogurt. Patients should take each dose at the same time each day with a meal, consuming no more than 1 dose a day. It is also important for patients to carry epinephrine.³ Treatment with PAHAP consists of 3 sequential phases that include initial dose escalation, up-titration, and maintenance. Each dose should be separated by a 20–30-minute observation period until all levels are completed; patients should be observed for at least 60 minutes after the last dose. PAHAP should be discontinued immediately if any symptoms requiring medical intervention, such as epinephrine, occur.³ Table 1 shows the summary of the levels and doses during the up-titration phase.⁴ In patients that successfully complete all 11 levels of up-titration, a 300 mg maintenance dose is initiated to maintain the effect of PAHAP. In the case of one to two missed doses, the patient may continue PAHAP therapy. Data is lacking regarding three or more missed doses.³

Table 1. Daily Dosing Configuration for Up-Dosing of Peanut (Arachis hypogaea) Allergen and Monitoring of Maintenance Therapy⁴

The most common adverse reactions experienced by participants who received PAHAP were irritation of the nasal and oral areas as well as the mild symptoms of an anaphylactic reaction. Due to the risk of anaphylaxis, the PAHAP therapy is only available through a Risk Evaluation and Mitigation Strategy (REMS) program and is contraindicated in those with uncontrolled asthma or history of eosinophilic esophagitis.

In children younger than four years of age, Palforzia has proven to be effective by increasing both desensitization and remission rates. The effectiveness and safety of peanut allergen powder has been proven clinically significant by the PALISADE, RAMSES, and POISED studies. However, the longevity of the treatment is questionable. The 2020 IMPACT study further solidified the success of the peanut allergen powder but has simultaneously increased the complexity of who should receive treatment and when it should be initiated.

References

1. Greer FR, Sicherer SH, Burks AW; Committee on Nutrition; Section on Allergy and Immunology. The effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, hydrolyzed formulas, and timing of introduction of allergenic complementary foods. Pediatrics. 2019;143(4): e20190281. Doi:10.1542/peds.2019-0281

2. Food Allergen Labeling and Consumer Protection Act of 2004 Q&A. U.S. Food and Drug Administration. https://www.fda.gov/food/food-allergensgluten-free-guidance-documents-regulatory-information/food-allergen-labeling-and-consumer-protection-act-2004-questions-and-answers. Published 2018. Accessed April 10, 2022.

3. FDA approves first drug for treatment of peanut allergy for children. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treatment-peanut-allergy-children. Published January 31, 2020. Accessed April 10, 2022.

4. Palforzia [Peanut (Arachis hypogaea) Allergen Powder-dnfp] [prescribing information]. Brisbane, CA: Aimmune Therapeutics, Inc; January 2020. Accessed March 10, 2021. https://www.palforzia.com/static/pi_palforzia.pdf.

5. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03126227. NLM identifier: NCT03126227. February 26, 2018. Accessed April 11, 2022.

6. Vickery BP, Berglund JP, Burk CM, et al. Early oral immunotherapy in peanut-allergic preschool children is safe and highly effective. J Allergy Clin Immunol. 2017;139(1):173-181.e8. doi: 10.1016/j.jaci.2016.05.027

7. Nadeau, Kari. The Peanut Oral Immunotherapy Study: Safety, Efficacy and Discovery - Full Text View - ClinicalTrials.gov, Stanford University, 2019, https://clinicaltrials.gov/ct2/show/NCT02103270.

8. Jones SM, Kim EH, Nadeau KC, et al. Efficacy and safety of oral immunotherapy in children aged 1-3 years with peanut allergy (the Immune Tolerance Network IMPACT trial): a randomized placebo-controlled study. Lancet. 2022;399(10322):359-371. doi:10.1016/S0140-6736(21)02390-4

9. Farbman KS, Michelson KA. Anaphylaxis in children. Curr Opin Pediatr. 2016;28(3):294-297.

10. Access and resources: Palforzia [peanut (arachis hypogaea) allergen powder-dnfp]. https://www.palforziapro.com/access. Accessed April 10, 2022.

Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist which enhances glucose-dependent insulin secretion by the pancreatic beta cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. Exenatide is an analogue of endogenous GLP-1. The mechanism involves binding to and activating the human GLP-1 receptor, leading to increased glucose dependent synthesis of insulin and secretion of insulin from pancreatic beta cells. Thus, insulin release from pancreatic beta cells occurs in the presence of elevated glucose concentrations.¹

In July 2021, the FDA approved exenatide extended release as the first once-weekly GLP-1 treatment option for children 10 years and older with type 2 diabetes (T2DM). Prior to this new approval, exenatide was only indicated as treatment in adult patients with T2DM. This approval provides a promising new therapeutic option for adolescents, as metformin and once daily liraglutide were the only approved non-insulin options prior. As of the date this article was written, treatment guidelines from the American Diabetes Association (ADA) have not been updated to include exenatide. While there is no current recommendation per ADA for exenatide’s use in the treatment algorithm, its place in therapy may be as an alternative to liraglutide. Liraglutide (Victoza) is a once daily subcutaneous injection that currently serves as adjunct treatment to diet and exercise for patients ages 10 years and older with uncontrolled blood glucose while on metformin and/or insulin.^2,3

A 24-week randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial was conducted to assess efficacy and safety of exenatide extended release (Bydureon) 2 mg once weekly compared to placebo in younger patients. The study included 82 patients between ages 10 and 17 years with type 2 diabetes (T2DM) treated with diet and exercise alone or on a current antidiabetic medication regimen. The primary endpoint of the study was the change in hemoglobin A1c from baseline to week 24. The average A1c at week 24 for the exenatide group was 7.88 (down from 8.13 at baseline), while the placebo group was 8.73 (up from 8.28 at baseline). In the exenatide group, 31% of patients achieved goal A1c at week 24 while only 8.3% achieved goal in the placebo group. Exenatide was superior to placebo in reducing hemoglobin A1c, and with a p<0.05 this study’s findings were statistically significant.¹

Exenatide extended release is administered as a subcutaneous injection 2 mg once weekly without regard to meals. It is not recommended for use in patients with an estimated glomerular filtration rate of < 45 mL/min. Injection sites should be rotated between the upper arm, thigh, and abdomen as needed. If used concomitantly with insulin, the same body region may be used, but injection sites should not be adjacent. Ideally, injection should be administered on the same day each week. However, if it is necessary to change injection days, allow at least 3 days between doses. Currently, extended release exenatide is only available as Bydureon BCise autoinjector. Bydureon BCise should be stored flat in the original package, protected from light, and kept in the refrigerator up to the expiration date or until it is used. It may be stored at room temperature (not exceeding 86°F) for no more than 4 weeks total if necessary. Each 2mg/0.85 mL autoinjector costs $227.17.¹ Due to the high cost of this medication, the manufacturer does offer a patient assistance program for those who are eligible. This program can be used by both insured and non-insured patients. However, patients with state or federally funded prescription insurance are not eligible.⁴

The most common adverse effects associated with exenatide are nausea, diarrhea, antibody development, injection site nodules/reactions. Exenatide extended release has a black box warning for risk of thyroid C-cell tumors. It was shown to cause benign and malignant C-cell tumors in rats. The human relevance of this finding has not been determined, so patients should be counseled to report symptoms of thyroid tumors (e.g., lump in the neck, dysphagia, hoarseness, or dyspnea) to their physician. Exenatide is also contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2.¹

In summary, exenatide is a promising new treatment option for this younger patient population. This once-weekly injection may provide a unique benefit which may improve adherence compared to liraglutide, which must be used daily, unless the patient has a fear of injections. With this new approval, exenatide should be considered as an option in those patients who are eligible and not well controlled on metformin or insulin therapy. However, cost may become a barrier for some patients, so the manufacturer-provided cost assistance may be beneficial for those who qualify. As always, it is crucial to make sure patients are appropriately counseled on the use of this medication, proper storage, and potential adverse effects. Since the ADA guidelines have not been updated to include exenatide for this population yet, it is important to stay up to date and look for exenatide in the treatment guidelines.

References:

1. Exenatide [package insert]. AstraZeneca Pharmaceuticals LP, Wilmington, DE; July 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209210s000lbl.pdf
2. American Diabetes Association. Children and Adolescents: Standards of Medical Care in Diabetes—2021. Diabetes Care. 2021;44(Supplement 1):S180-S199. doi:10.2337/dc21-S013
3. Liraglutide [package insert]. Novo Nordisk Inc., Plainsboro, NJ; August 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022341s027lbl.pdf
4. Savings Program. BYDUREON BCise® (exenatide extended-release) injectable suspension. Accessed October 26, 2021. https://www.bydureon.com/bydureon-bcise/savings-and-support.html#registration

Psoriasis is a multifactorial, autoimmune disease that presents as red patches with white scales on skin.¹ Although this manifestation appears cosmetic, psoriasis can have a significant negative effect on patient quality of life.  According to an international report by the World Health Organization, prevalence in countries ranges from 0.09% to 11.43% with at least 100 million people affected.² Despite its widespread presence and influence on patient quality of life, nontreatment and undertreatment continue to be a significant problem.  As stated by the National Psoriasis Foundation in an eight-year study of over 5000 patients, 52.3% of patients with psoriasis were dissatisfied with their treatment despite the various treatment options available for psoriasis. From this sample, 23.6% of patients with moderate psoriasis and 9.4% of patients with severe psoriasis were untreated.  In addition, 21.5% of patients who were treated for moderate to severe psoriasis were only managed with topical agents.³ 

According to the National Guidelines for Psoriasis, standard therapy usually begins with a topical corticosteroid, but as the severity increases, options for management shift to light-based phototherapy, oral systemic agents (e.g. Otezla or methotrexate), or biologics (e.g. Cimzia, Enbrel, Humira, or Remicade). Even patients on these more intensive therapy regimens are recommended to continually use a topical corticosteroid to provide rapid relief and management for flare-ups.  When choosing which topical agent(s) to use, benefit versus risk must be determined.  Often, the advantages of using a single therapy are outweighed by the efficacy of two or more medications.  As a result, combination therapies have become more of a “rule rather than an exception.”⁴ Nevertheless, with two separate monotherapies, drawbacks arise.  Different guidelines and schedules, higher cost, increased adverse effects, and decreased patient tolerability all contribute to lessened patient adherence.^4,5 

The only currently available topical combination product approved for psoriasis is calcipotriene 0.005%, a vitamin-D analogue, and betamethasone dipropionate 0.064%, a corticosteroid, available via an ointment or suspension (Taclonex and its generic), or a foam (Enstilar).  A new cream dosage form, Wynzora, was approved by the FDA in July 2020, also a combination of calcipotriene 0.005%, and betamethasone dipropionate 0.064%.^6,7 When used for psoriasis, cream formulations provide a less greasy option for use on skin while ointments offer protection (and increased dermal penetration) for thick and or cracked lesions.  Foam formulations are less greasy and may allow for more rapid absorption.⁸ While this makes a foam more cosmetically appealing, it is often a more expensive topical formulation.  Overall, no one type of topical formulation is completely preferred over another, so when determining the ideal formulation to use, both patient preference and individual disease severity/location should be considered.

Wynzora is indicated for the treatment of plaque psoriasis in patients 18 years and older.  Although Wynzora acts as both a vitamin D analog and corticosteroid through the combined pharmacological effects of calcipotriene and betamethasone dipropionate, the exact mechanism of action for management of plaque psoriasis is unknown.  It should be applied topically once daily for up to 8 weeks and discontinued earlier if symptoms of psoriasis resolve.  This medication should be directly applied to cover affected areas, and patients should be warned to not use more than 100 grams per week.  Data for use in pregnancy and while breast feeding is limited; both caution and limited use should be exercised if using in these circumstances.⁷ Wynzora is an aqueous, oil-in-water surfactant and is the only dual combination therapy available in a cream formulation.  Although this medication has less adverse effects than two separate monotherapies, adverse effects a patient might experience from taking Wynzora include headaches, upper respiratory infections, or application site irritation.⁷ 

Wynzora offers both improved efficacy and an enhanced patient safety profile, but it is not covered by most insurance plans.  This newly approved medication costs an average of $3,000 for 60 grams without any outside assistance or pharmacy programs.  With GoodRx, the average cost for this topical cream drops to around $1,200.  Even with this assistance, the cost to the average patient is a deterrent and may prove to be a barrier for some patients.  Nevertheless, Wynzora is an efficacious option for psoriasis and provides a new topical formulation option for combination therapies.  As such, it should be considered in certain patient cases.  In patients with uncontrolled psoriasis despite their current medication or who are non-adherent as a result of the negative effects of dual monotherapy regimen, Wynzora provides a reasonable alternative.  For patients with moderate to severe psoriasis who cannot afford the cost of biologics or phototherapy, Wynzora may prove to be the next most efficacious and less costly option to treat their symptoms.⁹ 

References:

1. Gudjonsson JE, Johnston A, Sigmundsdottir H, Valdimarsson H.  Immunopathogenic mechanisms in psoriasis.  Clin Exp Immunol. 2004; 135:1-8
2. Global report on psoriasis. World Health Organ. 2016. [2021-01-23].
3. Armstrong AW, Robertson AD, Wu J, Schupp C, Lebwohl MG. Undertreatment, treatment trends, and treatment dissatisfaction among patients with psoriasis and psoriatic arthritis in the United States: finds from the National Psoriasis Foundation surveys, 2003-2011.  JAMA Dermatol. 2013;149(10):1180-1185.
4. Lebwohl M, Menter A, Koo J, Feldman SR. Combination therapy to treat moderate to severe psoriasis.  J Am Acad Dermatol. 2004;50(3):416-430
5. Davis SA, Feldman SR. Combination therapy for psoriasis in the United States. J Drugs Dermatol. 2013;12(5):546-50
6. Wynzora. Package insert, MC2 Therapeutics Inc; 2020
7. Calcipotriene; Betamethasone. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. c2016- [cited 2016 April 4]. Available from: http://www.clinicalpharmacology.com
8. Kuehl B, Shear NH. The evolution of topical formulations in psoriasis. Skin Therapy Lett. 2018 July;23(4):5-9
9. Lee S, Xie L, Wang Y, Vaidya N, Baser O. Evaluating the effect of treatment persistence on the economic burden of moderate to severe psoriasis and/or psoriatic arthritis patients in the U.S. Department of Defense Population. J Manag Care Spec Pharm. 2018 July;24(7):654-663

Introduction

In August 2019, the American Academy of Neurology (AAN) and the American Headache Society (AHS) released updated practice guidelines for the acute treatment and the prevention of migraine in children and adolescents. There has been a 15 year drought since the last guidelines were published in 2004 and significant evidence has emerged since then to better inform clinical practice. The updated guidelines provide recommendations regarding appropriate prescription and non-prescription treatments as well as include patient counseling points for both behavioral and lifestyle modifications.

Guideline Updates Since 2004

In the 2004 guidelines, the authors hoped that future directions for pediatric migraine treatment and prevention would include developing a standardized criteria for the diagnosis of migraine headaches and determining response to treatment, establishing the safety and efficacy of currently available medications used to treat migraine headaches in adults, and conducting epidemiologic studies of the incidence or prevalence of status migraine in children and adolescents.¹ All of these concerns and more are addressed in the 2019 guidelines.

Diagnosis of migraine as a primary headache disorder is made by clinical criteria from the 3rd edition of the International Classification of Headache Disorders by the International Headache Society.^2,3 Epidemiological studies have confirmed that migraine is commonly experienced by children and adolescents, with a prevalence of 1%-3% in 3 to 7 year olds and increasing up to 8%-23% by the time patients are 15 years old.³ The current guidelines assess patient response to treatment using an endpoint of reduction of headache pain and associated symptoms at various time points.^2,3 Since then studies and case reports regarding the safety and efficacy of medications used to treat migraines in adults, as well as in children, have been published, allowing the 2019 guidelines to recommend even more treatments to pediatric patients. While the 2019 guidelines do include recommendations regarding patient counseling and education, this article will focus on pharmacologic agents for acute migraine treatment and prevention.

The 2019 guidelines for acute treatment of migraine in children and adolescents make the following recommendations²:

2019 Guideline Recommendations - ACUTE MIGRAINE TREATMENT

The 2019 guidelines for pharmacologic treatment for pediatric migraine prevention make the following recommendations³:

2019 Guideline Recommendations - MIGRAINE PREVENTION

Conclusion

Migraine treatment in pediatrics has greatly evolved since the last guidelines were published 15 years ago. While oral triptans are now being recommended in adolescents with migraine, many other treatments have limited evidence for their use and/or have failed to demonstrate themselves superior to placebo for migraine treatment or prevention.^2,3 As each pharmacologic agent for migraine offers both benefits and risks, patients and their caregivers should participate in shared decision-making regarding how to treat and/or prevent the patient’s migraines.³ Additionally, counseling on behavioral and lifestyle modifications remains an important mainstay of both migraine treatment and prevention and represents a key area where pharmacists can make a positive impact in the lives of their patients.

Sources:

1. Lewis D, Ashwal S, Hershey D, Yonker M, Silberstein S. Practice parameter: pharmacological treatment of migraine headache in children and adolescents: report of the American Academy of Neurology quality standards subcommittee and the practice committee of the child neurology society. Neurology. 2004; 63:2215-2224.
2. Oskoui M, Pringsheim T, Holler-Managan Y, et al. Practice guideline update summary: acute treatment of migraine in children and adolescents. Neurology. 2019:10; 93(11):487-499.
3. Oskoui M, Pringsheim T, Billinghurst L, et al. Practice guideline update summary: pharmacologic treatment for pediatric migraine prevention. Neurology. 2019: 10;93(11):500-509.

Endometriosis is one of the most common gynecological diseases, with some estimating 10% of women being affected. It is one of the leading causes of infertility and chronic pelvic pain.¹ Nearly 4 out of 10 women with infertility and 6 out of 10 with chronic pelvic pain have endometriosis. Additionally, some estimate that approximately 11% of women are undiagnosed because of the difficulty in diagnosing endometriosis due to the variability in symptoms.¹ Endometriosis is a chronic condition in which lesions are formed by the growth of endometrial or endometrial-like tissue outside the uterus. The lesions are most often found on the ovaries, fallopian tubes, behind and around the uterus, and on the bowels or bladder. Inflammation associated with the lesions cause pelvic pain during menstruation, bowel movements, urination, and during or after sex.² Other common symptoms include lower abdominal pain, heavy periods, spotting, and fatigue. Symptoms vary in severity among patients and may not always be associated with the menstrual cycle. Despite its prevalence and significant impact on patients’ lives, little is known about its causes, and treatments are limited to symptom control. Medical and surgical treatment options are available, but no treatment provides full relief of symptoms.¹

Current drug therapies for pain associated with endometriosis focus on hormone therapies to limit the progression of lesions, and pain relievers. Many patients initially self-treat with over-the-counter (OTC) NSAIDs until they find that OTC doses do not adequately control symptoms.  Instead they may opt for prescription-strength NSAIDs or opioids to get limited relief. Hormone treatments stop the ovaries from producing the hormones that facilitate the growth of the lesions. Often combined hormonal contraceptives (CHC) are tried initially because such therapies are well-tolerated and safe for long term use. There is some evidence that continuous dosing (skipping placebo) may further reduce pain.² Low estrogen or progestin-only products may offer additional benefits, but due to a lack of comparison studies, product selection is based on patient and prescriber preference.² Patients may try several different products to find best one for them. Despite being highly effective, Gonadotropin-releasing hormone (GnRH) agonists are second-line options due to their side effects, issues with long term use, and cost. GnRH agonists, such as leuprolide, goserelin, or nafarelin, suppress hormone secretion through downregulation of receptors, and may cause an initial flare that is associated with increased pain. The downregulation of receptors causes a functional oophorectomy and hypoestrogenic state, resulting in decreased bone mineral density, hot flashes, vaginal dryness, and insomnia that often requires the addition of hormone therapy.¹

New medications are in clinical trials. Of the 12 registered studies on endometriosis-related pain, six are in the United States. Four have sites in Alabama, and two are currently recruiting, including a Phase-3 trial for relugolix, and a Phase-2 trial for gefapixant. Gefapixant is a purinergic P2X3 receptor antagonist that presents a novel approach to treating endometriosis-associated pain. Nociceptive neurons contain P2X3 receptors that are associated with inflammatory, osteoarthritic, and neuropathic pain.⁴ Potential adverse effects for gefapixant are  dysgeusia (bad taste), ageusia (loss of taste), dry mouth, and numbness or tingling of the mouth. No patients left the trial due to these events.⁵ The SPIRIT1 trial is a 24-week study on the safety and benefits of once daily relugolix combined with low-dose estradiol-norethindrone. Relugolix is a nonpeptide oral GnRH receptor antagonist similar to the recently approved elagolix (Orilissa®). Unlike injectable GnRH agonists, these new receptor antagonists are taken by mouth daily and theoretically have less hypoestrogenic effects.⁶

Overall the management of endometriosis is a continuing process. No treatment option provides total relief, and patients must balance symptoms reduction with side effects. Research continues to reveal new aspects of how endometriosis develops and manifests. For many, the endometriosis-related pain is debilitating. Qualitative studies have characterized its negative impact on multiple aspects of daily life, such as finances, social life, sex, education, and employment⁷. Studies also show that lack of awareness compounds these negative impacts. As researchers work to improve treatment, practitioners and the public can also work to improve their understanding.

1 Vest K, Lynch SE. Endometriosis. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=2577§ionid=226724883. Accessed January 01, 2020

2 Committee on Gynecologic Practice. ACOG Practice Bulletin No. 114: Management of endometriosis. Obstet Gynecol . 2010;116(1):223–236.  [PubMed: 20567196]

3 NIH. (2017, January 31). What are the treatments for endometriosis? Retrieved January 1, 2020, from https://www.nichd.nih.gov/health/topics/endometri/conditioninfo/treatment .

4 Richards D, Gever JR, Ford AP, Fountain SJ. Action of MK-7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation. Br J Pharmacol. 2019 Jul;176(13):2279-2291. doi: 10.1111/bph.14677. Epub 2019 May 11. PubMed PMID: 30927255; PubMed Central PMCID: PMC6555852.

5  Morice AH, Kitt MM, Ford AP, Tershakovec AM, Wu WC, Brindle K, Thompson R, Thackray-Nocera S, Wright C. The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study. Eur Respir J. 2019 Jul;54(1). doi: 10.1183/13993003.00439-2019. Print 2019 Jul. PubMed PMID: 31023843.

6 Ellingrod VL, Gideon J. "Elagolix, an Oral GnRH Antagonist, Approved for Treatment of Endometriosis." Pharmacotherapy Updates , 4 January 2019. McGraw-Hill, New York, NY, 2019. AccessPharmacy. http://accesspharmacy.mhmedical.com/updatesContent.aspx?gbosid=453231§ionid=206576876