RxCe - Treating Recalcitrant Acne: Isotretinoin Materials

TREATING RECALCITRANT ACNE: ISOTRETINOIN AS AN OPTION

STEVEN MALEN, PharmD, MBA

Dr. Steven Malen graduated with a dual degree: Doctor of Pharmacy (PharmD) and Master of Business Administration (MBA) from the University of Rhode Island. Over his career, he has worked as a clinical pharmacist in the retail, specialty, and compounding sectors. He specialized and taught on topics from vaccines to veterinary compounding. Currently, Dr. Malen continues to write, teach, and consult various companies in the healthcare sector.

Topic Overview

Isotretinoin is an isomer of retinoic acid. In its oral form, it has been approved for use in the United States to treat recalcitrant severe acne for more than 30 years. It is also used to treat moderate acne that is treatment resistant. From isotretinoin’s introduction, there was evidence that it could cause birth defects in fetuses exposed to the drug during gestation, especially during the first trimester. This led to the creation of the Risk Evaluation and Mitigation Strategy (REMS) program called iPLEDGE. A study found that when pharmacists were involved with counseling patients who were prescribed isotretinoin, the patients’ outcomes improved.

Accreditation Statement:

RxCe.com LLC is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.

Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is

Pharmacist 0669-0000-23-104-H01-P

Pharmacy Technician 0669-0000-23-105-H01-T

Credits: 1 hour of continuing education credit

Type of Activity: Knowledge

Media: Internet/Home study Fee Information: $4.99

Estimated time to complete activity: 1 hour, including Course Test and course evaluation

Release Date: July 18, 2023 Expiration Date: July 18, 2026

Target Audience: This educational activity is for pharmacists.

How to Earn Credit: From July 18, 2023, through July 18, 2026, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “educational activity;” and

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Credit for this course will be uploaded to CPE Monitor®.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Identify the use of isotretinoin for acne

Describe the basic pharmacological profile, use, and clinical outcomes of isotretinoin treatment

Describe the potential contraindications and side effects

Discuss risk mitigation of isotretinoin through IPLEDGE and pharmacy counseling

Disclosures

The following individuals were involved in developing this activity: Steven Malen, PharmD, MBA, and Pamela Sardo, PharmD, BS. Pamela Sardo, PharmD, BS, was an employee of Rhythm Pharmaceuticals until March 2022 and has no conflicts of interest or relationships regarding the subject matter discussed. There are no financial relationships relevant to this activity to report or disclose by any of the individuals involved in the development of this activity.

Introduction

Since 1982, isotretinoin has been known as an effective treatment for acne; however, from isotretinoin’s introduction, there was evidence that it could cause birth defects in fetuses exposed to the drug during gestation, especially during the first trimester. This course discusses the basic pharmacological profile, use, and clinical outcomes of isotretinoin treatment, its contraindications and side effects, and risk mitigation of potential birth defects in women who take isotretinoin while pregnant.

History of Isotretinoin

Isotretinoin is an isomer of retinoic acid. In its oral form, it has been used in the United States to treat recalcitrant moderate or severe acne for more than 30 years.1 Isotretinoin was originally studied in the 1960s as a possible treatment or prevention of skin cancer,2 and its efficacy in this regard is still being studied. Studies have shown that this drug is an effective acne treatment.1,3 Over time and following many studies, in 1982, the US Food and Drug Administration (FDA) approved isotretinoin to treat recalcitrant moderate or severe acne.1 Due to the high efficacy of isotretinoin - in particular with severe cases of acne - the medication was widely prescribed, but reports of the drug’s teratogenic effects raised serious concerns about its use in women who could become pregnant when taking it.1,2 Its potential teratogenic effects were not unknown when the drug was introduced in 1982: The isotretinoin manufacturer included its possible teratogenic effects in its patient educational brochure.2

Following isotretinoin’s approval, the FDA analyzed its teratogenic effects, and the drug received a boxed warning.4 From 1988 to 2001, there were several different attempts by the manufacturer and the FDA to mitigate these side effects. This led to the creation of the Risk Evaluation and Mitigation Strategy (REMS) program called iPLEDGE, which was established in 2006. iPLEDGE is a strict process for prescribing and dispensing of isotretinoin products, including pregnancy tests as well as training for the prescriber,

pharmacy, and patients.5-7 The FDA requires visiting the iPLEDGE REMS website for up-to-date and detailed information about the program.6 The iPLEDGE website can be accessed through this link: https://ipledgeprogram.com/#Main.

The iPLEDGE program aims to reduce fetal exposure to isotretinoin.7 Women who become pregnant while taking isotretinoin are typically between the ages of 20 to 29 years.7 Since 2006, available data shows that the number of pregnancy-related adverse events for patients taking isotretinoin has decreased; however, pregnancies, abortions, and fetal defects associated with isotretinoin exposure remain problematic.7 Clinicians continue to look for ways to reduce complications for isotretinoin patients, while still prescribing this acne drug that may be the most effective option for some patients.7

Isotretinoin’s Teratogenic Effects

Isotretinoin induces apoptosis (cell death) and cell cycle arrest in human sebocytes (cells that make up sebaceous glands), emphasizing these as processes associated with its teratogenic effect.2 Fetal exposure to isotretinoin raises the risk of spontaneous abortion to approximately 20%,7 and the rate of elective abortions is much higher for women taking isotretinoin; it may be as high as 84%.8

There is a 20%-35% risk that a child born alive will have a developmental abnormality from embryonic or fetal exposure to isotretinoin.2,9 This is dramatic when compared to the 3% to 5% risk of congenital defects in infants in the general population.8 This risk is greatest if the fetus is exposed to the drug during the first trimester.8

Congenital malformations associated with children born of women who took isotretinoin during their pregnancies include serious craniofacial, cardiovascular, thymic, and central nervous system malformations.8,9 Thirty to 60% of children exposed to isotretinoin in utero reportedly showed neurocognitive impairment without the presence of physical defects.9

Clinical Pharmacology

Isotretinoin is in the retinoid family of drugs, which affect cell proliferation, generally causing cell death.10 The exact mechanism of action is unknown.

Mechanism of Action

Retinoids bind to retinoid receptors in the nucleus of cells, which have different effects on cells based on the type of retinoid receptors.10 With acne, retinoids reduce the size of sebaceous glands, which decreases sebum production as well as inhibiting keratinization. Sebum stimulates the growth of bacteria that cause acne, so isotretinoin has an indirect effect on acne. The inhibition of keratinization has a direct effect on the use case of keratosis follicularis and other keratinization disorders.10

Isotretinoin’s mechanism of action plays a significant role in causing birth defects.2,10 Retinoids affect cell development, so this can lead to a broad range of birth defects, including limb development and the nervous system.2,11 This also impacts the wide range of side effects, especially in higher doses and longer durations.10

Pharmacokinetics

Isotretinoin is administered orally. Distribution has not been fully characterized; however, unlike vitamin A, isotretinoin does not accumulate in the liver. It is unknown whether isotretinoin crosses the placenta or is excreted into breast milk. The drug is 99.9% bound to plasma proteins, primarily albumin.10,12 Isotretinoin is metabolized in the liver by CYP2C8, CYP2C9, CYP3A4, and CYP2B6.10,12

At least 3 metabolites [4-oxo-isotretinoin, retinoic acid (tretinoin), 4- oxo-retinoic acid (4-oxo-tretinoin)] have been identified in human plasma. All three metabolites have retinoid activity in vivo; however, the clinical

significance of the metabolites' activity is unknown.10 The half-lives of isotretinoin and its active metabolite, 4-oxo-isotretinoin, are about 10 to 24 hours and 38 hours, respectively. The metabolites of isotretinoin are eliminated in the feces and urine in relatively equal amounts.10,12

Labeled and Off-label Uses

Oral isotretinoin was introduced in the United States in 1982 and in Canada in 1983 for the treatment of severe recalcitrant acne.9 It is currently indicated for severe recalcitrant cystic acne vulgaris or nodular acne with multiple inflammatory nodules at least 5 mm in diameter. It is indicated in children 12 years and older and adults.10,12

In the intervening decades, isotretinoin has been used off-label. When discussing off-label uses for a drug, it is important to understand that the FDA has not completed safety and efficacy evaluations for off-label uses.13 Therefore, the FDA has not found that isotretinoin is safe and effective for these unapproved, off-label uses.13 Off-label uses include treating gram- negative folliculitis, recalcitrant rosacea, pyoderma facial, generalized lichen planus, psoriasis, cutaneous lupus erythematosus, and acne fulminans.9,14 Other off-label uses include keratinization disorders such as keratosis follicularis, lamellar ichthyosis, pityriasis rubra pilaris, juvenile chronic myelogenous leukemia, newly diagnosed, high-risk neuroblastoma, recurrent cervical cancer, advanced squamous cell head, and neck cancer, and aggressive squamous cell skin carcinoma.14,15

Dosage and Administration

Depending on the brand, oral doses of isotretinoin are available at 8 mg, 10mg, 16mg, 20mg, 24mg, 25mg, 30mg, 32mg, 35mg, and 40 mg.10,12 Isotretinoin products include Absorica and Absorica LD (lower dose form), Accutane (no longer available in the US), Amnesteem, Claravis, Isotretinoin, MYORISAN, Sotret, and ZENATANE.16 Not all of these products are available in all of these doses. The FDA Orange Book has no therapeutic equivalence

rating for Sotret.17 The Orange Book lists Absorica LD as a reference listed drug and lists AB therapeutic equivalence ratings for Amnesteem, Claravis, isotretinoin, MYORISAN, and ZENATANE.17

Maximum Dosage

The adult maximum dose (including geriatric patients) is 2 mg/kg/day orally for all formulations EXCEPT Absorica LD for cystic acne. The maximum dose for Absorica LD is 1.6 mg/kg/day orally for cystic acne. The maximum dose for adolescents and children 12 years of age is 1 mg/kg/day orally in all formulations EXCEPT Absorica LD for cystic acne. The maximum dose for adolescents and children is 0.8 mg/kg/day orally for Absorica LD. The safety and efficacy of isotretinoin have not been established for children younger than 12 years, infants, and neonates.10,12

Administration

If a patient is taking any formulation other than Absorica then it is important to take the medication with food to maximize absorption and efficacy of the medication.4,10,12 All formulations are taken twice daily and swallowed whole without opening capsules with a full glass of liquid. Isotretinoin is a hazardous drug, so opening capsules puts the patient and/or caregiver at risk and requires protective equipment. If medication is prepared as a liquid, then double chemotherapy gloves and a protective gown is required. Additionally, eye/face and respiratory protection may be required as well, either in preparation or administration.10,12 If acne resolves before the treatment course is completed, it may be best for the patient to continue taking the drug until the course is completed.10,12

Contraindications

Isotretinoin is contraindicated in people with paraben or retinoid hypersensitivity, and pregnancy due to birth defects. The purpose of the iPLEDGE program is “to prevent fetal exposure to isotretinoin and to inform

prescribers, pharmacists, and patients about isotretinoin’s serious risks and safe-use conditions.”16 The iPLEDGE program warnings are directed at patients who are pregnant or may get pregnant.16 Mothers should not breastfeed within 8 days of taking isotretinoin. Also, a patient may not donate blood within a month of taking isotretinoin.10,12

Warnings

Package inserts provide the following warnings:10,12

Psychiatric disorders may occur due to isotretinoin, including depression, psychosis, suicidal ideation, and aggressive behavior. The American Academy of Dermatology has issued a position paper supporting safe and responsible access to isotretinoin. They believe there is a correlation between isotretinoin use and depression or anxiety symptoms has been suggested, but an evidence-based causal relationship has not been established.18 The FDA labeling still recommends caution. The FDA labeling still recommends caution. Discontinuation of isotretinoin may not reverse symptoms; therefore, medical evaluation is recommended.

Pseudotumor cerebri or benign intracranial hypertension, is associated with taking isotretinoin, especially if taken with tetracycline. Symptoms include papilledema, visual disturbances, headache, nausea, and vomiting.

Acute pancreatitis has been associated with taking isotretinoin; therefore, isotretinoin should be stopped if triglycerides increase. Blood lipids should be checked periodically, especially with other medical conditions such as diabetes, obesity, and alcoholism.

Animal studies have shown that cardiovascular disease is 1.3 to 5.3 times higher while taking clinically appropriate doses of isotretinoin.

Vision and hearing impairment has occurred with patients taking isotretinoin and can persist after discontinuation. If either vision or hearing is affected, isotretinoin should be discontinued.

Hepatitis has occurred with patients taking isotretinoin, and 15% of clinical trial subjects experienced elevated liver enzymes.

Inflammatory bowel disease, including regional ileitis, can occur while taking isotretinoin and includes symptoms such as abdominal pain, rectal bleeding, and severe diarrhea. Isotretinoin should be stopped, and patients should seek medical attention.

Decreased bone mineral density has been associated with taking isotretinoin, especially when taken over the long term and with high doses. Patients taking isotretinoin to treat keratinization are administered the drug in higher doses, which leads to an increased risk of hyperostosis or too much growth of bone.

Premature epiphyseal closure may occur with isotretinoin which may affect the patient’s growth.

Adverse Reactions

A patient taking isotretinoin may experience an adverse reaction to the drug.2,10,19 The most common adverse reactions are dry lips, dry skin, dry eye, musculoskeletal discomfort (low back pain, myalgia, and arthralgia), fatigue, epistaxis, headache, nasopharyngitis, chapped lips, dermatitis, an increase in blood creatine kinase, cheilitis, upper respiratory tract infection, and a reduction in visual acuity.2,10,19 This is not an all-inclusive list of adverse events. For a more complete discussion, please refer to the full prescribing information of each product. In addition, Kapała, et al. (2022), studied adverse events from human clinical trials of patients receiving isotretinoin therapy, and they go into a deeper discussion of this topic.19

Drug Interactions

Some drugs may interact with isotretinoin. The package inserts list some of the more important drugs that should not be taken with isotretinoin.10 Tetracyclines or eravacycline taken with isotretinoin may increase cranial pressure leading to pseudotumor cerebri. Porfimer or verteporfin can interact with isotretinoin, leading to photosensitivity.10

Benzoyl peroxide taken with isotretinoin can increase skin side effects. Cholestyramine may bind with isotretinoin when taken 1 hour before or ~5 hours after. Lomitapide, methotrexate, or mipomersen taken with isotretinoin may contribute to liver toxicity.10

Methoxsalen can cause burns or phototoxicity. It can also cause fetal harm and should not be given to patients prescribed isotretinoin.20 Orlistat, available over the counter and in generic prescription forms, can decrease isotretinoin’s absorption. It is recommended to be taken at least 2 hours before or after isotretinoin. Topical agents containing salicylic acid, when taken with isotretinoin, can lead to skin dryness. Isotretinoin taken with warfarin can decrease warfarin’s anticoagulant effects.10

There are many additional drug interactions to consider. Please consult the full prescribing information of each product for additional drug interaction details.

Guidelines for Isotretinoin Therapy

As mentioned above, isotretinoin is approved by the FDA for treating severe recalcitrant acne vulgaris.10,21 The American Academy of Dermatology also recommends isotretinoin for “moderate acne that is either treatment- resistant or that produces physical scarring or significant psychosocial distress, is an indication for treatment with oral isotretinoin.”21

The FDA dosing guidelines recommend taking isotretinoin twice daily due to pharmacokinetic data. Clinicians state that the second dose is usually not taken due to poor compliance.21 Even though it is not an FDA-approved dose schedule, clinicians prescribe a once-daily regimen, with double the dose.21 The prescribing information for Absorica states that once-daily dosing is not recommended. Dosing can be an opportunity for a pharmacist to collaborate with the primary healthcare provider by discussing dosing options

and counseling the patient on the recommended treatment plan to optimize adherence and patient outcomes.

The American Academy of Dermatology has also issued guidelines for isotretinoin therapy.22 Low-dose isotretinoin can be used to treat acne effectively and reduce the frequency and severity of medication-related side effects. By comparison, some clinicians use alternative high dosing in an attempt to decrease a relapse of acne.21 A retrospective analysis with 80 patients revealed high-dose therapy, ≥1.3mg/kg/day, produced 100% skin clearance, and 12.5% required repeat treatment within three years.21 The study reported it was well tolerated by the patients. Overall, the studies show a lower recurrence rate as the doses increased from 42% recurrence with low doses to 10% recurrence with high-dose regimens.21

Some clinicians use intermittent dosing (i.e., less than daily).23 The American Academy of Dermatology does not recommend intermittent dosing of isotretinoin.22

All patients, male and female, treated with isotretinoin, must adhere to the iPLEDGE risk management program.6,24 Females of child-bearing potential taking isotretinoin should be counseled regarding various contraceptive methods, including user-independent forms.22,24 Male patients taking isotretinoin should use contraception during sexual intercourse as a small amount of isotretinoin can be present in semen and therefore cause birth defects.24

Routine monitoring of liver function tests, serum cholesterol, and triglycerides at baseline and again until response to treatment is established is recommended. Routine monitoring of complete blood count is not recommended.22 Prescribing physicians and pharmacists should monitor their patients for any indication of inflammatory bowel disease and depressive symptoms and educate them about the potential risks of isotretinoin.22

The FDA recommends a maximum of 5 months duration of isotretinoin treatment to minimize short- and long-term side effects.21 Despite this recommendation, systematic reviews of prescription claim data show that 44% of patients take isotretinoin beyond this threshold.21

Poor isotretinoin treatment plan adherence is a concern. Only 46% of patients take the medication properly.21 Studies have shown this is partially due to patients stopping due to acne resolution despite instruction from clinicians to finish the course. Another cause of poor adherence is not taking isotretinoin with food (not a concern with Absorica products), as 59% of adolescents skip breakfast.21

Lookalike or Soundalike Concerns

Within the Institute of Safe Medication Practices website, ISOtretinoin is listed in the List of Confused Drug Names with tretinoin.25 ISOtretinoin is listed with TALL man lettering.25,26 Tretinoin is a topical pharmaceutical product that is also used for acne.25,26 If a prescription is received for ISOtretinoin with directions that read for a topical product, it is prudent to call the physician to clarify which product and application they are requesting.

Storage and Handling

All isotretinoin products must be protected from light and stored at room temperature (68-77 degrees F).10 Isotretinoin is a hazardous drug, so if a capsule must be opened or if the liquid form is handled, then appropriate protective equipment must be worn during preparation and administration.10

Patient Counseling

A study found that when pharmacists were involved with counseling patients who were prescribed isotretinoin, the patients’ outcomes improved.27 The authors described that first, a clinical pharmacist completes patient appointments and isotretinoin follow-ups under the training and direction of a

dermatological specialist. The physician completes the initial evaluation, diagnosis, and prescribing of isotretinoin. The clinical pharmacist engages in subsequent follow-up in conjunction with the physician.27 Primary outcomes are patient symptoms and quality of life, acne grade and severity, and side effects. Secondary outcomes are navigation of the iPLEDGE website, number of misses in pick-up windows, and adherence to doctor appointments.27 Preliminary results in 50 patients demonstrated significant improvement in primary and secondary outcomes. Patient acne grade decreased, while satisfaction increased; there was also a decreased risk of missed pick-up windows and improved doctor appointment adherence compared with the national standard.27 A clinical pharmacist-led iPLEDGE program can also reduce the time managing isotretinoin while maintaining the same quality of care for patients with severe acne.27

Pharmacists also have a counseling opportunity if a patient is prescribed isotretinoin and wants to take over-the-counter acne medication. Topical agents containing salicylic acid can lead to skin dryness in combination with isotretinoin. Also, as mentioned above, male patients taking isotretinoin should be counseled to use contraception during sexual intercourse as a small amount of isotretinoin can be present in semen and therefore cause birth defects. Pharmacy technicians can give limited information that is on-label, e.g., advising a patient not to operate heavy equipment when taking a specific drug. Pharmacy technicians should refer the patient to the pharmacist if a question arises regarding drug use and indications, pharmacokinetics, drug interaction, or adverse events.

Clinical Pearls

Pharmacy technicians are ideally positioned to assist with processing isotretinoin prescriptions accurately. Postmarketing reports show that isotretinoin may cause major depression, psychosis, and, rarely, suicidal ideation. If a pharmacy technician receives a refill request for isotretinoin and a new prescription for medication indicated for depression or other mood disorders, the pharmacist should be notified. Isotretinoin often contributes to

very dry lips. Pharmacy technicians can share the location of various lip balms if the patient asks. Due to the risk of photosensitivity, pharmacy technicians can share the location of sunscreen if the patient reveals plans for exposure to the sun. If the patient brings an over-the-counter benzoyl peroxide product to the pharmacy counter with the isotretinoin prescription, inform the pharmacist so the pharmacist can counsel the patient on the possibility of enhanced skin irritation, dryness, and redness from the concomitant use of the products.

Summary

Isotretinoin is an isomer of retinoic acid. In its oral form, it has been used in the United States to treat recalcitrant moderate or severe acne for more than 30 years. Isotretinoin induces apoptosis (cell death) and cell cycle arrest in human sebocytes (cells that make up sebaceous glands), emphasizing these as processes associated with its teratogenic effect. There is a 20%-35% risk that a child born alive will have a developmental abnormality from embryonic or fetal exposure to isotretinoin. This is dramatic when compared to the 3% to 5% risk of congenital defects in infants in the general population. This risk is greatest if the fetus is exposed to the drug during the first trimester.

All patients treated with isotretinoin must adhere to the iPLEDGE risk management program. Females of child-bearing potential taking isotretinoin should be counseled regarding various contraceptive methods, including user- independent forms. Male patients should use contraception during sexual intercourse as a small amount of isotretinoin can be present in semen and therefore cause birth defects. Pharmacist involvement can result in improved outcomes for patients who were prescribed isotretinoin.

Course Test

The adult maximum oral dose for isotretinoin, Absorica LD, for treating cystic acne is

2 mg/kg/day.

1 mg/kg/day.

0.8 mg/kg/day.

1.6 mg/kg/day.

Which statement is most accurate about the pharmacology and mechanism of isotretinoin?

It binds to retinoid receptors in the bladder

Retinoids increase the size of sebaceous glands

It binds to retinoid receptors in the nucleus of the cell

Retinoids enhance keratinization on the face

may be taken without food.

Absorica

Accutane

Claravis

Myorisan

A patient may not donate blood within a of taking isotretinoin.

day

week

month

year

True or False: iPLEDGE is only required for female patients prescribed isotretinoin.

True

False

Taking with isotretinoin may increase cranial pressure leading to pseudotumor cerebri.

porfimer

methoxsalen

orlistat

tetracycline or eravacycline

Orlistat (available as OTC and prescription) must be taken at least

hours before or after isotretinoin.

A patient must be at least years of age to take isotretinoin for acne.

Common side effects of isotretinoin include:

Dry skin, dry lips, dry and irritated eyes

Enhanced fertility. Diarrhea

Increased mouth saliva, euphoria

Increased appetite, decreased sunburn risk

The FDA recommends a maximum of months duration of isotretinoin treatment to minimize side effects.

References

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2009;1(3):162-169. doi:10.4161/derm.1.3.9364

Draghici CC, Miulescu RG, Petca RC, Petca A, Dumitrașcu MC, Șandru F. Teratogenic effect of isotretinoin in both fertile females and males (Review). Exp Ther Med. 2021;21(5):534. doi:10.3892/etm.2021.9966

Özkoca D, Caf N, Alacagöz Yılmaz NN, Uzunçakmak TK, Özdil A, Atsü AN. Skeletal Side Effects of Systemic Isotretinoin Treatment: Do They Depend on Age, Gender, Treatment Duration, Daily Dose and Isotretinoin-Naiveness? [published online ahead of print, 2023 Apr 1]. Dermatol Pract Concept. 2023;13(2):e2023121. doi:10.5826/dpc.1302a121

ACCUTANEⓇ (isotretinoin). Roche Laboratories Inc. 2002. https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/18662s05 1lbl.pdf. Accessed July 17, 2023.

Abroms L, Maibach E, Lyon-Daniel K, Feldman SR. What is the best

approach to reducing birth defects associated with isotretinoin?. PLoS Med. 2006;3(11):e483. doi:10.1371/journal.pmed.0030483

iPLEDGE Risk Evaluation and Mitigation Strategy (REMS). US Food and Drug Administration. January 14, 2022. https://www.fda.gov/drugs/postmarket-drug-safety-information- patients-and-providers/ipledge-risk-evaluation-and-mitigation-strategy- rems. Accessed July 12, 2023.

Tkachenko E, Singer S, Sharma P, Barbieri J, Mostaghimi A. US Food and Drug Administration Reports of Pregnancy and Pregnancy-Related Adverse Events Associated With Isotretinoin. JAMA Dermatol. 2019;155(10):1175-1179. doi:10.1001/jamadermatol.2019.1388

Bérard A, Azoulay L, Koren G, Blais L, Perreault S, Oraichi D. Isotretinoin, pregnancies, abortions and birth defects: a population- based perspective. Br J Clin Pharmacol. 2007;63(2):196-205. doi:10.1111/j.1365-2125.2006.02837.x

Choi JS, Koren G, Nulman I. Pregnancy and isotretinoin therapy. CMAJ.

2013;185(5):411-413. doi:10.1503/cmaj.120729

ABSORICA® (isotretinoin). Ranbaxy Laboratories Inc. 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021951s0 05lbl.pdf. Accessed July 12, 2023.

Das BC, Thapa P, Karki R, et al. Retinoic acid signaling pathways in development and diseases. Bioorg Med Chem. 2014;22(2):673-683. doi:10.1016/j.bmc.2013.11.025

Prescriber's Digital Reference. isotretinoin - Drug Summary. PDR. 2023. https://www.pdr.net/drug-summary/Claravis-isotretinoin-1651#15. Accessed May 3, 2023.

Understanding unapproved use of approved drugs "off label." US Food and Drug Administration. February 5, 2018. https://www.fda.gov/patients/learn-about-expanded-access-and-other- treatment-options/understanding-unapproved-use-approved-drugs- label. Accessed July 12, 2023.

Nickle SB, Peterson N, Peterson M. Updated Physician's Guide to the Off-label Uses of Oral Isotretinoin. J Clin Aesthet Dermatol. 2014;7(4):22-34.

Niemeyer CM, Loh ML, Cseh A, et al. Criteria for evaluating response and outcome in clinical trials for children with juvenile myelomonocytic leukemia. Haematologica. 2015;100(1):17-22. doi:10.3324/haematol.2014.109892

US Food and Drug Administration. Isotretinoin Capsule Information. FDA. October 12, 2021. https://www.fda.gov/drugs/postmarket-drug- safety-information-patients-and-providers/isotretinoin-capsule- information. Accessed July 12, 2023.

Orange Book: approved drug products with therapeutic equivalence evaluations. June 2023. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm. Accessed July 12, 2023.

American Academy of Dermatology. Position Statement on Isotretinoin. AAD. February 19, 2018. https://server.aad.org/Forms/Policies/Uploads/PS/PS-Isotretinoin.pdf?. Accessed July 13, 2023.

Kapała J, Lewandowska J, Placek W, Owczarczyk-Saczonek A. Adverse Events in Isotretinoin Therapy: A Single-Arm Meta-Analysis. Int J Environ Res Public Health. 2022;19(11):6463. Published 2022 May 26. doi:10.3390/ijerph19116463

Uvadex. Prescribing information. Patheon Manufacturing Services, LLC. January 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020969s0 10lbl.pdf. Accessed July 17, 2023.

Leyden JJ, Del Rosso JQ, Baum EW. The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions. J Clin Aesthet Dermatol. 2014;7(2 Suppl):S3-S21.

Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris [published correction appears in J Am Acad Dermatol. 2020 Jun;82(6):1576]. J Am Acad Dermatol. 2016;74(5):945-73.e33. doi:10.1016/j.jaad.2015.12.037

Lee JW, Yoo KH, Park KY, et al. Effectiveness of conventional, low-dose and intermittent oral isotretinoin in the treatment of acne: a randomized, controlled comparative study. Br J Dermatol. 2011;164(6):1369-1375. doi:10.1111/j.1365-2133.2010.10152.x

The iPLEDGE REMS. Prescriber Guide. 2021. https://ipledgeprogram.com/ResourceDownloadRaw/GuideBestPractices

/. Accessed July 17, 2023.

ISMP List of Confused Drug Names. Institute of Safe Medication Practices. February 2019. https://www.ismp.org/system/files/resources/2019- 07/confuseddrugnames_201902.pdf. Accessed July 12/2023.

Look-Alike Drug Names with Recommended Tall Man (Mixed Case). 2023. https://www.ismp.org/recommendations/tall-man-letters-list. Accessed July 12/2023.

Tran H, Le P. PA06 Impact of clinical pharmacist-led isotretinoin management and acne care education at a multispecialty clinic. Br J Dermatol. 2023;188(4 Suppl):ljad113.310. doi.org/10.1093/bjd/ljad113.310

DISCLAIMER

The information provided in this course is general in nature, and it is solely designed to provide participants with continuing education credit(s). This course and materials are not meant to substitute for the independent, professional judgment of any participant regarding that participant’s professional practice, including but not limited to patient assessment, diagnosis, treatment, and/or health management. Medical and pharmacy practices, rules, and laws vary from state to state, and this course does not cover the laws of each state; therefore, participants must consult the laws of their state as they relate to their professional practice.

Healthcare professionals, including pharmacists and pharmacy technicians, must consult with their employer, healthcare facility, hospital, or other organization, for guidelines, protocols, and procedures they are to follow. The information provided in this course does not replace those guidelines, protocols, and procedures but is for academic purposes only, and this course’s limited purpose is for the completion of continuing education credits.

Participants are advised and acknowledge that information related to medications, their administration, dosing, contraindications, adverse reactions, interactions, warnings, precautions, or accepted uses are constantly changing, and any person taking this course understands that such person must make an independent review of medication information prior to any patient assessment, diagnosis, treatment and/or health management. Any discussion of off-label use of any medication, device, or procedure is informational only, and such uses are not endorsed hereby.

Nothing contained in this course represents the opinions, views, judgments, or conclusions of RxCe.com LLC. RxCe.com LLC is not liable or responsible to any person for any inaccuracy, error, or omission with respect to this course, or course material.

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