Isotretinoin


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Hannah Pile


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Updated:
10/9/2019 10:27:46 AM

Indications

Isotretinoin is an oral prescription medication that affects sebaceous glands and is used in the treatment of severe acne. The drug was approved by the US Food and Drug Administration (FDA) in 1982 for the treatment of severe, resistant, nodular acne that is unresponsive to conventional therapy, including systemic antibiotics.

Non-FDA Approved Indications

Isotretinoin has been used for moderate acne, cutaneous T-cell lymphomas, neuroblastoma, and prevention of squamous cell carcinoma in high-risk patients. Clinicians have also utilized isotretinoin in the treatment of rosacea, folliculitis, and pyoderma faciale.[1]

Mechanism of Action

Isotretinoin is an orally administered systemic retinoid. At a pharmacologic strength of 0.5 to 1.0 mg/kg per day, isotretinoin is an effective acne therapy. While the exact mechanism of action is unknown, at pharmacologic doses, isotretinoin inhibits sebaceous gland function and keratinization. The drug has been observed to reduce both the sebaceous gland size and sebum production.

In neuroblastoma (off-label use), isotretinoin has been shown to decrease cell proliferation and induce differentiation.[1][2]

Administration

Isotretinoin is administered orally in the form of a capsule. The drug has low bioavailability and is highly lipophilic. The patient can maximize the oral absorption of isotretinoin by taking the drug with a meal. Isotretinoin should be taken with a full glass of water to avoid esophageal irritation.

Initial dosing of isotretinoin is commonly at 0.5 mg/kg per day, and then gradually increased to a dose of 1.0 mg/kg per day according to patient tolerance. Typical therapy requires a 15- to 20-week course of daily isotretinoin administration to achieve complete prolonged remission of the disease.[1][3]

Adverse Effects

Cheilitis or dry lips are the most common dose-dependent adverse effect seen in about 90% of patients taking isotretinoin. Dry skin (xerosis), dry mouth (xerostomia), dry nose, and sun sensitivity are also very common adverse effects seen in patients taking isotretinoin. Sun protection and skin moisturizers and barriers are important patient education topics before starting the medication. Patients should also avoid any skin resurfacing procedures (waxing, dermabrasion, laser therapy) during treatment and at least six months after treatment to prevent skin irritation and scarring.

Hypertriglyceridemia and increased erythrocyte sedimentation rate are also very common side effects of isotretinoin therapy. Frequent laboratory monitoring is indicated during the induction period and throughout treatment with isotretinoin to monitor for these common adverse effects.

Other Potential Adverse Effects

Itching (pruritis), irritation, hair thinning, skin fragility, dry eyes, skin infections, rash, bone or joint pain, muscle aches, and joint pain (arthralgias); back and joint pain is most common in the pediatric population

Other Potential Laboratory Abnormalities

Decreased high-density lipoproteins (HDLs), increased liver function tests (LFTs), increased creatinine phosphokinase (CPK), decreased hemoglobin and hematocrit, decreased erythrocyte and leukocyte counts, and increased platelet counts. In the rare event that neutropenia or agranulocytosis should occur, isotretinoin should be discontinued.

There have been controversial associations with isotretinoin in patients who also suffer from inflammatory bowel disease or depression. However, recent meta-analyses have not shown an association with isotretinoin and these diseases.

Serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported and warrant prompt cessation of isotretinoin if they occur during therapy.

There are also reports of acute pancreatitis in patients taking isotretinoin with both normal and elevated serum triglyceride levels. Therapy should be discontinued if symptoms of pancreatitis occur.

Caution

Patients taking isotretinoin should avoid blood donation while on isotretinoin and for one month after discontinuing treatment due to the risk of embryo-fetal toxicity.

Reports also exist of episodes of depression and psychosis in patients taking isotretinoin. Even though the correlation is controversial, screening for depression, suicidal ideation, past suicide attempts, and aggressive and/or violent behaviors should take place prior to prescribing isotretinoin.

Pseudotumor cerebri (benign intracranial hypertension) has presented in cases of patients taking isotretinoin with concomitant use of tetracyclines. For this reason, tetracyclines should not be administered with isotretinoin. If patients develop signs or symptoms of pseudotumor cerebri, prompt cessation isotretinoin is necessary, and the patient should receive a referral to a neurologist for further evaluation.[4][5][6]

Contraindications

Black Box Warning

Isotretinoin was a pregnancy category X drug under the previous FDA system and is contraindicated in women who are pregnant or who may become pregnant. There have been severe, documented congenital disabilities when pregnant women have taken isotretinoin. To prescribe and receive isotretinoin, the Food and Drug Administration requires prescribers and patients to register with the iPLEDGE program. iPLEDGE ensures the fulfillment of appropriate requirements before the distribution of isotretinoin to prevent the use of this medication during pregnancy. These requirements include negative pregnancy tests and documented abstinence or the use of birth control before and while taking isotretinoin.

Isotretinoin is contraindicated in patients who have hypersensitivity to any of its components, which includes vitamin A and preservatives within the gel capsule.[1][7]

Monitoring

Females of Child-Bearing Potential (FCBP)

Two negative pregnancy tests are necessary before the initiation of therapy with isotretinoin. The first pregnancy test occurs up to 30 days prior to medication initiation. The second pregnancy test must occur at least 19 days after the first negative pregnancy test and within the first five days of the patient’s menstrual cycle. Each subsequent month the patient must have a recorded negative pregnancy test to continue therapy. After discontinuation of therapy, a final pregnancy test should take place at 30 days following therapy completion.

Females of child-bearing potential (FCBP) must be on two effective forms of birth control or complete abstinence while receiving isotretinoin therapy. The iPLEDGE program defines abstinence as no sex or sexual contact with any male 24 hours a day, 7 days a week. The iPLEDGE program does not recommend abstinence as a way to prevent pregnancy while on isotretinoin. If a patient chooses birth control, one of the birth control methods must be a “primary form” which includes tubal sterilization, partner’s vasectomy, intrauterine device, or hormonal (combination birth control pills, skin patches, shots, under-the-skin implants, or vaginal rings). Secondary forms include male latex condoms, diaphragm, cervical cap, or vaginal sponge, all with the co-use of spermicide. Natural family planning, birth control pills without estrogen, female condoms, withdrawal, and cervical shield are not acceptable forms of birth control according to the iPLEDGE program.

Pretreatment Monitoring (All Patients)

Liver function tests (LFTs), fasting lipid profile (including triglycerides), blood glucose, creatinine phosphokinase (CPK), and complete blood counts (CBC) with differential should be drawn before initiating therapy with isotretinoin. Screening for mood alteration, psychosis, aggression, suicidal ideation, skin changes, and visual changes should also take place prior to starting therapy.

Ongoing monitoring (All Patients)

Liver function tests (LFTs) and lipids should require monitoring at a biweekly interval until establishing a response to isotretinoin.[1]

Toxicity

There is no commonly used antidote to isotretinoin intoxication. Reports of acute intoxication indicate exacerbations of common, well-known isotretinoin side-effects, which include cutaneous xerosis and cheilitis.[1]

Enhancing Healthcare Team Outcomes

Isotretinoin may be prescribed by any clinician, including the nurse practitioner. While the drug is effective for the treatment of acne, all prescribers should be familiar with the drug's adverse effect profile- of which one of the most serious is teratogenicity.  Isotretinoin is a pregnancy category X drug and is contraindicated in women who are pregnant or who may become pregnant. There have been severe, documented congenital disabilities when pregnant women have taken isotretinoin. To prescribe and receive isotretinoin, the Food and Drug Administration requires prescribers and patients to register with the iPLEDGE program. iPLEDGE ensures the meeting of appropriate requirements before the distribution of isotretinoin to prevent the use of this medication during pregnancy. These requirements include negative pregnancy tests and documented abstinence or the use of birth control before and while taking isotretinoin.[8][9]

Given the nature of isotretinoin therapy, an interprofessional healthcare team approach is absolutely necessary. Pharmacists will play a vital role in working with the patient for iPLEDGE, contacting and keeping in touch with the prescriber, and coordinating with the prescriber's nursing staff to ensure therapy is administered correctly and in the proper situation, particularly in the case of female patients. Nurses also need to provide counsel, monitor for adverse events, and can collaborate with the pharmacist regarding contraceptive measures for female patients. Both the pharmacists and nurses need an open line to the prescriber so any concerns can be addressed immediately. This interprofessional team methodology applies to any medication, but is especially necessary with isotretinoin, to achieve satisfactory and safe therapeutic outcomes for the patient. [Level V]


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Isotretinoin - Questions

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A 19-year-old male presents to his provider with complaints of severe nodular-cystic acne. He states that his previous provider prescribed topical and oral antibiotics, but they did not provide much relief. The provider considers prescribing a drug that has highly teratogenic side-effects in pregnant women but is known to reduce both the sebaceous gland size and sebum production. What is the most common complaint of patients taking the most likely drug?



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A 27-year-old male presents to the provider with complaints of severe acne. He adds that he has been washing his face with antiseptic soap twice daily and is avoiding sunlight. Moreover, he says antibiotics have provided no relief, and he wants a stronger medication. On examination, his face is covered with pus-filled papules and cystic pores. The provider decides to initiate Isotretinoin. Which of the following laboratory parameters need to be monitored regularly in this patient after the initiation of this drug?



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A 21-year old male presents to the provider with multiple pus-filled pimple and pores. After further history and evaluation, the provider prescribes him a drug for severe, resistant, nodular acne. He is warned of possible dry mouth and lips as common side effects of the given drug. Treatment with this drug will increase colonization of the skin with which of the following organisms?



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A 23-year-old male presents to the provider with complaints of severe acne. He states he has seen numerous providers and has had no relief with antibiotics or Benzoyl peroxide. He adds that the acne is making it difficult for him to attend social gatherings. On examination, numerous pus-filled pimples and red tender bumps cover the patient's face. Which of the following is the best drug of choice for this patient's condition?



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A 16-year-old female presents to the provider with severe cystic acne. She says she has always had sweaty skin and is sick of her acne. She adds that she has tried numerous over the counter creams and cleansers. Last month she was given a course of antibiotics and states that provided minimal relief. On examination, her face is covered with pus-filled papules and clogged pores. She says that she read on the internet about the use of Isotretinoin and wants a prescription for that. Which of the following is a severe side effect that must be addressed before prescribing the drug?



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Isotretinoin - References

References

Zaenglein AL,Pathy AL,Schlosser BJ,Alikhan A,Baldwin HE,Berson DS,Bowe WP,Graber EM,Harper JC,Kang S,Keri JE,Leyden JJ,Reynolds RV,Silverberg NB,Stein Gold LF,Tollefson MM,Weiss JS,Dolan NC,Sagan AA,Stern M,Boyer KM,Bhushan R, Guidelines of care for the management of acne vulgaris. Journal of the American Academy of Dermatology. 2016 May     [PubMed]
Strauss JS,Krowchuk DP,Leyden JJ,Lucky AW,Shalita AR,Siegfried EC,Thiboutot DM,Van Voorhees AS,Beutner KA,Sieck CK,Bhushan R, Guidelines of care for acne vulgaris management. Journal of the American Academy of Dermatology. 2007 Apr     [PubMed]
Goldsmith LA,Bolognia JL,Callen JP,Chen SC,Feldman SR,Lim HW,Lucky AW,Reed BR,Siegfried EC,Thiboutot DM,Wheeland RG, American Academy of Dermatology Consensus Conference on the safe and optimal use of isotretinoin: summary and recommendations. Journal of the American Academy of Dermatology. 2004 Jun     [PubMed]
On SC,Zeichner J, Isotretinoin updates. Dermatologic therapy. 2013 Sep-Oct     [PubMed]
Eichenfield LF,Krakowski AC, A novel patient support program to address isotretinoin adherence: proof-of-concept analysis. Journal of drugs in dermatology : JDD. 2015 Apr     [PubMed]
Huang YC,Cheng YC, Isotretinoin treatment for acne and risk of depression: A systematic review and meta-analysis. Journal of the American Academy of Dermatology. 2017 Jun     [PubMed]
Lee SY,Jamal MM,Nguyen ET,Bechtold ML,Nguyen DL, Does exposure to isotretinoin increase the risk for the development of inflammatory bowel disease? A meta-analysis. European journal of gastroenterology     [PubMed]
Boos MD,Ginsberg BA,Peebles JK, Prescribing isotretinoin for transgender youth: A pledge for more inclusive care. Pediatric dermatology. 2019 Jan;     [PubMed]
Lee KC,Bercovitch L, Circumventing iPLEDGE: Circumventing ethical responsibility? Journal of the American Academy of Dermatology. 2017 Dec;     [PubMed]

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