ISOTRETINOIN

• INDICATION

• Isotretinoin is indicated for the treatment of severe recalcitrant nodular acne in patients 12 years of age and older
• Nodules are inflammatory lesions with a diameter of 5 mm or greater
• The nodules may become suppurative or hemorrhagic
• “Severe,” by definition, means “many” as opposed to “few or several” nodules
• Because of significant adverse reactions associated with its use, isotretinoin should be reserved for patients with multiple severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics [1]

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• MECHANISM OF ACTION

• Isotretinoin is a retinoid, which when administered in pharmacologic doses of 0.5 - 1 mg/kg/day, inhibits sebaceous gland function and keratinization
• Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion
• The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with isotretinoin and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation
• The exact mechanism of action of isotretinoin is unknown [1]

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• EFFICACY

• Overview
• Isotretinoin is the most effective therapy for severe acne
• The response to isotretinoin is directly related to the cumulative dose of the medication received
• Higher doses (1 mg - 2 mg/kg/day; cumulative doses 120 - 150 mg/kg) have been shown to achieve higher response rates in trials than lower doses (0.5 mg/kg/day; cumulative doses < 120 mg/kg)


• In general, the following response rates have been seen with isotretinoin:
• Acne-free after one course of therapy - 40%
• Acne recurrences after isotretinoin that respond to typical treatments (topicals and antibiotics) - 40%
• Acne recurrences after isotretinoin that requires repeat isotretinoin - 10 - 20% [2,3]

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• SIDE EFFECTS

• Overview
• Major side effects of isotretinoin are related to its mechanism of action which involves inhibiting sebum production and keratinization
• These actions have a drying effect which can cause significant irritation
• Side effects are dose-dependent meaning higher doses tend to cause more severe side effects
• Isotretinoin can also affect liver functions and triglyceride levels in a significant number of patients

• Data from study where the average cumulative dose was 170 mg/kg
• Reference [3]

Side effects	Incidence (% of patients)
Dry lips (cheilitis)	100%
Dry skin	100%
Nosebleeds	34%
Dry eyes	32%
Itching	32%
Retinoid dermatitis	32%
Joint aches	29%
Muscle aches	26%
Headaches	13%
Hair changes	11%
Nail changes	11%
Mood changes	8%
Vision changes	5%
Triglyceride levels > 300 mg/dl	5%

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• CONTRAINDICATIONS

• Pregnancy
• Isotretinoin is a known teratogen (causes birth defects)
• It must not be taken by women who are pregnant or who are trying to become pregnant
• Sexually-active females of childbearing potential should use extreme caution while taking isotretinoin in order to avoid pregnancy
• The iPLEDGE® program (see iPLEDGE® below) was developed in the U.S. in order to help prevent pregnancy in women taking isotretinoin [1]


• Blood donation
• Because isotretinoin is a known teratogen (causes birth defects), people who are taking it should not donate blood during therapy and for 1 month after discontinuing therapy [1]

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• PRECAUTIONS

• Psychiatric illness
• Depression, psychosis, and suicidal ideation have been reported in patients taking isotretinoin
• A causal link between psychiatric symptoms and isotretinoin has not been proven
• Patients on isotretinoin who experience psychiatric symptoms should notify their healthcare professional immediately [1, 4]


• Lipid abnormalities
• Marked elevations in triglycerides have occurred in about 25% of patients taking isotretinoin in clinical trials
• Decreases in HDL levels have occurred in 15% of patients, and increases in total cholesterol levels have occurred in 7% of patients
• Lipid monitoring is recommended during therapy (see lab monitoring below)
• Extremely elevated triglyceride levels (≥ 800 mg/dl) need to be addressed. Other lipid effects are typically transient and insignificant. [1]


• Liver toxicity
• Liver toxicity has occurred in some patients taking isotretinoin
• Mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals in clinical trials
• Liver enzyme monitoring is recommended during isotretinoin therapy (see lab monitoring below)


• Sun exposure
• Isotretinoin causes the skin to be more sensitive to the sun
• Patients should limit sun exposure and wear sunscreen while taking


• Contact lenses
• Dry eyes caused by isotretinoin may make contact lenses difficult to wear [1]


• Inflammatory bowel disease (Crohn's disease and ulcerative colitis)
• There have been case reports of inflammatory bowel disease associated with isotretinoin use
• Studies that have explored a possible link between isotretinoin use and inflammatory bowel disease have found no definitive association between the two [5]


• Decreased bone mineral density (BMD)
• Decreased bone mineral density has been reported in patients taking isotretinoin
• Studies that have evaluated the effects of isotretinoin on BMD have not found a significant effect [6, 7]


• Hyperostosis (overgrowth of bone)
• Hyperostosis has been reported in patients taking very high doses of isotretinoin for disorders of keratinization
• This effect has not been documented in patients taking doses that are typical for acne [1, 7]


• Premature epiphyseal closure
• Case reports of premature epiphyseal closure have been reported in patients taking isotretinoin
• A causal link has not been established [1]


• Hearing impairment
• Hearing impairment has been reported in patients taking isotretinoin
• A causal link between hearing impairment and isotretinoin has not been established
• This adverse event is rare [1]


• Pseudotumor cerebri
• There have been case reports of pseudotumor cerebri in patients taking isotretinoin
• A causal link between pseudotumor cerebri and isotretinoin has not been established [1]


• Serious skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Serious skin reactions have been reported in some patients taking isotretinoin
• These reactions are rare [1]


• Pancreatitis
• Pancreatitis has been reported in some patients taking isotretinoin
• Pancreatitis has occurred in patients with high and normal triglyceride levels
• This adverse event is rare [1]


• Corneal opacities
• Case reports of corneal opacities have been documented in patients taking isotretinoin
• This adverse event is rare [1]


• Decreased night vision
• Decreased night vision has been reported in some patients taking isotretinoin
• This adverse event is rare [1]


• Abnormal wound healing
• Delayed wound healing and keloid formation have been reported in patients receiving isotretinoin and in those who had recently taken isotretinoin
• In studies, a causal link has not been established
• Elective procedures like dermabrasion or laser resurfacing should be delayed 6 - 12 months after finishing isotretinoin [9]


• Increased blood sugar
• Increased blood sugars have been reported in some patients taking isotretinoin
• This effect is rare [1]


• Elevated creatine phosphokinase (CPK)
• Elevated CPK levels have been reported in some patients taking isotretinoin
• The risk may be higher with strenuous physical activity
• Rare cases of rhabdomyolysis have been reported [1]

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• DOSAGE FORMS

• Overview
• Isotretinoin is often referred to by its original trade name, Accutane®. Accutane® is no longer manufactured.
• There are currently 5 generic versions of isotretinoin available. Four of the generics also have their own trade names (Amnesteem, Myorisan, Claravis, Zenatane). Absorica® is not considered bioequivalent and it does not have a generic.
• Pharmacies must be registered with the iPLEDGE® program in order to dispense isotretinoin

• * Price based on cost of thirty 40 mg capsules
• ^✝ Absorica® is rated BX and cannot be substituted for with other isotretinoin products

Isotretinoin
Name	Dosage form	Price*
Absorica® (rated BX✝)	10, 20, 25, 30, 35, 40 mg capsule	$800 - $900
Amnesteem®	10, 20, 40 mg capsule	$150 - $250
Claravis®	10, 20, 30, 40 mg capsule	$150 - $250
Myorisan®	10, 20, 30, 40 mg capsule	$150 - $250
Zenatane®	10, 20, 30, 40 mg capsule	$150 - $250

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• DOSING

• OVERVIEW
• Dosing for isotretinoin is based on body weight
• In studies, higher doses have been found to decrease the need for retreatment
• Higher doses also increase the risk of side effects
• Dosing is often expressed in one of two ways:
• Daily dose: mg/kg/day
• Cumulative dose: (mg/kg/day) X (# of days of therapy)

• DOSING RECOMMENDATIONS
• General dosing guidelines
• 0.5 to 1 mg/kg/day given in two divided doses for 15 to 20 weeks
• All forms of isotretinoin (except Absorica®) should be taken with food. Food greatly increases absorption. Absorica® may be taken with or without food.
• Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day
• Cumulative dosing in the range of 120 - 150 mg/kg increases the chance of prolonged remission
• If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued [1, 2, 8]


• American Academy of Dermatology 2016 dosing recommendations:
Severe Acne
• Start with 0.5 mg/kg/day for 1 month, then increase to 1.0 mg/kg/day
• The goal cumulative dose is 120 - 150 mg/kg [9]
Moderate Acne
• Low-dose isotretinoin may be beneficial
• Low dose regimens are typically 0.25 - 0.4 mg/kg/day for 24 weeks [9,10]


• RETREATMENT
• After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated [1,8]

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• DRUG INTERACTIONS

• Drugs that interact with isotretinoin
• Vitamin A supplements - vitamin A supplements should not be taken with isotretinoin
• Tetracyclines - there have been case reports of pseudotumor cerebri occurring during concomitant treatment with isotretinoin and tetracycline antibiotics. Isotretinoin should not be taken with tetracyclines.
• Metabolism - In vitro studies have shown isotretinoin to be a substrate of CYP2C8, CYP2C9, CYP3A4, and CYP2B6. Inducers and inhibitors of these enzymes may affect isotretinoin levels.


• Drugs that interact with birth control pills
• Patients should be aware that certain medications may reduce the effectiveness of their birth control while taking isotretinoin
• See oral contraceptive drug interactions and birth control methods for more

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• LAB MONITORING

• Overview

• Excluding pregnancy tests, lab monitoring recommendations for isotretinoin therapy vary across publications, and there is no consensus guideline. Some practitioners do not check labs at all.
• A study in JAMA Dermatology pooled the lab results during isotretinoin treatment across 26 trials (doses ≥ 40 mg/day, N=1574 patients) and reported their averages along with 95% confidence intervals. Laboratory values for lipid levels, hepatic function, and complete blood cell counts were evaluated. All of the averages and 95% confidence intervals fell within the normal range for each lab. [PubMed abstract]
• The American Academy of Dermatology recommends routine monitoring of liver function tests and lipids. It does not recommend monitoring complete blood cell counts (CBC). [9]
• The lab recommendations below are a practical starting point. Some patients may require other testing, less testing, or more frequent testing.



• Initial labs

• All patients
• Liver function tests
• Fasting lipid profile (triglycerides)
• Females who can become pregnant
• First Pregnancy test - urine or serum, does not have to be CLIA-certified. Isotretinoin cannot be prescribed after this test. (iPLEDGE® requirement)
• Second Pregnancy test
• The second pregnancy test must be performed at least 19 days after the first
• Second test may be urine or serum at a CLIA-certified lab
• For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period, immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month
• For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month
• The patient must be using her two forms of contraception for at least 30 days prior to beginning therapy on isotretinoin, and her second pregnancy test must occur after this 30 day period is complete (iPLEDGE® requirement)

• One month after starting treatment

• All patients
• Liver function tests (LFTs)
• If normal, and dose is unchanged, stop checking. If dose is increased, repeat testing 4 weeks after each dose increase.
• Some publications recommend monthly LFTs throughout the course of therapy
• Fasting lipid profile (triglycerides)
• If normal, and dose is unchanged, stop checking. If dose is increased, repeat testing 4 weeks after each dose increase.
• Some publications recommend monthly fasting lipid profiles throughout the course of therapy
• Females who can become pregnant
• Pregnancy test monthly during therapy and one month after therapy ends - urine or serum at a CLIA-certified lab (iPLEDGE® requirement)

• Abnormal lab results

• Liver function tests
• If ≥ 3 X Upper limits of normal - consider decreasing dose or holding therapy. Recheck in 2 weeks.
• Fasting lipid profile
• If triglycerides ≥ 600 mg/dl, consider decreasing dose or holding therapy. Consider low fat diet and/or fish oil. Recheck in 2 weeks.



• Special patient populations

• Diabetics - increase blood sugar surveillance. Isotretinoin may cause an increase in blood sugars.
• Muscle aches with strenuous activity - consider checking CPK. Isotretinoin may increase CPK levels in some patients.

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• IPLEDGE PROGRAM

• Overview

• The iPLEDGE® program was approved by the U.S. Food and Drug Administration in 2005. The primary purpose of the program is to prevent pregnancies during isotretinoin therapy.
• The program requires providers, patients, and pharmacies to register on a website before they can prescribe, fill a prescription, or dispense isotretinoin
• A link to the website is available here - iPLEDGE® website
• The program has guidelines for pregnancy tests and birth control methods that must be followed in order for a patient to receive isotretinoin
• Specific requirements for each registrant are detailed below



• Prescriber instructions

• Male or female who cannot become pregnant
• Initial visit
• Step 1 - Give patient isotretinoin educational kit (male or female who cannot become pregnant) and obtain the unique patient ID number from the kit
• Step 2 - Counsel patient on the side effects of isotretinoin. Counsel patient not to share the drug or donate blood.
• Step 3 - Have patient sign the informed consent in the educational kit. Put signed consent in patient's medical record and give a copy to the patient.
• Step 4 - Go online and register patient in the iPLEDGE® program (see iPLEDGE® website). You will need the ID number from the kit.
• Step 5 - Prescribe one month of isotretinoin. Prescription can be filled for 30 days only. Prescription must be filled at a registered pharmacy.
• Monthly follow-up visits
• Step 1 - Counsel patient not to share the drug or donate blood
• Step 2 - Go online and confirm that you have counseled the patient
• Step 3 - Prescribe one month of isotretinoin. Prescription can be filled for 30 days only. Prescription must be filled at a registered pharmacy.
• During last month of therapy, confirm that patient knows not to donate blood for 30 days after their last dose. When isotretinoin is discontinued, it must be entered in the iPLEDGE® website.


• Female who can become pregnant (see definition below)
• Initial visit
• Step 1 - Give patient isotretinoin educational kit (female who can become pregnant) and obtain the unique patient ID number from the kit
• Step 2 - Counsel patient on the side effects of isotretinoin. Counsel patient on the teratogenic risks of isotretinoin and the contraception requirements of the iPLEDGE® program (see contraception below). If the provider wishes to refer a patient for counseling, there is a section in the educational kit that explains how to do this. Counsel patient not to share the drug or donate blood.
• Step 3 - Have patient sign the two informed consents in the educational kit. Put signed consent in patient's medical record and give a copy to the patient.
• Step 4 - Go online and register patient in the iPLEDGE® program (see iPLEDGE® website). You will need the ID number from the kit.
• Step 5 - Perform urine or serum pregnancy test (CLIA-certified not necessary)
• Step 6 - Confirm that patient is on 2 forms of approved contraception (see contraception below). Abstinence is another option and is discussed below (see abstinence).
• Step 7 - Have patient follow-up in about 30 days
• First follow-up visit
• Step 1 - Confirm that patient has used 2 acceptable forms of birth control for last 30 days (see contraception below)
• Step 2 - Order second pregnancy test (urine or serum, must be CLIA-certified). See second pregnancy test above for details on test timing.
• Step 3 - Counsel patient on using 2 forms of birth control and not to share the drug or donate blood
• Step 4 - Enter pregnancy results on iPLEDGE® website
• Step 5 - Prescribe one month of isotretinoin. Prescription can be filled for 7 days only (day 1 is the day pregnancy test is collected). Prescription must be filled at a registered pharmacy.
• IF PATIENT FAILS TO GET PRESCRIPTION FILLED WITHIN 7 DAYS - Patient must wait at least 19 days and repeat the second pregnancy test
• Monthly follow-up visits
• Step 1 - Confirm that patient has used 2 acceptable forms of birth control for last 30 days (see contraception below)
• Step 2 - Order pregnancy test (urine or serum, must be CLIA-certified). See second pregnancy test above for details on test timing.
• Step 3 - Counsel patient on using 2 forms of birth control and not to share the drug or donate blood.
• Step 4 - Enter pregnancy results on iPLEDGE® website
• Step 5 - Prescribe one month of isotretinoin. Prescription can be filled for 7 days only (day 1 is the day pregnancy test is collected). Prescription must be filled at a registered pharmacy.
• Patient should have follow-up visit at the end of therapy and 30 days after her last dose. Pregnancy tests and reporting are required at these visits. Counsel patient not to donate blood and to use contraception for 30 days after her last dose. When isotretinoin is discontinued, it must be entered in the iPLEDGE® website.



• Patient instructions

• Male or female who cannot become pregnant
• The patient will receive a password in the mail 5 - 10 business days after the prescriber enters them in the system. The patient must follow the instructions with the password to register in the iPLEDGE® system.
• The patient must present their iPLEDGE® card that comes in the education kit to the pharmacy in order to receive their prescription
• Female who can become pregnant (see definition below)
• The patient will receive a password in the mail 5 - 10 business days after the prescriber enters them in the system. The patient must follow the instructions with the password to register in the iPLEDGE® system.
• Each month, the patient must logon to the iPLEDGE® website and enter her 2 forms of birth control. She must also answer 2 questions about the program and pregnancy prevention.
• The patient can only enter her information in the website after the prescriber has entered the results of her pregnancy test
• The prescription cannot be dispensed until the patient has entered her information and answered her questions
• The patient must present her iPLEDGE® card that comes in the education kit to the pharmacy in order to receive her prescription



• Definition of female who can become pregnant

• A women is considered of childbearing potential unless she meets one of the following criteria:
• Has had a hysterectomy
• Has undergone bilateral oophorectomy (ovary removal)
• Is in menopause
• NOTE: The iPLEDGE® program considers a woman who has undergone tubal ligation to be potentially childbearing
• Menopause is defined as the following:
• If age > 54 years - no menses and serum FSH in the menopause range
• If age < 54 years - no menses and negative serum or urine pregnancy test with concurrently elevated serum FSH level in the postmenopausal range, depressed estradiol (E2) level in the postmenopausal range, and absent serum progesterone level




• iPLEDGE® acceptable contraceptive methods

Primary form	Secondary forms
Tubal sterilization	Male latex condom
Partner's vasectomy	Diaphragm with spermicide
Copper IUD and Mirena®	Cervical cap with spermicide
Combination oral contraceptive pills	Vaginal sponge
Ortho Evra® patch
Depo Provera®
Nuvaring®
Implanon® implant

• Popular methods that are unacceptable:
• Progesterone-only pills
• IUD Progesterone T
• Female condoms




• Abstinence

• Abstinence can be entered as the birth control method on the iPLEDGE® website
• Abstinence without appropriate contraception is not recommended for patients in the iPLEDGE® program who are or have been sexually active
• Abstinence may be appropriate when it is a lifestyle choice (e.g., religious practice) and not just a social circumstance (e.g., not having a current partner)
• If, after counseling, a sexually active patient chooses abstinence without contraception, she must understand that isotretinoin is not recommended for any female patient of childbearing potential who cannot or will not follow the contraceptive requirements of the iPLEDGE® program

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• BIBLIOGRAPHY

• NOTE: PMID = PubMed reference # - See PubMed website
• 1 - Absorica® PI
• 2 - PMID 15814882 NEJM review
• 3 - PMID 24173086 JAMA trial
• 4 - PMID 21880356 Lancet review
• 5 - PMID 23426480 Isotretinoin and IBD
• 6 - PMID 18477161
• 7 - PMID 15523348
• 8 - Claravis® PI
• 9 - PMID 26897386 - Guidelines of care for the management of acne vulgaris, J Am Acad Dermatol, 2016
• 10 - PMID 21114478 - Effectiveness of conventional, low-dose and intermittent oral isotretinoin in the treatment of acne: a randomized, controlled comparative study, Br J Dermatol, 2011