Accutane

Oral Retinoids for Acne

Hazardous Drugs Classification
NIOSH (Draft) 2020 List: Table 2
Approved by FDA after NIOSH 2016 list published.
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.

Absorica and Absorica LD may be administered without regard to meals. Administer all other isotretinoin formulations with food to maximize GI absorption. Failure to take certain isotretinoin formulations with food will significantly decrease absorption. Do not crush or open capsules. To minimize the risk of esophageal irritation, all isotretinoin formulations should be swallowed whole with a full glass of liquid.
All prescribers, patients, and pharmacists MUST comply with the conditions of the iPLEDGE REMS program when prescribing, dispensing, or receiving isotretinoin.
PRESCRIBERS must register and be activated in the iPLEDGE REMS program and must agree to comply with the following requirements:
determine reproductive status of all patients prior to initiating treatment
provide contraception counseling to patients who can get pregnant prior to and during treatment, or refer patients who can get pregnant to an expert for such counseling
provide scheduled pregnancy testing, and verify and document the negative pregnancy test results prior to writing each prescription, for no more than a 30-day supply
follow requirements described in the following booklets:
Guide to Best Practices for the iPLEDGE Program
Prescriber Contraception Counseling Guide
Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin
MALE PATIENTS AND FEMALES OF NON-REPRODUCTIVE POTENTIAL must:
understand the risks and benefits of the drug
comply with the REMS requirements described in the booklet entitled Guide to Isotretinoin for Patients Who Cannot Get Pregnant
sign a Patient Information/Informed Consent form
obtain the prescription within 30 days of the office visit
FEMALES OF REPRODUCTIVE POTENTIAL WHO ARE NOT PREGNANT must:
understand the risks and benefits of the drug
comply with the REMS requirements described in the booklet entitled Guide to Isotretinoin for Patients Who Can Get Pregnant and Birth Control Workbook (including the pregnancy testing and contraception requirements)
sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects form
demonstrate comprehension of the safe-use conditions of the program every month
obtain the prescription within 7 days of the pregnancy test collection
PHARMACIES must register and be activated with iPLEDGE, only dispense isotretinoin to patients who are authorized to receive the drug, and agree to comply with REMS requirements described in the booklet entitled Pharmacist Guide; specifically, the "Key Information for Pharmacists" section which includes the following dispensing information:
prescriptions must be obtained no later than the "Do Not Dispense To After" date, if not obtained, then the RMA must be reversed in the iPLEDGE Program system and the product returned to the inventory
no more than a 30-day supply, with Medication Guide, may be dispensed
refills require a new prescription and a new authorization from the iPLEDGE system
WHOLESALERS AND DISTRIBUTORS must register with iPLEDGE and agree to comply with the REMS requirements.[49581] [50393] [50394] [50395]

erythema multiforme / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
fetal death / Delayed / Incidence not known
spontaneous fetal abortion / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
vasculitis / Delayed / Incidence not known
glomerulonephritis / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
rhabdomyolysis / Delayed / Incidence not known
epiphyseal closure / Delayed / Incidence not known
bone fractures / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
ileus / Delayed / Incidence not known
esophageal ulceration / Delayed / Incidence not known
stroke / Early / Incidence not known
retinal hemorrhage / Delayed / Incidence not known
seizures / Delayed / Incidence not known
increased intracranial pressure / Early / Incidence not known
suicidal ideation / Delayed / Incidence not known
night blindness / Delayed / Incidence not known
keratitis / Delayed / Incidence not known
optic neuritis / Delayed / Incidence not known
visual impairment / Early / Incidence not known
corneal opacification / Delayed / Incidence not known
hearing loss / Delayed / Incidence not known
proteinuria / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known

hypertriglyceridemia / Delayed / 25.0-25.0
elevated hepatic enzymes / Delayed / 15.0-15.0
hypercholesterolemia / Delayed / 7.0-7.0
impaired wound healing / Delayed / Incidence not known
hematoma / Early / Incidence not known
contact dermatitis / Delayed / Incidence not known
erythema / Early / Incidence not known
diabetes mellitus / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
chest pain (unspecified) / Early / Incidence not known
osteopenia / Delayed / Incidence not known
hyperostosis / Delayed / Incidence not known
osteoporosis / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
thrombocytosis / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
anemia / Delayed / Incidence not known
inflammatory bowel disease / Delayed / Incidence not known
esophagitis / Delayed / Incidence not known
colitis / Delayed / Incidence not known
constipation / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
pseudotumor cerebri / Delayed / Incidence not known
depression / Delayed / Incidence not known
hallucinations / Early / Incidence not known
euphoria / Early / Incidence not known
psychosis / Early / Incidence not known
conjunctivitis / Delayed / Incidence not known
blurred vision / Early / Incidence not known
photophobia / Early / Incidence not known
conjunctival hyperemia / Early / Incidence not known
cataracts / Delayed / Incidence not known
hematuria / Delayed / Incidence not known
pyuria / Delayed / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known
palpitations / Early / Incidence not known
sinus tachycardia / Rapid / Incidence not known
hyperuricemia / Delayed / Incidence not known
edema / Delayed / Incidence not known
lymphadenopathy / Delayed / Incidence not known

back pain / Delayed / 29.0-29.0
arthralgia / Delayed / 22.0-22.0
musculoskeletal pain / Early / 16.0-16.0
cheilitis / Delayed / Incidence not known
hirsutism / Delayed / Incidence not known
skin hyperpigmentation / Delayed / Incidence not known
rash / Early / Incidence not known
photosensitivity / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
xerosis / Delayed / Incidence not known
alopecia / Delayed / Incidence not known
hyperhidrosis / Delayed / Incidence not known
acneiform rash / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
flushing / Rapid / Incidence not known
skin hypopigmentation / Delayed / Incidence not known
seborrhea / Delayed / Incidence not known
xerostomia / Early / Incidence not known
purpura / Delayed / Incidence not known
myalgia / Early / Incidence not known
diarrhea / Early / Incidence not known
vomiting / Early / Incidence not known
gingivitis / Delayed / Incidence not known
weight loss / Delayed / Incidence not known
abdominal pain / Early / Incidence not known
nausea / Early / Incidence not known
weakness / Early / Incidence not known
insomnia / Early / Incidence not known
headache / Early / Incidence not known
paresthesias / Delayed / Incidence not known
malaise / Early / Incidence not known
lethargy / Early / Incidence not known
dizziness / Early / Incidence not known
drowsiness / Early / Incidence not known
fatigue / Early / Incidence not known
syncope / Early / Incidence not known
anxiety / Delayed / Incidence not known
emotional lability / Early / Incidence not known
ocular pruritus / Rapid / Incidence not known
xerophthalmia / Early / Incidence not known
ocular irritation / Rapid / Incidence not known
lacrimation / Early / Incidence not known
diplopia / Early / Incidence not known
tinnitus / Delayed / Incidence not known
libido decrease / Delayed / Incidence not known
menstrual irregularity / Delayed / Incidence not known
epistaxis / Delayed / Incidence not known
nasal dryness / Early / Incidence not known
pharyngitis / Delayed / Incidence not known
infection / Delayed / Incidence not known

Isotretinoin is contraindicated for use during pregnancy. Although not every exposure to isotretinoin has resulted in a birth defect, there is an extremely high risk that birth defects can occur if pregnancy occurs while taking isotretinoin in any amount even for a short period of time. Documented birth defects associated with isotretinoin include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, thymus, and parathyroid glands. Spontaneous abortion and premature births have also been reported. To prevent isotretinoin exposure during pregnancy, the iPLEDGE program has been developed. This program requires prescribers, pharmacists and patients to comply with certain conditions prior to prescribing, dispensing or receiving isotretinoin. Patients must sign a Patient Information/Consent form about isotretinoin and birth defects, in addition to the consent form, all patients should receive information about other potentially serious risks. If pregnancy does occur during treatment, use of the drug must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Prescribers should report all cases of pregnancy to the FDA MedWatch program at 800-FDA-1088 and the iPLEDGE pregnancy registry at 866-495-0654.[49581] [50395]

Absorica, Absorica LD, Accutane, Amnesteem, Claravis, MYORISAN, Sotret, ZENATANE

Rx

Oral retinoid; synthetic 13-cis isomer of naturally occurring tretinoin
Used primarily for severe, recalcitrant nodular acne
Due to teratogenicity potential, only available through isotretinoin iPLEDGE REMS program

0.5 to 1 mg/kg/day PO, given in 2 divided doses, for 15 to 20 weeks or until the total cyst count decreases by 70%, whichever occurs first. Absorica may be taken with or without food; however, all other formulations should be taken with food. Once daily dosing is not recommended. Long term use of isotretinoin has not been studied; do not exceed the recommended dosing duration. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dosages up to 2 mg/kg/day PO given in 2 divided doses. Prior to upward dosage adjustments, patients should be questioned regarding their compliance with food and administration instructions. Adult Max: 2 mg/kg/day PO. If further treatment with isotretinoin is necessary, do not reinitiate therapy for at least 2 months following completion of the previous course. Due to significant adverse effects associated with its use, isotretinoin should be reserved for the treatment of patients with severe nodular acne that is unresponsive to conventional therapy, including antibiotics.

0.5 to 1 mg/kg/day PO, given in 2 divided doses, for 15 to 20 weeks or until the total cyst count decreases by 70%, whichever occurs first. Absorica may be taken with or without food; however, all other formulations should be taken with food. Once daily dosing is not recommended. Long term use of isotretinoin has not been studied; do not exceed the recommended dosing duration. If further treatment with isotretinoin is necessary, do not reinitiate therapy for at least 2 months following completion of the previous course. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Due to significant adverse effects associated with its use, isotretinoin should be reserved for the treatment of patients with severe nodular acne that is unresponsive to conventional therapy, including antibiotics. Given careful consideration prior to use in this population, especially for those patients where a known metabolic or structural bone disease exists.

NOTE: Due to different bioavailability and recommended dosage, Absorica LD is not substitutable with other formulations of isotretinoin.

0.4 to 0.8 mg/kg/day PO, given in 2 divided doses with or without food, for 15 to 20 weeks or until the total cyst count decreases by 70%, whichever occurs first. Once daily dosing is not recommended. Long term use of isotretinoin has not been studied; do not exceed the recommended dosing duration. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dosages up to 1.6 mg/kg/day PO given in 2 divided doses. Prior to upward dosage adjustments, patients should be questioned regarding their compliance. Adult Max: 1.6 mg/kg/day PO. If further treatment with isotretinoin is necessary, do not reinitiate therapy for at least 2 months following completion of the previous course. Due to significant adverse effects associated with its use, isotretinoin should be reserved for the treatment of patients with severe nodular acne that is unresponsive to conventional therapy, including antibiotics.

0.4 to 0.8 mg/kg/day PO, given in 2 divided doses with or without food, for 15 to 20 weeks or until the total cyst count decreases by 70%, whichever occurs first. Once daily dosing is not recommended. Long term use of isotretinoin has not been studied; do not exceed the recommended dosing duration. If further treatment with isotretinoin is necessary, do not reinitiate therapy for at least 2 months following completion of the previous course. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Due to significant adverse effects associated with its use, isotretinoin should be reserved for the treatment of patients with severe nodular acne that is unresponsive to conventional therapy, including antibiotics. Given careful consideration prior to use in this population, especially for those patients where a known metabolic or structural bone disease exists.

Dosages up to 4 mg/kg/day PO have been used. The specific disease and its severity will determine the appropriate dosage.

100 mg/m2/day orally resulted in 2 complete (CR) and 3 partial (PR) responses in 10 patients with juvenile chronic myelogenous leukemia in a multicenter, pilot study. The isotretinoin dosage could be increased by 25% each week after 1 month of therapy and some patients received up to 200 mg/m2/day. CR was defined as white blood cell (WBC) normalization and resolution of organomegaly and PR was defined as a greater than 50% decrease in WBC count and organomegaly. Additionally, one patient had a minimal response (defined as a 26% to 50% decrease in WBC count and organomegaly). The duration of response was 6 to 83 months in responding patients; 3 patients received a bone marrow transplant.

160 mg/m2/day PO divided in 2 divided doses for 14 days repeated every 28 days for 6 cycles was studied in 258 pediatric patients aged 1 to 18 years with no evidence of progressive disease following 5 cycles of induction chemotherapy and either high-dose chemotherapy followed by autologous bone marrow transplantation or 3 additional cycles of chemotherapy in a randomized, phase III trial. At median follow-up of 36 months, the 3-year event-free survival (EFS) rate (46% vs. 29%; p = 0.027) but not the 3-year overall survival (OS) rate (56% vs. 50%; p = 0.45) was significantly improved in patients who received isotretinoin compared with patients who did not receive isotretinoin. At a median follow-up of 8 years, the 5-year EFS (42% vs. 31%; p = 0.1219) and OS (50% vs. 39%; p = 0.1946) rates were not significantly improved in patients who received isotretinoin compared with no isotretinoin when evaluated using a log-rank comparison, although the 5-year OS rate was statistically superior with isotretinoin therapy when a log (-log(.)) transformation evaluation was used (p = 0.0006). Additionally, the 5-year EFS rate was significantly improved in patients who received ABMT and isotretinoin compared with patients who continued receiving chemotherapy with no isotretinoin (p = 0.0038). Grade 3 or 4 infection occurred in 12% of patients who received isotretinoin.

The dosage has not been established, although 1 mg/kg/day PO (rounded to the nearest 10 mg) divided into 2 doses has been studied in a phase II trial. Isotretinoin (n = 42) or tretinoin (n = 21) plus interferon alfa 3 million units/m2/day subcutaneously was studied in 63 patients; patient accrual was stopped in the tretinoin arm due to a low response in the first 20 patients. Of 39 evaluable patients who received isotretinoin plus interferon alfa, 3 patients (8%) experienced a partial response lasting 17, 22, and 24 weeks. Additionally, the median progression-free survival time was 3 months and the median overall survival time was 8 months in patients who received isotretinoin plus interferon alfa. Grade 3 and 4 toxicities reported in the isotretinoin plus interferon alfa arm included malaise and fatigue (26%), anemia (21%), and granulocytopenia (10%).

50 mg/m2/day PO with interferon alfa 3 million international units/m2 SC 3 times weekly and alfa-tocopherol 1200 international units/day POfor 12 months following surgery, radiotherapy, or both was studied in 45 patients with locally advanced stage III or IV squamous-cell carcinoma of the head and neck in a nonrandomized, phase II study. Therapy was well tolerated with 86% of patients able to complete the full 12 months of therapy. At a median follow-up of 49.4 months, the 3- and 5-year progression-free survival rates were 82.2% and 80%, respectively, and the 3- and 5-years overall survival rates were 88.9% and 81.3%, respectively. Additionally, only 1 secondary primary tumor (acute promyelocytic leukemia) was reported. Serious toxicities reported in this study include grade 3 arthralgia/myalgia (9%), fatigue (7%), and weight loss (7%) and grade 3 and 4 infection (4%). One patient developed optic neuritis which resolved after withdrawing therapy.

Use has not been established, although 1 mg/kg/day PO plus interferon alfa 3 million units subcutaneously 3 times weekly for 6 months (median duration, 4.9 months) has been studied. Isotretinoin/interferon alfa was administered as adjuvant therapy following surgery or radiation therapy (RT) in 31 patients and compared to 34 patients who received no adjuvant therapy following surgery or RT in a randomized, phase III study. All patients had aggressive squamous-cell skin cancer defined as tumor size 2 cm or larger, perineural invasion, evidence of deep invasion, or proven metastases. At a median follow-up of 21.5 months, the primary endpoint of recurrence- and second primary tumor (SPT)-free survival rate was not significantly different in patients who received adjuvant therapy compared with patients who did not receive adjuvant therapy (hazard ratio = 1.13; 95% CI, 0.53 to 2.41). Additionally, the 2-year cumulative recurrence - and SPT-free survival rates were 51.5% and 62.4% for patients who received adjuvant therapy and no adjuvant therapy, respectively. Grade 3 and 4 toxicities reported in the adjuvant treatment arm included fatigue (26%), dry eye or conjunctivitis (19%), dry skin and skin rash (16%), and cheilitis (13%).

†Indicates off-label use

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Adapalene; Benzoyl Peroxide: (Moderate) Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.
Albuterol; Budesonide: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Azelastine; Fluticasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Beclomethasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Benzoyl Peroxide: (Moderate) Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.
Benzoyl Peroxide; Clindamycin: (Moderate) Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.
Benzoyl Peroxide; Erythromycin: (Moderate) Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.
Benzoyl Peroxide; Sulfur: (Moderate) Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.
Betamethasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Budesonide: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Budesonide; Formoterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Budesonide; Glycopyrrolate; Formoterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Cholestyramine: (Moderate) Cholestyramine can bind with and possibly decrease the oral absorption of isotretinoin. To minimize drug interactions, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of cholestyramine.
Ciclesonide: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Colestipol: (Moderate) Colestipol can bind with and possibly decrease the oral absorption of isotretinoin. Administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of colestipol.
Corticosteroids: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Cortisone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Deflazacort: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Dexamethasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) L-methylfolate and isotretinoin should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with isotretinoin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Eravacycline: (Major) Avoid the concomitant use of isotretinoin and eravacycline due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances.
Ethanol: (Minor) Alcohol consumption can increase the risk for isotretinoin-related hypertriglyceridemia; patients experiencing hyperlipidemia while on isotretinoin should be advised to limit their alcohol intake.
Fludrocortisone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Flunisolide: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Fluticasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Fluticasone; Salmeterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Fluticasone; Umeclidinium; Vilanterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Fluticasone; Vilanterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Formoterol; Mometasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Fosphenytoin: (Minor) Long-term use of fosphenytoin has been associated with osteomalacia. No formal clinical studies have been conducted to assess if there is an additive or interactive effect on bone loss between fosphenytoin and isotretinoin therapy. Patients receiving fosphenytoin or other anticonvulsants that may affect the bone should receive isotretinoin therapy with caution.
Hydrocortisone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Levomefolate: (Minor) L-methylfolate and isotretinoin should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with isotretinoin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Lomitapide: (Moderate) Caution should be exercised when lomitapide is used with other medications known to have potential for hepatotoxicity, such as isotretinoin. The effect of concomitant administration of lomitapide with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
Methotrexate: (Moderate) Concomitant use of systemic retinoids, such as isotretinoin, and methotrexate could increase risk of liver-related side effects of methotrexate and such patients should be monitored closely during methotrexate therapy.
Methoxsalen: (Moderate) Use methoxsalen and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
Methylprednisolone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Mipomersen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as isotretinoin. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
Mometasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Olopatadine; Mometasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Orlistat: (Moderate) The bioavailability of orally administered retinoids may be decreased during coadministration with isotretinoin. In patients receiving orally-administered retinoids along with orlistat, close monitoring is recommended. In addition, the manufacturer recommends that fat-soluble vitamin analogues be administered at least 2 hours before or after the administration of orlistat to limit effects on oral absorption.
Palovarotene: (Major) Avoid concomitant use of palovarotene and other retinoids, such as isotretinoin, due to the risk for hypervitaminosis A.
Phenytoin: (Minor) Long-term use of phenytoin has been associated with osteomalacia. No formal clinical studies have been conducted to assess if there is an additive or interactive effect on bone loss between phenytoin and isotretinoin therapy. Patients receiving phenytoin or other anticonvulsants that may affect the bone should receive isotretinoin therapy with caution.
Porfimer: (Major) Avoid coadministration of porfimer with retinoids due to the risk of increased photosensitivity. Porfimer is a light-activated drug used in photodynamic therapy; all patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like retinoids may increase the risk of a photosensitivity reaction.
Prednisolone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Prednisone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Salicylic Acid: (Moderate) Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy.
Sodium Thiosulfate; Salicylic Acid: (Moderate) Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy.
Tetracyclines: (Major) Avoid the concomitant use of isotretinoin and systemic tetracyclines due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Pseudotumor cerebri has been reported with both systemic retinoid and tetracycline use alone. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances.
Tretinoin; Benzoyl Peroxide: (Moderate) Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.
Triamcinolone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Valoctocogene Roxaparvovec: (Major) Avoid concomitant use of isotretinoin and valoctocogene roxaparvovec. Concomitant use may reduce factor VIII activity independent of hepatotoxicity.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with retinoids is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like retinoids may increase the risk of a photosensitivity reaction.
Warfarin: (Moderate) Isotretinoin can decrease the anticoagulation effects of warfarin. If these drugs are coadministered, monitor INR and adjust warfarin doses as needed.

Absorica/Absorica LD/Accutane/Amnesteem/Claravis/Isotretinoin/MYORISAN/Sotret/ZENATANE Oral Cap: 8mg, 10mg, 16mg, 20mg, 24mg, 25mg, 30mg, 32mg, 35mg, 40mg

2 mg/kg/day PO (all formulations EXCEPT Absorica LD) for cystic acne; 1.6 mg/kg/day PO (Absorica LD) for cystic acne.

2 mg/kg/day PO (all formulations EXCEPT Absorica LD) for cystic acne; 1.6 mg/kg/day PO (Absorica LD) for cystic acne.

1 mg/kg/day PO (all formulations EXCEPT Absorica LD) for cystic acne; 0.8 mg/kg/day PO (Absorica LD) for cystic acne.

12 years: 1 mg/kg/day PO (all formulations EXCEPT Absorica LD) for cystic acne; 0.8 mg/kg/day PO (Absorica LD) for cystic acne.
younger than 12 years: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Retinoids are intracrine and paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction. Cells regulate the formation of specific retinoid isomers depending upon the cellular action required. The numerous effects of retinoids reflect the complex biology of the nuclear receptors that mediate retinoid activity. Retinoids exert their effects through binding to specific nuclear retinoid receptors, which are members of the steroid-thyroid superfamily of nuclear receptors. Retinoid receptors are divided into retinoid X receptors (RXRs) and retinoic acid receptors (RARs); both types can be further divided into 3 subtypes: Alpha, beta, and gamma. These receptor subtypes are further divided into many isoforms. Retinoid receptors are structurally similar but have different affinities for different types of retinoids and distribution varies throughout the body resulting in a wide range of actions. Isotretinoin acts primarily on the RAR family of receptors.
 
The primary action of isotretinoin in the treatment of acne is a reversible inhibition of sebum production through a reduction in the size of sebaceous glands and possible inhibition of follicular keratinization. The latter mechanism may be responsible for its beneficial effects in treating keratinization disorders. Sebum production can be reversibly reduced to 10% of pretreatment levels. Given in high dosages, isotretinoin can indirectly reduce the concentration of Propionibacterium acnes bacteria through decreased sebum production. Isotretinoin may inhibit prostaglandin E2 and collagenase, which would account for its antiinflammatory effect.
 
The role of retinoids in fetal development is to specify positional information for cells in developing limbs and possibly in the nervous system. In all age groups, retinoids are required for normal growth and proliferation of epithelial tissues. Dysregulation of retinoids may contribute to lung, gastric, uterine, bladder, testicular, breast, prostate, pancreatic, and skin cancers.

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. Isotretinoin is metabolized in the liver by CYP2C8, CYP2C9, CYP3A4, and CYP2B6. At least 3 metabolites [4-oxo-isotretinoin, retinoic acid (tretinoin), 4-oxo-retinoic acid (4-oxo-tretinoin)] have been identified in human plasma. All of three metabolites have retinoid activity in vivo; however, the clinical significance of the metabolites' activity is unknown. 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.
 
Affected cytochrome P450 isoenzymes: none

Isotretinoin is highly lipophilic and therefore, oral absorption is enhanced when given with a high-fat meal. With the exception of Absorica and Absorica LD, isotretinoin formulations should be administered with a meal to enhance bioavailability; however, in general, foods high in cholesterol or fat should be avoided to reduce the risk of developing hypertriglyceridemia. Compared to Accutane, Absorica is bioequivalent when taken with a high-fat meal. However, under fasting conditions, the Absorica AUC is approximately 83% higher and therefore, this formulation is not interchangeable with Accutane or its generic equivalents. Peak plasma concentrations are attained within approximately 3 hours under fasted conditions. Under fed conditions, the peak plasma concentrations are reached in approximately 5 to 6 hours.

Isotretinoin is contraindicated for use during pregnancy. Although not every exposure to isotretinoin has resulted in a birth defect, there is an extremely high risk that birth defects can occur if pregnancy occurs while taking isotretinoin in any amount even for a short period of time. Documented birth defects associated with isotretinoin include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, thymus, and parathyroid glands. Spontaneous abortion and premature births have also been reported. To prevent isotretinoin exposure during pregnancy, the iPLEDGE program has been developed. This program requires prescribers, pharmacists and patients to comply with certain conditions prior to prescribing, dispensing or receiving isotretinoin. Patients must sign a Patient Information/Consent form about isotretinoin and birth defects, in addition to the consent form, all patients should receive information about other potentially serious risks. If pregnancy does occur during treatment, use of the drug must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Prescribers should report all cases of pregnancy to the FDA MedWatch program at 800-FDA-1088 and the iPLEDGE pregnancy registry at 866-495-0654.[49581] [50395]

According to the manufacturer, breast-feeding women should not receive isotretinoin due to the potential adverse effects to the nursing infant. Lactating women who are exposed to isotretinoin should avoid breast-feeding during treatment and for at least 8 days after the last dose. It is unknown whether isotretinoin is distributed into breast milk, effects the breast-fed infant, or effects milk production. Vitamin A, which is structurally related to isotretinoin, is present in breast milk. A topical agent may be preferred (e.g., azelaic acid, benzoyl peroxide, clindamycin, erythromycin, tretinoin) for the treatment of acne in a nursing mother, especially while nursing a neonate or preterm infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.