Isotretinoin

The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice ( > 600 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the rat dose for total body surface area and > 300 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects.

Accutane (isotretinoin) causes serious birth defects at any dosage (see Boxed CONTRAINDICATIONS AND WARNINGS). Female patients of childbearing potential who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the Boxed CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in PRECAUTIONS. Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female patient who is or might become pregnant, for 1 month after the overdose. All patients with isotretinoin overdose should not donate blood for at least 1 month.

Isotretinoin can cause severe, life-threatening birth defects. Never use isotretinoin if you are pregnant.

Women of child-bearing potential must agree in writing to use two specific forms of birth control and have regular pregnancy tests before, during, and after taking isotretinoin.

Isotretinoin is available only under a special program called iPLEDGE. It is dangerous to try and purchase isotretinoin on the Internet or from vendors outside of the United States.

Do not take vitamin supplements containing vitamin A while you are taking isotretinoin.

Do not donate blood while taking isotretinoin and for at least 30 days after you stop taking it.

Isotretinoin is part of the drug class:

• Retinoids for topical use in acne

Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Isotretinoin and certain other medicines can interact with each other, sometimes causing serious side effects. Especially tell your doctor if you take:

• Vitamin A supplements. Vitamin A in high doses has many of the same side effects as isotretinoin. Taking both together may increase your chance of getting side effects.
• tetracycline antibiotics such as doxycycline, tetracycline, or minocycline (Minocin).
• progestin-only birth control pills (mini-pills) such as Camilla, and Norethindrone.
• Dilantin (phenytoin).
• corticosteroids such as dexamethasone, hydrocortisone, or fludrocortisone (Florinef).
• St. John’s wort.

These medicines should not be used with isotretinoin unless your doctor tells you it is okay.

Know the medicines you take. Keep a list of them to show to your doctor and pharmacist. Do not take any new medicine without talking with your doctor.

Do not breastfeed while taking isotretinoin and for one month after stopping isotretinoin. It is not known if isotretinoin is excreted in human breast milk or if it will harm your nursing baby. Tell your doctor if you are breastfeeding before you receive isotretinoin.

take isotretinoin exactly as prescribed. You must also follow all the instructions of the iPLEDGE program. Before prescribing isotretinoin, your doctor will:

• explain the iPLEDGE program to you
• have you sign the Patient Information/Informed Consent form (for all patients). Female patients who can get pregnant must also sign another consent form.

You will not be prescribed isotretinoin if you cannot agree to or follow all the instructions of the iPLEDGE program.

• You will get no more than a 30 day supply of isotretinoin at a time. This is to make sure you are following the iPLEDGE program. You should talk with your doctor each month about side effects.
• The amount of isotretinoin you take has been specially chosen for you. It is based on your body weight, and may change during treatment.
• Take isotretinoin 2 times a day with a meal, unless your doctor tells you otherwise. Swallow your isotretinoin capsules whole with a full glass of liquid. Do not chew or suck on the capsule. Isotretinoin can hurt the tube that connects your mouth to your stomach (esophagus) if it is not swallowed whole.
• If you miss a dose, just skip that dose. Do not take two doses at the same time.
• If you take too much isotretinoin or overdose, call your doctor or poison control center right away.
• Your acne may get worse when you first start taking isotretinoin. This should last only a short while. Talk with your doctor if this is a problem for you.
• You must return to your doctor as directed to make sure you don’t have signs of serious side effects. Your doctor may do blood tests to check for serious side effects from isotretinoin. Female patients who can get pregnant will get a pregnancy test each month.
• Female patients who can get pregnant must agree to use two separate forms of effective birth control at the same time one month before, while taking and for one month after taking isotretinoin. You must access the iPLEDGE system to answer questions about the program requirements and to enter your two chosen forms of birth control. To access the iPLEDGE system, go to www.ipledgeprogram.com or call 1-866-495-0654.

You must talk about effective birth control methods with your doctor or go for a free visit to talk about birth control with another doctor or family planning expert. Your doctor can arrange this free visit, which will be paid for by the company that makes isotretinoin.

If you have sex at any time without using two forms of effective birth control, get pregnant or miss your expected period, stop using isotretinoin and call your doctor right away.

What you should avoid while taking isotretinoin:

• Do not get pregnant while taking isotretinoin and for one month after stopping isotretinoin. See “Isotretinoin Precautions" section.
• Do not breastfeed while taking isotretinoin and for one month after stopping isotretinoin. It is not known if isotretinoin can pass through your milk and harm the baby.
• Do not give blood while you take isotretinoin and for one month after stopping isotretinoin. If someone who is pregnant gets your donated blood, her baby may be exposed to isotretinoin and may be born with birth defects.
• Do not take other medicines or herbal products with isotretinoin unless you talk to your doctor.
• Do not drive at night until you know if isotretinoin has affected your vision. Isotretinoin may decrease your ability to see in the dark.
• Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion, or laser procedures, while you are using isotretinoin and for at least 6 months after you stop. isotretinoin can increase your chance of scarring from these procedures. Check with your doctor for advice about when you can have cosmetic procedures.
• Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet lights. Isotretinoin may make your skin more sensitive to light.
• Do not share isotretinoin with other people. It can cause birth defects and other serious health problems.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on your weight.

The recommended dosage range for isotretinoin is 0.5 to 2 mg/kg/day given in two divided doses.

The typical target dose is 1 mg/kg/day.

• Store at room temperature
• Protect from light.
• Keep isotretinoin and all medicines out of the reach of children.

Storage

Oral

15–30°C in tight, light-resistant containers.2 105

• Has pharmacologic actions similar to those of other retinoids (e.g., vitamin A, tretinoin);7 principal pharmacologic effect appears to be regulation of cell (e.g., epithelial) proliferation and differentiation.8 9

• Exact mechanism(s) of action in the treatment of nodulocystic acne is not fully understood but appears to include inhibition of sebaceous gland function and follicular keratinization.1 8 29 30 93

• Exact mechanism(s) of action in treatment of neoplasms has not been conclusively determined7 42 48 90 but may involve effects mediated via cytosol-binding proteins,42 inhibition of ornithine decarboxylase activity,48 49 50 51 52 and effects on the immune system.65 78

• Has teratogenic and abortifacient effects.105 (See Boxed Warning.)

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For isotretinoin, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to isotretinoin or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of isotretinoin in children younger than 12 years of age. Safety and efficacy have not been established.

isotretinoin should be used with caution in teenagers, especially those with bone problems or diseases.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of isotretinoin in the elderly. However, elderly patients may have a greater risk of problems and side effects when taking isotretinoin.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking isotretinoin, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using isotretinoin with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Chlortetracycline
• Demeclocycline
• Desogestrel
• Dienogest
• Doxycycline
• Drospirenone
• Estradiol Cypionate
• Estradiol Valerate
• Ethinyl Estradiol
• Ethynodiol Diacetate
• Etonogestrel
• Levonorgestrel
• Lymecycline
• Meclocycline
• Medroxyprogesterone Acetate
• Mestranol
• Methacycline
• Minocycline
• Norelgestromin
• Norethindrone
• Norgestimate
• Norgestrel
• Oxytetracycline
• Rolitetracycline
• Tetracycline

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using isotretinoin with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use isotretinoin, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of isotretinoin. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcoholism, severe or
• Allergy to aspirin, history of or
• Diabetes or
• Metabolism disorder, family history of or
• Severe weight problems—Use with caution. May increase risks for more serious problems.

• Anorexia (eating disorder) or
• Epiphyseal closure, premature or
• Osteomalacia (softening of the bones) or
• Osteoporosis (brittle bones), childhood or family history of or
• Other bone disorders or diseases—Use with caution. It is not known whether isotretinoin affects bone loss.

• Asthma or
• Depression, history of or
• Eye or vision problems or
• Hearing problems or
• Heart disease or
• Hepatitis or
• Hypertriglyceridemia (high triglycerides in the blood) or
• Intestinal disorders, history of or
• Pancreatitis (inflammation of the pancreas) or
• Pseudotumor cerebri (swelling in the brain) or
• Psychosis, history of or
• Vitamin A overdose (too much vitamin A in the body)—Use with caution. May make these conditions worse.

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• It is used to treat pimples (acne).
• It may be given to you for other reasons. Talk with the doctor.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Absorica: 10 mg, 20 mg [contains soybean oil]

Absorica: 25 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #6 (sunset yellow), soybean oil, tartrazine (fd&c yellow #5)]

Absorica: 30 mg [contains soybean oil]

Absorica: 35 mg [contains fd&c blue #2 (indigotine), soybean oil]

Absorica: 40 mg [contains soybean oil]

Amnesteem: 10 mg, 20 mg, 40 mg [contains soybean oil]

Claravis: 10 mg [contains fd&c yellow #6 (sunset yellow), soybean oil]

Claravis: 20 mg [contains soybean oil]

Claravis: 30 mg

Claravis: 40 mg [contains fd&c yellow #6 (sunset yellow), soybean oil]

Myorisan: 10 mg, 20 mg [contains soybean oil]

Myorisan: 30 mg

Myorisan: 40 mg [contains fd&c yellow #6 (sunset yellow), soybean oil]

Zenatane: 10 mg [contains brilliant blue fcf (fd&c blue #1), edetate disodium, fd&c yellow #10 (quinoline yellow), methylparaben, propylparaben, soybean oil]

Zenatane: 20 mg [contains edetate disodium, methylparaben, propylparaben, soybean oil]

Zenatane: 30 mg [contains edetate disodium, fd&c blue #2 aluminum lake, fd&c yellow #10 (quinoline yellow), methylparaben, propylparaben, soybean oil]

Zenatane: 40 mg [contains brilliant blue fcf (fd&c blue #1), edetate disodium, fd&c blue #2 (indigotine), fd&c yellow #10 (quinoline yellow), methylparaben, propylparaben, soybean oil]

• Acne Products
• Antineoplastic Agent, Retinoic Acid Derivative
• Retinoic Acid Derivative

Refer to adult dosing.

Acne (severe recalcitrant nodular): Children ≥12 years to Adolescents ≤17 years: Oral:

Manufacturer’s labeling: 0.5 to 1 mg/kg/day in 2 divided doses for 1 to 20 weeks; may discontinue earlier if the total cyst count decreases by >70%. Adjust dose according to the appearance of clinical side effects and/or response of the disease.

Alternate dosing: 0.5 mg/kg/day in 2 divided doses for 1 month, then increase to 1 mg/kg/day in 2 divided doses as tolerated until a cumulative dose of 120 to 150 mg/kg is reached (AAD [Zaenglein 2016]).

Acne (moderate) (off-label use): Children ≥12 years to Adolescents ≤17 years: Oral: 20 mg/day (~0.3 to 0.4 mg/kg/day) for 6 months (Amichai 2006) or 0.3 to 0.5 mg/kg/day for 15 to 20 weeks (AAD [Zaenglein 2016])

Neuroblastoma, high-risk (off-label use): Children and Adolescents: Oral: 160 mg/m2/day (in 2 divided doses) days 15 through 28 of a 28-day treatment cycle for 6 cycles (regimen also includes dinutuximab, sargramostim, and aldesleukin) (Yu 2010) or 160 mg/m2/day (in 2 divided doses) days 1 through 14 every 28 days for 6 cycles, beginning after continuation chemotherapy or transplantation (Matthay 1999)

Store at 20°C to 25°C (68°F to 77° F); excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from light.

Isotretinoin must not be used by women and adolescents who are pregnant or who may become pregnant. There is an extremely high risk that severe birth defects can result if pregnancy occurs while taking isotretinoin in any amount, even for short periods of time. Potentially, any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected.

Birth defects that have been documented following isotretinoin exposure include abnormalities of the face, eyes, ears, skull, CNS, cardiovascular system, and thymus and parathyroid glands. Cases of intelligence quotient (IQ) scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion, and premature births have been reported.

Documented external abnormalities include skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases, death has occurred with some of the abnormalities previously noted.

If pregnancy does occur during treatment of a female patient who is taking isotretinoin, isotretinoin must be discontinued immediately and she should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Because of isotretinoin's teratogenicity and to minimize fetal exposure, isotretinoin is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE. Isotretinoin must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Isotretinoin must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE.

CBC with differential and platelet count, baseline sedimentation rate, glucose, CPK; signs of depression, mood alteration, psychosis, aggression, severe skin reactions; changes in vision

Pregnancy test (for all female patients of childbearing potential): Two negative tests with a sensitivity of at least 25 milliunits/mL prior to beginning therapy (the second performed at least 19 days after the first test and performed during the first 5 days of the menstrual period immediately preceding the start of therapy); monthly tests to rule out pregnancy prior to refilling prescription and one month after discontinuation (Absorica).

Lipids: Prior to treatment and at weekly or biweekly intervals until response to treatment is established. Test should not be performed <36 hours after consumption of ethanol.

Liver function tests: Prior to treatment and at weekly or biweekly intervals until response to treatment is established.

When used for oncology indications, monitor adherence.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dry mouth, dry eyes, dry skin, dry lips, nasal irritation, or contact lens discomfort. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), seizures, nausea, vomiting, severe headache, dizziness, severe diarrhea, rectal bleeding, rectal pain, severe abdominal pain, signs of depression (suicidal ideation, anxiety, emotional instability, illogical thinking, suicidal ideation), aggressive behavior, signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of esophageal problems (angina, difficulty swallowing, or heartburn), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of a pancreas problem (pancreatitis; severe abdominal pain, severe back pain, severe nausea, or vomiting), eye pain, muscle pain, joint pain, bone pain, bruising, bleeding, loss of strength and energy, urinary retention, change in amount of urine passed, back pain, hearing impairment, tinnitus, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Suspected hepatitis or patients with liver function test elevations that do not normalize: Discontinue use; etiologies should be further investigated.

Data not available