Professional Drug Information > Accutane Roche

Isotretinoin (Systemic)

VA CLASSIFICATION
Primary: DE751
Secondary: DE890

Commonly used brand name(s): Accutane; Accutane Roche.

Another commonly used name is
13- cis-retinoic acid ^{03}.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiacne agent (systemic)—

antirosacea agent (systemic)—

keratinization stabilizer (systemic)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations

Note: FOR INFORMATION REGARDING PROBLEMS THAT HAVE OCCURRED DURING PREGNANCY SEE THE PREGNANCY/REPRODUCTION SECTION OF PRECAUTIONS TO CONSIDER.

Since isotretinoin is a teratogen in pregnant females , it should be prescribed only by physicians experienced in its use ^{01}. Isotretinoin should not be used in females of childbearing potential, unless the patient is unresponsive to or intolerant of other treatments and can accept the strict measures to prevent pregnancy during treatment and for 1 month after treatment discontinuation ^{{01} {04}}.

FOR FEMALES OF CHILDBEARING POTENTIAL:

• Use of isotretinoin is contraindicated in females of childbearing potential, unless all of the following criteria have been met:    • Patient shows severe, disfiguring, nodular acne ^{01} or one of the other accepted indications.
   • Patient is capable of complying with the mandatory contraceptive measures, even if she has a history of infertility. Two effective forms of contraception should be used at least 1 month before isotretinoin therapy begins, during therapy, and for 1 month following discontinuation of therapy. Contraceptive measures are not needed for patients who have had a hysterectomy or for those planning to abstain from sexual intercourse. ^{01}
   • Patient is not pregnant, as concluded from a negative pregnancy test. The pregnancy test should be performed after normal menstrual cycles are achieved and within 1 week prior to initiation of isotretinoin therapy. If isotretinoin therapy is initiated, it should begin within the same week as the pregnancy test, on Day 2 or Day 3 of the menstrual period ^{01}.
   • Patient receives both verbal and written warnings of the hazards associated with pregnancy during and following isotretinoin therapy and she acknowledges in writing her responsibility to avoid pregnancy ^{01}.
   • Patient understands treatment instructions and intends to follow them ^{01}.



For males and females:

• During treatment and 1 month after discontinuation of isotretinoin treatment, patients should not donate blood intended for transfusion purposes. Although the risk is small, a blood transfusion from such donors to pregnant women during their first trimester may expose the fetus to the medication ^{01}.


Accepted

Acne vulgaris (treatment)—Isotretinoin is indicated in the treatment of severe, recalcitrant nodular acne, where severe is defined as numerous lesions of at least 5 millimeters in diameter that may be suppurative or hemorrhagic. [Isotretinoin is also indicated for severe, inflammatory acne and acne conglobata. Taking into consideration its potential adverse effects, isotretinoin may be considered in patients with moderately severe acne who are prone to scarring or dyspigmentation.] Because of its potential adverse effects, isotretinoin should be reserved for patients who are unresponsive to or intolerant of conventional therapy, including systemic antibiotics ^{{01} {19} {20} {21} {22}}.

[Folliculitis, gram-negative (treatment) ]¹or
[Rosacea, severe (treatment)]¹—Isotretinoin is used in the treatment of gram-negative folliculitis ^{{25} {26}} and severe rosacea ^{{23} {24} {25}}.

[Hidradenitis suppurativa (treatment) ]¹—Isotretinoin is used in the treatment of hidradenitis suppurativa and is more effective for less established conditions and for those mild in severity (less scarring) ^{{28} {29}}. Complete suppression or prolonged remission is uncommon ^{{27} {28} {29}}. Using isotretinoin as adjunctive therapy to intralesional steroids, systemic antibiotics, or local surgery has proved beneficial for some patients with hidradentitis suppurativa ^{27}.

[Keratinization disorders]¹, such as [Ichthyosis, lamellar]¹ , [Keratosis follicularis]¹ , [Palmoplantar keratoderma]¹ , [Pityriasis rubra pilaris]¹—Isotretinoin has been used for treatment of severe keratinization disorders, such as lamellar ichthyosis ^{30}, keratosis follicularis (Darier's disease) ^{31}, palmoplantar keratoderma (keratosis palmaris et plantaris) ^{32}, and pityriasis rubra pilaris (PRP) ^{{33} {34} {35}}. Longer periods of isotretinoin therapy are usually required for keratinization disorders than for acne vulgaris, thus increasing the risk of side effects, including skeletal changes ^{{30} {31} {32} {33} {34} {35}}.

Unaccepted
Isotretinoin should not be used in the treatment of mild to moderate acne vulgaris that may be successfully controlled with topical acne medications and products or systemic antibiotics ^{04}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Vitamin A derivative (retinoid) ^{01}.
Molecular weight—
    300.44 ^{03}


Chemical name
    Retinoic acid, 13- cis- ^{01}.

Mechanism of action/Effect:

The exact mechanism of action for isotretinoin is not known. Although isotretinoin is produced naturally in the body and is a retinoid, it does not bind directly to any of the two classes of nuclear retinoic acid receptors (RARs or RXRs) or their subclasses of receptors (alpha, beta, and gamma receptors). It does isomerize rapidly to all- trans-retinoic acid (tretinoin) and may metabolize to other compounds that act as a ligand for a retinoid receptor to alter gene expression and cause transcription or transrepression changes in protein synthesis. ^{{16} {18}} Other pathways outside of the retinoid receptor pathway may be responsible for the sebosuppressive action of isotretinoin ^{16}.

Antiacne agent (systemic) and antirosacea agent (systemic)—The exact mechanism of action is not known. However, isotretinoin reduces sebaceous gland size and inhibits sebaceous gland activity, thereby decreasing sebum secretion. This action is probably responsible for the rapid initial clinical improvement in nodular acne. Isotretinoin also has been shown to decrease the number of Propionibacterium acnes organisms within the follicle. However, since isotretinoin has no effect on P. acnes in vitro , this action is probably a secondary effect due to decreased sebum secretion and the resulting decrease in nutrients and not a direct effect of isotretinoin. In addition, isotretinoin has been shown to have anti-keratinizing and anti-inflammatory actions. The exact role of these actions in clinical improvement of nodular acne is not known, especially with respect to prolonged remissions. ^{{21} {22} {24} {25}}

Hidradenitis suppurativa—If given early enough in the treatment of hidrandenitis suppurativa, isotretinoin may prevent a potentially affected apocrine gland from being occluded by ductal hypercornification ^{27}.

Keratinization stabilizer (systemic)—Isotretinoin is thought to interfere with the terminal differentiation of keratinocytes ^{{36} {37}}.

Absorption:

Rapidly absorbed from the gastrointestinal tract; amount absorbed increases when isotretinoin is taken with food ^{01}. Data suggest that isotretinoin and 4-oxo-isotretinoin may be reabsorbed from the bile ^{02}.

Distribution:

Radiolabeled doses administered to rats showed high concentrations of radioactivity in many tissues after 15 minutes, maximizing at 1 hour and declining to nondetectable concentrations in most tissues after 24 hours. Low radioactive concentrations in rats were still detectable in the liver, ureter, ovary, and adrenal and lacrimal glands after 7 days. ^{01}

Protein binding:

Very high (99.9%), almost exclusively to albumin ^{01}.

Biotransformation:

Metabolized in liver and possibly in the gut wall. The major identified metabolite in blood and urine is 4-oxo-isotretinoin ^{{01} {02}}; other identified metabolites are tretinoin and 4-oxo-tretinoin ^{02}.

Half-life:

Isotretinoin—

• 10 to 20 hours, terminal half-life ^{01}.


• 90 hours, biologic half-life, following a radiolabeled 80-mg dose ^{01}.


4-oxo-isotretinoin (major metabolite)—25 hours (range 17 to 50 hours), elimination half-life ^{01}.

Time to peak plasma concentration

Isotretinoin—Approximately 3 hours, following an 80-mg dose ^{01}.

4-oxo-isotretinoin—6 to 20 hours, following an 80-mg dose of isotretinoin ^{01}.

Peak plasma concentration

Isotretinoin—98 to 535 nanograms per mL (mean, 256 nanograms per mL) in acne patients, following an 80-mg dose ^{01}. Steady-state blood concentration for isotretinoin is 160 ± 19 nanograms per mL, following doses of 40 mg twice a day ^{01}.

4-oxo-isotretinoin—87 to 399 nanograms per mL, following an 80-mg dose of isotretinoin ^{01}. Steady-state blood concentration for 4-oxo-isotretinoin concentration exceeded that of isotretinoin after about 6 hours, following doses of 40 mg of isotretinoin twice a day ^{01}.

Elimination:
    Biliary or feces—83% ^{01}.
    Renal—65% ^{01}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to acitretin, tretinoin, or vitamin A derivatives may be sensitive to this medication also, since isotretinoin is related to both retinoic acid and retinol (vitamin A). Also, paraben-sensitive patients may be sensitive to isotretinoin capsules, since the gelatin capsule contains the preservatives methylparaben and propylparaben. ^{01}

Carcinogenicity/Tumorigenicity

Studies in the Fischer 344 rat given isotretinoin doses of 8 or 32 mg per kg of body weight (mg/kg) per day for more than 18 months show an increased incidence of pheochromocytoma and, at the higher dose, adrenal medullary hyperplasia. However, pheochromocytoma is known to occur with a relatively high frequency in the particular species of rat tested. At doses of 8 and 32 mg/kg per day, rats show a decreased incidence of hepatic adenomas, hepatic angiomas, and leukemia. ^{01}

Mutagenicity

Isotretinoin was not found to be mutagenic in a series of tests or assays, including the Ames test (for one of two laboratories), Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay ^{01}. In one laboratory, isotretinoin produced a weakly positive response for the Ames test when the test was conducted with metabolic activation ^{01}.

Pregnancy/Reproduction
Fertility—
Reproduction studies in male and female rats receiving isotretinoin in doses of 2, 8, or 32 mg/kg a day show no evidence of adverse effects on gonadal function, fertility, or conception rate. However, reproduction studies in male dogs receiving isotretinoin in doses of 20 or 60 mg/kg a day for approximately 30 weeks show incomplete testicular atrophy and microscopic evidence of depression of spermatogenesis. Studies in human males receiving isotretinoin for the treatment of nodular acne show no clinically significant changes in the number, motility, or morphology of spermatozoa in the ejaculate or in the production of ejaculate volume. ^{01}

Pregnancy—
Isotretinoin is teratogenic in humans and is contraindicated during pregnancy. Unless abstinence is the chosen method, it is recommended that the patient use two forms of effective contraception to prevent pregnancy, starting 1 month before initiation of treatment, during treatment, and for 1 month after discontinuation of treatment ^{01}.

Although not every fetus exposed to isotretinoin has been affected, the risk is high that an infant will have a deformity or abnormality if the pregnancy occurred while the mother was taking isotretinoin, even for a short period of time. Whenever an unexpected pregnancy occurs during the time of teratogenic risk, the risk-benefit ratio of continuing the pregnancy must be considered. The risks include: 15% incidence of major malformations, 5% incidence of perinatal mortality, 16% incidence of premature birth, and 40% incidence of spontaneous abortion. ^{{01} {09}}

Major human fetal deformities or abnormalities associated with the use of isotretinoin include:    • Central nervous system (CNS) abnormalities, including hydrocephalus, microcephaly, and cranial nerve deficit;
   • Eye abnormalities, including microphthalmia;
   • Heart defects;
   • Parathyroid deficiency;
   • Skeletal or connective tissue abnormalities, including absence of terminal phalanges, alterations of the skull and cervical vertebra, and malformations of hip, ankle, and forearm; facial dysmorphia; cleft or high palate; low-set ears, micropinna, and small or absent external auditory canals; meningomyelocele; multiple synostoses; and syndactyly; and
   • Thymus gland abnormality ^{{01} {09}}.


Cases of intelligence quotient scores lower than 85 have been reported with or without other CNS abnormalities ^{{01} {09}}.

One study of pregnant rats, who were given isotretinoin in doses of 5, 15, and 50 mg/kg a day on gestation days 7 through 15, produced no teratogenicity; in another study, isotretinoin was teratogenic in doses of 150 mg/kg a day. When rats were administered isotretinoin in doses of 5, 15, or 32 mg/kg a day on the 14th day of gestation through the 21st day of lactation, pup mortality increased, secondary to reduced maternal food intake. ^{02}

In one study of pregnant New Zealand white rabbits given isotretinoin in doses of 1, 3, and 10 mg/kg of isotretinoin per day on the 7th through 18th days of gestation, no teratogenic or embryotoxic effects were seen at 1 and 3 mg/kg a day, but the 10 mg/kg dose caused nine of thirteen rabbits to abort and produced teratogenic effects in the remaining litters. ^{02}

FDA Pregnancy Category X ^{01}.

Breast-feeding

It is not known whether isotretinoin is distributed into breast milk. Isotretinoin is not recommended for use in women who are breast-feeding because of isotretinoin's potential to cause adverse effects in nursing infants. ^{01}

Pediatrics

The long-term use of isotretinoin in children has not been studied ^{02}. Although appropriate studies on the relationship of age to the effects of isotretinoin have not been performed in the pediatric population, many preteens have a high rate of clinical relapse for acne vulgaris ^{10}. Prepubertal children may be more sensitive to some effects of isotretinoin ^{11}. During clinical trials of disorders of keratinization that use higher doses of isotretinoin than that used for acne vulgaris, two children showed x-ray changes suggestive of premature epiphyseal closure ^{01}.



Adolescents

Adolescents may have a high rate of clinical relapse ^{10} for acne vulgaris.


Geriatrics


No information is available on the relationship of age to the effects of isotretinoin in geriatric patients.


Dental

Isotretinoin can increase or decrease saliva production ^{01}. Continuing dryness of the mouth may increase the risk of dental disease, including tooth decay, gum disease, and fungal infection. Having regular dental checkups and using artificial saliva or dissolving sugarless candy or ice in the mouth may help to reduce the incidence of dental problems. Patient should check with a physician or dentist if dry mouth continues for more than 2 weeks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Photosensitizing medications, other, such as sulfonamides, tetracyclines, or thiazide diuretics    (although isotretinoin is not phototoxic or photoallergenic^{12}, it may increase the patient's sensitivity to sunlight or ultraviolet light for several months as the horny layer of skin thins^{12}; concurrent use of isotretinoin and these medications may increase susceptibility to sunburn)


Retinoids, other, systemic, such as:
» Acitretin
» Tretinoin, oral
Vitamin A and its derivatives, including vitamin supplements containing vitamin A^{12} or
Retinoids, topical, such as adapalene, tazarotene, and tretinoin     (concurrent use of retinoids or doses of vitamin A larger than the minimum recommended daily allowance (RDA) increase the risk of clinical symptoms resembling those of excessive vitamin A intake or toxicity, also called hypervitaminosis A^{12})


» Tetracyclines, oral, including minocycline    (can increase intracranial pressure; concomitant use with isotretinoin is not recommended because of the combination's potential to exacerbate this effect^{01}{12}{15})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]), serum and
Alkaline phosphatase (ALP), serum and
Aspartate aminotransferase (AST [SGOT]), serum and
Gamma-glutamyltransferase (GGT), serum and
Lactate dehydrogenase (LDH), serum    (increases in concentrations have occurred in about 10 to 20% of patients^{01}; some of these concentrations returned to normal levels with dosage reduction or continued administration of isotretinoin; if normalization does not readily occur or if hepatitis is suspected, isotretinoin should be discontinued^{01})


Blood, urine and
Creatine kinase (CK) concentration, serum and
Glucose concentration, fasting, plasma or serum and
Uric acid concentration, urine and
Urinalysis, protein    (increases have occurred in less than 10% of patients. Elevated CK concentrations have occurred in some patients engaging in vigorous physical activity^{01})


High-density lipoprotein (HDL) concentration    (decreases in serum HDL concentrations have occurred in about 16% of patients; this effect is reversible upon discontinuation of medication^{{01}{13} {14}})


Platelet counts, whole blood and
Sedimentation rate, erythrocyte (ESR), whole blood    (elevated sedimentation rates have been reported in about 40% of patients; increases in platelet counts have occurred in about 10 to 20% of patients^{01})


Red blood cell indices, whole blood and
White blood cell count, whole blood    (decreases have occurred in about 10 to 20% of patients^{01})


Triglyceride, plasma and
Cholesterol, total, serum    (elevated plasma triglyceride concentrations occur in about 25% of patients and are dose-related^{01}{13}. Triglyceride concentrations greater than 500 mg/dL were experienced by 32 of 298 patients treated for all diagnoses and by 5 of 135 patients treated for nodular acne^{02}; elevation of serum triglycerides to concentrations in excess of 800 mg/dL occasionally has been associated with acute pancreatitis^{12}{13}. A minimal increase in serum total cholesterol concentration has occurred in about 7% of patients; these effects are reversible upon discontinuation of medication^{01}{13})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Conditions predisposing to hypertriglyceridemia, such as
High alcohol intake, or history of
Hypertriglyceridemia, family history of
Obesity    (isotretinoin may increase plasma triglyceride concentrations and, to a lesser extent, total cholesterol and may decrease high density lipoprotein [HDL] cholesterol concentrations, possibly increasing the risk of cardiovascular disease for patients with these conditions who take isotretinoin over a long period of time^{01})


Diabetes mellitus, or family history of    (possible alteration in blood glucose concentrations; insulin requirements do not appear to be affected when isotretinoin is used for treatment of acne for several months^{12}. Isotretinoin may increase plasma triglyceride concentrations and decrease HDL cholesterol concentrations, possibly increasing the risk of cardiovascular disease for patients with diabetes mellitus who take isotretinoin over a long period of time^{01}{13})


Sensitivity to retinoids, vitamin A (also called retinol), or their derivatives^{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood count, complete (CBC), whole blood    (baseline determinations are recommended prior to therapy and may be repeated as needed after 4 to 6 weeks of therapy^{01})


Glucose, fasting, plasma or serum and/or
Glucose, 2-hour postprandial, plasma or serum    (recommended during therapy in patients known or suspected to have diabetes mellitus because some patients have experienced problems in controlling their blood glucose^{01})


Lipid profile, serum    (recommended under fasting conditions prior to therapy, then repeated at 1- or 2-week intervals until the lipid response to isotretinoin is established, which usually occurs within 4 weeks. After 1 month, the test is repeated only if there are significant increases in blood lipid concentrations, or if the patient has associated risk factors. Following consumption of alcohol, 36 hours should elapse before determining blood lipid concentrations^{01}{12})


Liver profile, serum    (recommended prior to therapy and at 1- or 2-week intervals until the hepatic function response is established, or as determined by the physician. Testing is repeated only if there are liver function abnormalities at 1 month. Since transient abnormalities of liver function have been reported, special monitoring is warranted for patients with a history of liver disease and for those patients undergoing vigorous physical exercise^{01}{12})


Occult blood, stool^{38}    (periodic monitoring recommended to detect inflammatory bowel disease)


Pregnancy testing    (recommended within 1 week of treatment initiation, on a monthly basis thereafter during treatment, and 1 month after treatment discontinuation; testing serves to remind the patient of the importance of avoiding pregnancy. If pregnancy occurs, patient should be counseled on whether to continue the pregnancy^{01}{02}{12})






Side/Adverse Effects

Note: Most side/adverse reactions in nodular acne patients have been reversible upon discontinuation of therapy^{01}.
Studies in animals have shown that prolonged isotretinoin therapy increased the incidence of focal calcification; fibrosis and inflammation of the myocardium; calcification of coronary, pulmonary, and mesenteric arteries; and metastatic calcification of the gastric mucosa. Also, long bone fractures have been reported in rats given isotretinoin at a dosage of 32 mg per kg of body weight (mg/kg) per day for 15 weeks^{01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Arthralgia ^{01}{12}(bone or joint pain; difficulty in moving)
    
burning, redness, itching, or other signs of inflammation of eyes —incidence about 40% ^{01}{12}
    
cheilitis (scaling, redness, burning, pain, or other signs of inflammation of lips)—incidence 90%^{01}{12}{16}
    
epistaxis ^{01}(nosebleeds )—incidence of up to 80% in treatment of acne^{01}{12}
    
skin infection —incidence about 5%^{01}{12}
    
skin rash —incidence about 10% ^{01}

Incidence rare
    
Bleeding or inflammation of gums
    
cataracts or corneal opacities ^{01}{15}(blurred vision or other changes in vision)
    
decreased night vision (decreased vision after sunset and before sunrise)— may occur suddenly, may continue after treatment discontinuation^{01}{12}
    
hepatitis ^{01}(yellow eyes or skin)
    
inflammatory bowel disease or regional ileitis ( rectal bleeding; severe abdominal or stomach pain; severe diarrhea)^{01}{38}
    
mental depression
psychosis
or suicidal ideation ^{01}(attempts at suicide or thoughts of suicide; changes in behavior)
    
optic neuritis ^{01}( pain or tenderness of eyes)
    
pseudotumor cerebri ^{01}{15}( blurred vision or other changes in vision; headache, severe or continuing; nausea ; vomiting)
    
skeletal hyperostosis ^{01}{12}(back pain; bone or joint pain; difficulty in moving; stiff, painful muscles)—generally with long-term treatment ^{17}

Note: If symptoms of inflammatory bowel disease, visual disturbances, or signs or symptoms of pseudotumor cerebri occur, isotretinoin should be discontinued. Inflammatory bowel disease or regional ileitis may not appear until months to a year or more after isotretinoin has been discontinued.^{38} Patients with signs or symptoms of pseudotumor cerebri should be referred to a neurologist for further diagnosis and care.^{01}{15}
Although isotretinoin has caused corneal opacities and diffuse interstitial skeletal hyperostosis in patients treated for acne, these conditions occur more frequently when higher doses of isotretinoin are used in patients who are treated for keratinization disorders^{01}. A more extensive skeletal hyperostosis occurs in adults who use a mean dose of 2.24 mg of isotretinoin per kg of body weight a day. Premature closure of the epiphyses in children has occurred.^{01}
Mental depression, psychosis , or suicidal ideation is uncommon with isotretinoin treatment and is probably more prevalent in patients being treated for severe acne. The mechanism for these side/adverse effects is unknown. In many patients, mental depression subsided with discontinuation of isotretinoin and recurred when treatment was resumed. Any patient continuing to experience these effects after treatment discontinuation may need further evaluation^{01}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Delayed or exaggerated healing response (crusting of skin )^{10}
    
difficulty in wearing contact lenses —may continue after treatment discontinuation^{12}
    
dryness of eyes —may continue after treatment discontinuation ^{12}
    
dryness of mouth or nose —incidence 80% in treatment of acne^{12}{16}
    
dryness or itching of skin —incidence 80% in treatment of acne
    
headache, mild —incidence about 5%
    
increased sensitivity of skin to sunlight — incidence about 5%^{12}
    
peeling of skin on palms of hands or soles of feet — incidence about 5%
    
stomach upset —incidence about 5%
    
thinning of hair —incidence less than 10%, may continue after treatment discontinuation^{01}
    
unusual tiredness —incidence about 5%^{01}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
    
Abdominal pain ^{02}
    
dizziness ^{02}
    
drowsiness ^{01}
    
intracranial pressure, elevated ^{01}{15}(headache, severe; nausea; vomiting)
    
irritability ^{01}
    
itchy skin ^{01}


Treatment of overdose
To decrease absorption—Evacuation of stomach should be considered within 2 hours of ingestion of acute overdose. Medication should be discontinued in patients with symptoms of overdose who were given therapeutic doses. ^{02}

Monitoring—    • Monitor for increased intracranial pressure ^{{02} {15}}.
   • Female patients of childbearing potential should have a pregnancy test at time of overdose and 1 month later; if positive, teratogenic risk and continuance of pregnancy should be discussed ^{02}.
   • Blood samples should be collected and isotretinoin and metabolite concentrations determined. ^{02}


Supportive care—Female patients of childbearing potential need to use two effective contraceptive methods for 1 month after overdose ^{01} or until isotretinoin and its metabolites are no longer measurable in the blood ^{02}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Isotretinoin (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to isotretinoin, acitretin, tretinoin, or vitamin A derivatives

Pregnancy—Not taking isotretinoin during pregnancy because it causes birth defects in humans. In addition, not taking if there is a chance that pregnancy may occur during treatment or within 1 month following treatment. Not taking isotretinoin unless an effective form of contraception is used for at least 1 month before beginning treatment. Contraception must be continued during treatment and for 1 month after isotretinoin is stopped





Breast-feeding—Although it is not known whether isotretinoin passes into the breast milk, medication is not recommended during breast-feeding because it may cause unwanted effects in nursing babies





Use in children—Preadolescents may be more sensitive to the effects of isotretinoin and preadolescents and adolescents may experience high rates of relapse for acne vulgaris

Other medications, especially retinoids, such as acitretin, tretinoin (oral); or tetracyclines (oral)

Proper use of this medication
» Reading accompanying patient information before using this medication

» For women of reproductive potential—Special precautions are needed before beginning treatment to ensure that the patient is not pregnant, such as using an effective form of birth control for 1 month before initiating treatment, obtaining a negative pregnancy test after a normal menstrual period pattern has been established and within 1 week before initiating treatment, then starting medication on Day 2 or 3 of normal menses. Women of reproductive age or potential are required to use two forms of contraception during treatment, beginning at least 1 month before initiation of treatment with isotretinoin and continuing for 1 month after medication is discontinued

» Taking isotretinoin dose with food

» Importance of not taking more medication than the amount prescribed

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress during therapy

» Stopping medication immediately and checking with physician if pregnancy is suspected, since isotretinoin causes birth defects in humans

» Checking with physician if skin condition does not improve within 1 to 2 months, full improvement may take 5 to 6 months; expecting that skin irritation may occur or skin condition may worsen within the first several weeks of treatment but will lessen in severity with continued use

» Not donating blood to a blood bank during treatment or for 30 days after isotretinoin therapy has been completed to prevent possibility of a pregnant patient receiving the blood

» Understanding that vision impairment can occur, including sudden night vision impairment, photophobia, blurred vision, or dryness of eyes. Vision problems can make driving a car or operating machinery dangerous

Checking with physician anytime vision problems occur; wearing contact lenses may be uncomfortable

Understanding that dental problems can occur resulting from dryness of mouth and may increase dental disease, including tooth decay, gum disease, and fungus infections; regular dental appointments are needed and use of sugarless candy or saliva substitute or melting ice in mouth may be necessary to lessen dental problems

» Minimizing exposure of skin to wind, cold temperatures, and sunlight, including limiting exposure on cloudy days, to avoid sunburn, dryness, or irritation, especially during the first months of treatment. Also, not using artificial sunlight or sunlamp, unless directed otherwise by physician

Using sunscreen preparations (minimum sun protection factor [SPF] of 15) and wearing protective clothing over exposed areas and UV-blocking sunglasses when sunlight exposure cannot be avoided; avoiding direct sunlight between 10 a.m. and 3 p.m.; checking with physician at any time skin becomes too dry or irritated; choosing proper skin products to reduce skin dryness or irritation

» Not using vitamin A or vitamin A–containing supplements in doses that exceed the minimum recommended daily allowances (RDA)

Patients with diabetes mellitus: Understanding that use of isotretinoin may alter blood glucose concentrations; insulin requirements do not appear to be affected when using isotretinoin for treatment of acne for several months


Side/adverse effects
Signs of potential side effects, especially arthralgia; burning, redness, itching, or other signs of inflammation of eye; cheilitis; epistaxis; skin infection; or skin rash; bleeding or inflammation of gums; cataracts; corneal opacities; decreased night vision; hepatitis; inflammatory bowel disease; regional ileitis; mental depression, psychosis, or suicidal ideation; optic neuritis; pseudotumor cerebri; or skeletal hyperostosis


General Dosing Information
Generally, the initial dose of isotretinoin should be individualized according to the patient's weight and the severity and location of the disease ^{02}.

Diet/Nutrition
Isotretinoin should be given with food ^{01}.

For use as an antiacne agent
Prescribing or dispensing a 30-day supply of isotretinoin may encourage communication to reinforce criteria for pregnancy prevention ^{02}.

Isotretinoin doses of 0.5 and 1 mg per kilogram of body weight (mg/kg) a day provide initial clearing of nodular acne, but the need to re-treat the patient is less with the larger dose, providing that it can be tolerated by the patient ^{01}. For best, long-lasting results and to lessen the chance of re-treatment, most physicians aim to achieve a cumulative isotretinoin dose of 100 to 150 mg/kg ^{04}.

Higher doses of isotretinoin (i.e., up to 2 mg/kg per day) may be required in patients whose disease is very severe or is primarily located on the chest and back instead of on the face ^{01}.

During the initial period of isotretinoin therapy, transient exacerbation of acne may occur ^{01}. Severe flares sometimes occur. This usually can be prevented by starting with a lower initial dose for a short time, such as 0.5 mg/kg per day or less for 2 weeks.

Following 4 or more weeks of therapy, dosage adjustment should be based on response of the disease to isotretinoin and the occurrence of side effects ^{01}.

Improvement in nodular acne may occur after 1 to 2 months, but marked improvement may require 4 to 5 months of therapy. Also, improvement may continue after discontinuation of isotretinoin use. ^{01}

In most patients, a single course of therapy may result in complete and prolonged remission of severe nodular acne. However, if a second course of therapy is necessary, it should not be initiated for at least 8 weeks (possibly 16 to 20 weeks, depending on individual response) after completion of the first course. Improvement in the condition may continue following discontinuation of isotretinoin use ^{01}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

ISOTRETINOIN CAPSULES

Usual adult and adolescent dose
Acne vulgaris
Oral, 0.5 mg per kg of body weight a day for two to four weeks, then increased to 1 mg per kg of body weight per day for twelve ^{02} to twenty weeks ^{01}; the maximum recommended dose is 2 mg per kg of body weight per day ^{{01} {02}}.

[Folliculitis, gram-negative]¹ or
[Rosacea, severe]¹
Oral, 0.5 to 1 mg per kg of body weight per day in two divided doses.

[Hidradenitis suppurativa (treatment)]¹
Oral, 1 mg per kg of body weight per day for four months. A lower dose of 0.5 to 1 mg per kg may be effective if isotretinoin is used as adjunctive therapy. ^{27}

[Keratinization disorders]¹
Oral, up to 4 mg per kg of body weight per day, the dosage depending on the specific disease and its severity, for up to four months. Lowest dose to achieve clinical effect should be used.


Strength(s) usually available
U.S.—


10 mg (Rx) [Accutane (edetate disodium) ( methylparaben) (propylparaben)^{01}]


20 mg (Rx) [Accutane (edetate disodium) ( methylparaben) (propylparaben)^{01}]


40 mg (Rx) [Accutane (edetate disodium) ( methylparaben) (propylparaben)^{01}]

Canada—


10 mg (Rx) [Accutane Roche (methylparaben) ( propylparaben)^{02}]


40 mg (Rx) [Accutane Roche (methylparaben) ( propylparaben)^{02}]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant container, unless otherwise specified by manufacturer ^{02}.

Auxiliary labeling:
   • Do not take this medication if you become pregnant.
   • Take with food.
   • Avoid prolonged or excessive exposure to sunlight.
   • May cause dizziness or blurred vision.
   • This medication may impair your ability to drive or operate machinery. Use care until you become familiar with its effects.

Note: Include patient directions when dispensing.
Counsel female patients about using two forms of birth control 1 month before starting treatment, during treatment, and for 1 month after discontinuing treatment.
Counsel male and female patients:    • Not to donate blood for transfusion during treatment and for at least 1 month after discontinuing treatment.
   • Be aware that sudden night vision inadequacies can occur, which can be hazardous when operating a vehicle.

Revised: 01/04/2000

References

1. Accutane package insert (Roche—US), Rev 2/98, Rec 3/98.
   

2. Accutane Roche product monograph (Hoffmann-La Roche—Canada), Rev 5/26/94, Rec 2/27/98.
   

3. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1997. p. 399.
   

4. Cunliffe WJ, van de Kerkhof PCM, Caputo R, et al. Roaccutane treatment guidelines: results of an international survey. Dermatology 1997; 194: 351-7.
   

5. Ho V, Schachter D, Miller R, et al. Acne management for the 90s: current treatment guidelines. Can J Diagn 1995; Suppl: 5-25.
   

6. Stern RS. When a uniquely effective drug is teratogenic: the case of isotretinoin. N Engl J Med 1989; 320: 1007-9.
   

7. Pastuszak A, Koren G, Rieder MJ. Use of the retinoid pregnancy program in Canada: patterns of contraception use in women treated with isotretinoin and etretinate. Reprod Toxicol 1994; 8: 63-8.
   

8. Lehucher-Ceyrac D, Weber-Buisset WJ. Isotretinoin and acne: a prospective analysis of 188 cases over 9 years. Dermatology 1993; 186: 123-8.
   

9. Adams J. Similarities in genetic mental retardation and neuroteratogenic syndromes. Pharmacol Biochem Behav 1996 Dec; 55(4): 683-90.
   

10. Leyden JJ. Oral isotretinoin: how can we treat difficult acne patients? Dermatology 1997; 195 Suppl 1: 29-33.
    

11. Strasburger VC. Acne: what every pediatrician should know about treatment. Pediatr Clin North Am 1997 Dec; 44(6): 1505-23.
    

12. Meigel WN. How safe is oral isotretinoin? Dermatology 1997; 195 Suppl 1: 22-8.
    

13. Georgala S, Schulpis KH, Potouridou I, et al. Effects of isotretinoin therapy on lipoprotein (a) serum levels. Int J Dermatol 1997; 36: 863-4.
    

14. Lestringant GG, Frossard PM, Agarwal M, et al. Variations in lipid and lipoprotein levels during isotretinoin treatment for acne vulgaris with special emphasis on HDL-cholesterol. Int J Dermatol 1997; 36: 859-62.
    

15. Lee AG. Pseudotumor cerebri after treatment with tetracycline and isotretinoin for acne. Cutis 1995 Mar; 55(3): 165-8.
    

16. Ott F, Bollag W, Geiger J-M. Oral 9-cis-retinoic acid versus 13-cis-retinoic acid in acne therapy. Dermatology 1996; 193: 124-6.
    

17. Warrell Jr. Differentiation agents. In: DeVita VT Jr, Hellman S, Rosenberg SA. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven; 1997. p. 483-90.
    

18. Mayne ST, Lippman SM. Cancer prevention: chemopreventive agents. In: DeVita VT Jr, Hellman S, Rosenberg SA. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven; 1997. p. 585-99.
    

19. Lester RS, Schachter GD, Light MJ. Isotretinoin and tetracycline in the management of severe nodulocystic acne. Int J Dermatol 1985 May; 24(4): 252-7.
    

20. Jones DH, King K, Miller AJ, et al. A dose-response study of 13-cis-retinoic acid in acne vulgaris. Br J Dermatol 1983 Mar; 108(3): 333-43.
    

21. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol 1984 Mar; 10(3): 490-6.
    

22. Peck GL, Olsen TG, Butkus D, et al. Isotretinoin versus placebo in the treatment of cystic acne. J Am Acad Dermatol 1982; 6(4 Pt 2 Suppl): 751-6.
    

23. Hoting E, Paul E, Plewig G. Treatment of rosacea with isotretinoin. Int J Dermatol 1986; 25(10): 660-3.
    

24. Marsden JR, Shuster S, Neugebauer. Response of rosacea to isotretinoin. Clin Exp Dermatol 1984 Sep; 9(5): 484-8.
    

25. Plewig G, Nikolowski J, Wolff H. Action of isotretinoin in acne rosacea and gram-negative folliculitis. J Am Acad Dermatol 1982; 6(4 Pt 2 Suppl): 766-85.
    

26. James WD, Leyden JJ. Treatment of gram-negative folliculitis with isotretinoin: positive clinical and microbiologic response. J Am Acad Dermatol 12(2 Pt 1): 319-324.
    

27. Norris JFB, Cunliffe WJ. Failure of treatment of familial widespread hidradenitis suppurativa with isotretinoin. Clin Exp Dermatol 1986 Nov; 11(6): 579-83.
    

28. Dicken CH, Powell ST, Spear KL. Evaluation of isotretinoin treatment of hidradenitis suppurativa. J Am Acad Dermatol 1984 Sep; 11(3): 500-2.
    

29. Brown CF, Gallup DG, Brown VM. Hidradenitis suppurativa of the anogenital region: response to isotretinoin. Am J Obstet Gynecol 1988 Jan; 158(1): 12-5.
    

30. Baden HP, Buxman MM, Weinstein GD, et al. Treatment of ichthyosis with isotretinoin. J Am Acad Dermatol 1982 Apr; 6(4 Pt 2 Suppl): 716-20.
    

31. Dicken CH, Bauer EA, Hazen PG, et al. Isotretinoin treatment of Darier"s disease. J Am Acad Dermatol 1982 Apr; 6(4 Pt 2 Suppl): 721-6.
    

32. Bergfeld WF, Derbes VJ, Elias PM, et al. The treatment of keratosis palmaris et plantaris with isotretinoin. J Am Acad Dermatol 1982 Apr; 6(4 Pt 2 Suppl): 727-31.
    

33. Goldsmith LA, Weinrich AE, Shupack J. Pityriasis rubra pilaris response to 13-cis-retinoic acid (isotretinoin). J Am Acad Dermatol 1982 Apr; 6(4 Pt 2 Suppl): 710-5.
    

34. Dicken CH. Isotretinoin treatment of pityriasis rubra pilaris. J Am Acad Dermatol 1987 Apr; 16(2 Pt 1): 727-31.
    

35. Borok M, Lowe NJ. Pityriasis rubra pilaris: further observations of systemic retinoid therapy. J Am Acad Dermatol 1990 May; 22(5 Pt 1): 792-5.
    

36. Ruiz-Maldonado R, Tamayo L. Retinoids in keratinizing diseases and acne. Pediatr Clin North Am 1983 Aug; 30(4): 721-34.
    

37. Ward A, Brogden RN, Heel RC, et al. Isotretinoin: a review of its pharmacological properties and therapeutic efficacy in acne and other skin disorders. Drugs 1984 Jul; 28(1): 6-37.
    

38. Prokop LD. Isotretinoin: possible component cause of inflammatory bowel disease. Am J Gastroenterol 1999 Sep; 94(9): 2568.
    

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