A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Accutane Warnings, Precautions, Pregnancy, Nursing, Abuse - Isotretinoin
Accutane Warnings, Precautions, Pregnancy, Nursing, Abuse - Isotretinoin
WARNINGS
Psychiatric Disorders
Accutane may cause depression, psychosis and, rarely, suicidal
ideation, suicide attempts, suicide, and aggressive and/or violent behaviors.
Discontinuation of Accutane therapy may be insufficient; further evaluation
may be necessary. No mechanism of action has been established for these events
(see ADVERSE REACTIONS: Psychiatric). Prescribers
should read the brochure, Recognizing Psychiatric Disorders in Adolescents
and Young Adults: A Guide for Prescribers of Accutaneâ
(isotretinoin).
Pseudotumor Cerebri
Accutane use has been associated with a number of cases of
pseudotumor cerebri (benign intracranial hypertension), some of which involved
concomitant use of tetracyclines. Concomitant treatment with tetracyclines should
therefore be avoided. Early signs and symptoms of pseudotumor cerebri include
papilledema, headache, nausea and vomiting, and visual disturbances. Patients
with these symptoms should be screened for papilledema and, if present, they
should be told to discontinue Accutane immediately and be referred to a neurologist
for further diagnosis and care (see ADVERSE REACTIONS:
Neurological).
Pancreatitis
Acute pancreatitis has been reported in patients with
either elevated or normal serum triglyceride levels. In rare instances, fatal
hemorrhagic pancreatitis has been reported. Accutane should be stopped if
hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms
of pancreatitis occur.
Lipids
Elevations of serum triglycerides in excess of 800 mg/dL have
been reported in patients treated with Accutane. Marked elevations of serum
triglycerides were reported in approximately 25% of patients receiving Accutane
in clinical trials. In addition, approximately 15% developed a decrease in high-density
lipoproteins and about 7% showed an increase in cholesterol levels. In clinical
trials, the effects on triglycerides, HDL, and cholesterol were reversible upon
cessation of Accutane therapy. Some patients have been able to reverse triglyceride
elevation by reduction in weight, restriction of dietary fat and alcohol, and
reduction in dose while continuing Accutane.5
Blood lipid determinations should be performed before Accutane
is given and then at intervals until the lipid response to Accutane is established,
which usually occurs within 4 weeks. Especially careful consideration must be
given to risk/benefit for patients who may be at high risk during Accutane therapy
(patients with diabetes, obesity, increased alcohol intake, lipid metabolism
disorder or familial history of lipid metabolism disorder). If Accutane therapy
is instituted, more frequent checks of serum values for lipids and/or blood
sugar are recommended (see PRECAUTIONS: Laboratory
Tests).
The cardiovascular consequences of hypertriglyceridemia associated
with Accutane are unknown. Animal Studies: In rats given 8 or 32 mg/kg/day
of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1.0 mg/kg/day
after normalization for total body surface area) for 18 months or longer, the
incidences of focal calcification, fibrosis and inflammation of the myocardium,
calcification of coronary, pulmonary and mesenteric arteries, and metastatic
calcification of the gastric mucosa were greater than in control rats of similar
age. Focal endocardial and myocardial calcifications associated with calcification
of the coronary arteries were observed in two dogs after approximately 6 to
7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30
to 60 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after
normalization for total body surface area).
Hearing Impairment
Impaired hearing has been reported in patients taking Accutane;
in some cases, the hearing impairment has been reported to persist after therapy
has been discontinued. Mechanism(s) and causality for this event have not been
established. Patients who experience tinnitus or hearing impairment should discontinue
Accutane treatment and be referred for specialized care for further evaluation
(see ADVERSE REACTIONS: Special Senses).
Hepatotoxicity
Clinical hepatitis considered to be possibly or probably related
to Accutane therapy has been reported. Additionally, mild to moderate elevations
of liver enzymes have been observed in approximately 15% of individuals treated
during clinical trials, some of which normalized with dosage reduction or continued
administration of the drug. If normalization does not readily occur or if hepatitis
is suspected during treatment with Accutane, the drug should be discontinued
and the etiology further investigated.
Inflammatory Bowel Disease
Accutane has been associated with inflammatory bowel disease
(including regional ileitis) in patients without a prior history of intestinal
disorders. In some instances, symptoms have been reported to persist after Accutane
treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding
or severe diarrhea should discontinue Accutane immediately (see ADVERSE
REACTIONS: Gastrointestinal).
Skeletal
Bone Mineral Density
Effects of multiple courses of Accutane on the developing musculoskeletal
system are unknown. There is some evidence that long-term, high-dose, or multiple
courses of therapy with isotretinoin have more of an effect than a single course
of therapy on the musculoskeletal system. In an open-label clinical trial (N=217)
of a single course of therapy with Accutane for severe recalcitrant nodular
acne, bone density measurements at several skeletal sites were not significantly
decreased (lumbar spine change >-4% and total hip change >-5%) or were
increased in the majority of patients. One patient had a decrease in lumbar
spine bone mineral density >4% based on unadjusted data. Sixteen (7.9%) patients
had decreases in lumbar spine bone mineral density >4%, and all the other
patients (92%) did not have significant decreases or had increases (adjusted
for body mass index). Nine patients (4.5%) had a decrease in total hip bone
mineral density >5% based on unadjusted data. Twenty-one (10.6%) patients
had decreases in total hip bone mineral density >5%, and all the other patients
(89%) did not have significant decreases or had increases (adjusted for body
mass index). Follow-up studies performed in 8 of the patients with decreased
bone mineral density for up to 11 months thereafter demonstrated increasing
bone density in 5 patients at the lumbar spine, while the other 3 patients had
lumbar spine bone density measurements below baseline values. Total hip bone
mineral densities remained below baseline (range –1.6% to -7.6%) in 5 of 8 patients
(62.5%).
In a separate open-label extension study of 10 patients, ages
13-18 years, who started a second course of Accutane 4 months after the first
course, two patients showed a decrease in mean lumbar spine bone mineral density
up to 3.25% (see PRECAUTIONS: Pediatric Use).
Spontaneous reports of osteoporosis, osteopenia, bone fractures,
and delayed healing of bone fractures have been seen in the Accutane population.
While causality to Accutane has not been established, an effect cannot be ruled
out. Longer term effects have not been studied. It is important that Accutane
be given at the recommended doses for no longer than the recommended duration.
Hyperostosis
A high prevalence of skeletal hyperostosis was noted in clinical
trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally,
skeletal hyperostosis was noted in 6 of 8 patients in a prospective study of
disorders of keratinization.6 Minimal skeletal hyperostosis and calcification
of ligaments and tendons have also been observed by x-ray in prospective studies
of nodular acne patients treated with a single course of therapy at recommended
doses. The skeletal effects of multiple Accutane treatment courses for acne
are unknown.
In a clinical study of 217 pediatric patients (12 to 17 years)
with severe recalcitrant nodular acne, hyperostosis was not observed after 16
to 20 weeks of treatment with approximately 1 mg/kg/day of Accutane given in
two divided doses. Hyperostosis may require a longer time frame to appear. The
clinical course and significance remain unknown.
Premature Epiphyseal Closure
There are spontaneous reports of premature epiphyseal closure
in acne patients receiving recommended doses of Accutane. The effect of multiple
courses of Accutane on epiphyseal closure is unknown.
Vision Impairment
Visual problems should be carefully monitored. All Accutane
patients experiencing visual difficulties should discontinue Accutane treatment
and have an ophthalmological examination (see ADVERSE
REACTIONS: Special Senses).
Corneal Opacities
Corneal opacities have occurred in patients receiving Accutane
for acne and more frequently when higher drug dosages were used in patients
with disorders of keratinization. The corneal opacities that have been observed
in clinical trial patients treated with Accutane have either completely resolved
or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug
(see ADVERSE REACTIONS: Special Senses).
Decreased Night Vision
Decreased night vision has been reported during Accutane therapy
and in some instances the event has persisted after therapy was discontinued.
Because the onset in some patients was sudden, patients should be advised of
this potential problem and warned to be cautious when driving or operating any
vehicle at night.
PRECAUTIONS
The Accutane Pregnancy Prevention and Risk Management Programs
consist of the System to Manage Accutane Related Teratogenicity (S.M.A.R.T.)
and the Accutane Pregnancy Prevention Program (PPP). S.M.A.R.T. should be followed
for prescribing Accutane with the goal of preventing fetal exposure to isotretinoin.
It consists of: 1) reading the booklet entitled System to Manage Accutane
Related Teratogenicity (S.M.A.R.T.) Guide to Best Practices, 2) signing
and returning the completed S.M.A.R.T. Letter of Understanding containing
the Prescriber Checklist, 3) a yellow self-adhesive Accutane Qualification Sticker
to be affixed to the prescription page. In addition, the patient educational
material, Be Smart, Be Safe, Be Sure, should be used with each patient.
The following further describes each component:
1) The S.M.A.R.T. Guide to Best Practices includes:
Accutane teratogenic potential, information on pregnancy testing, specific information
about effective contraception, the limitations of contraceptive methods and
behaviors associated with an increased risk of contraceptive failure and pregnancy,
the methods to evaluate pregnancy risk, and the method to complete a qualified
Accutane prescription.
2) The S.M.A.R.T. Letter of Understanding attests
that Accutane prescribers understand that Accutane is a teratogen, have read
the S.M.A.R.T. Guide to Best Practices, understand their responsibilities
in preventing exposure of pregnant females to Accutane and the procedures for
qualifying female patients as defined in the boxed CONTRAINDICATIONS
AND WARNINGS.
The Prescriber Checklist attests that Accutane prescribers
know the risk and severity of injury/birth defects from Accutane; know how to
diagnose and treat the various presentations of acne; know the risk factors
for unplanned pregnancy and the effective measures for avoidance; will refer
the patient for, or provide, detailed pregnancy prevention counseling to help
the patient have knowledge and tools needed to fulfill their ultimate responsibility
to avoid becoming pregnant; understand and properly use throughout the Accutane
treatment course, the revised risk management procedures, including monthly
pregnancy avoidance counseling, pregnancy testing, and use of qualified prescriptions
with the yellow self-adhesive Accutane Qualification Sticker.
3) The yellow self-adhesive Accutane Qualification Sticker
is used as documentation that the prescriber has qualified the female patient
according to the qualification criteria (see boxed CONTRAINDICATIONS
AND WARNINGS).
4) Accutane Pregnancy Prevention Program (PPP) is a systematic
approach to comprehensive patient education about their responsibilities and
includes education for contraception compliance and reinforcement of educational
messages. The PPP includes information on the risks and benefits of Accutane
which is linked to the Accutane Medication Guide dispensed by pharmacists with
each prescription.
Male and female patients are provided with separate booklets.
Each booklet contains information on Accutane therapy, including precautions
and warnings, an Informed Consent/Patient Agreement form, and a toll-free line
which provides Accutane information in 13 languages.
The booklet for male patients, Be Smart, Be Safe, Be Sure,
Accutane Risk Management Program for Men, also includes information about
male reproduction, a warning not to share Accutane with others or to donate
blood during Accutane therapy and for 1 month following discontinuation of Accutane.
The booklet for female patients, Be Smart, Be Safe, Be Sure,
Accutane Pregnancy Prevention and Risk Management Program for Women, also
includes a referral program that offers females free contraception counseling,
reimbursed by the manufacturer, by a reproductive specialist; a second Patient
Information/Consent form concerning birth defects, obtaining her consent to
be treated within this agreement; an enrollment form for the Accutane Survey;
and a qualification checklist affirming the conditions under which female patients
may receive Accutane. In addition, there is information on the types of contraceptive
methods, the selection and use of appropriate, effective contraception, and
the rates of possible contraceptive failure; a toll-free contraception counseling
line; and patient education videos — the video "Be Prepared, Be Protected"
and the video "Be Aware: The Risk of Pregnancy While on Accutane".
General
Although an effect of Accutane on bone loss is not established,
physicians should use caution when prescribing Accutane to patients with a genetic
predisposition for age-related osteoporosis, a history of childhood osteoporosis
conditions, osteomalacia, or other disorders of bone metabolism. This would
include patients diagnosed with anorexia nervosa and those who are on chronic
drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects
vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant.
Patients may be at increased risk when participating in sports
with repetitive impact where the risks of spondylolisthesis with and without
pars fractures and hip growth plate injuries in early and late adolescence are
known. There are spontaneous reports of fractures and/or delayed healing in
patients while on treatment with Accutane or following cessation of treatment
with Accutane while involved in these activities. While causality to Accutane
has not been established, an effect cannot be ruled out.
INFORMATION FOR PATIENTS AND PRESCRIBERS
· Patients should be instructed
to read the Medication Guide supplied as required by law when Accutane is dispensed.
The complete text of the Medication Guide is reprinted at the end of this document.
For additional information, patients should also read the Patient Product
Information, Important Information Concerning Your Treatment with Accutaneâ
(isotretinoin). All patients should sign the Informed Consent/Patient Agreement.
· Females of childbearing potential
should be instructed that they must not be pregnant when Accutane therapy is
initiated, and that they should use 2 forms of effective contraception 1 month
before starting Accutane, while taking Accutane, and for 1 month after Accutane
has been stopped. They should also sign a consent form prior to beginning Accutane
therapy. They should be given an opportunity to enroll in the Accutane Survey
and to review the patient videotapes provided by the manufacturer to the prescriber.
The videos include information about contraception, the most common reasons
that contraception fails, and the importance of using 2 forms of effective contraception
when taking teratogenic drugs and comprehensive information about types of potential
birth defects which could occur if a woman who is pregnant takes Accutane at
any time during pregnancy. Female patients should be seen by their prescribers
monthly and have a urine or serum pregnancy test performed each month during
treatment to confirm negative pregnancy status before another Accutane prescription
is written (see boxed CONTRAINDICATIONS AND WARNINGS).
· Accutane is found in the semen
of male patients taking Accutane, but the amount delivered to a female partner
would be about 1 million times lower than an oral dose of 40 mg. While the no-effect
limit for isotretinoin-induced embryopathy is unknown, 20 years of postmarketing
reports include 4 with isolated defects compatible with features of retinoid
exposed fetuses. None of these cases had the combination of malformations characteristic
of retinoid exposure, and all had other possible explanations for the defects
observed.
· Patients may report mental
health problems or family history of psychiatric disorders. These reports should
be discussed with the patient and/or the patient’s family. A referral to a mental
health professional may be necessary. The physician should consider whether
or not Accutane therapy is appropriate in this setting (see WARNINGS:
Psychiatric Disorders).
· Patients should be informed
that they must not share Accutane with anyone else because of the risk of birth
defects and other serious adverse events.
· Patients should not donate
blood during therapy and for 1 month following discontinuance of the drug because
the blood might be given to a pregnant woman whose fetus must not be exposed
to Accutane.
· Patients should be reminded
to take Accutane with a meal (see DOSAGE AND
ADMINISTRATION). To decrease the risk of
esophageal irritation, patients should swallow the capsules with a full glass
of liquid.
· Patients should be informed
that transient exacerbation (flare) of acne has been seen, generally during
the initial period of therapy.
· Wax epilation and skin resurfacing
procedures (such as dermabrasion, laser) should be avoided during Accutane therapy
and for at least 6 months thereafter due to the possibility of scarring (see
ADVERSE REACTIONS: Skin and Appendages).
· Patients should be advised
to avoid prolonged exposure to UV rays or sunlight.
· Patients should be informed
that they may experience decreased tolerance to contact lenses during and after
therapy.
· Patients should be informed
that approximately 16% of patients treated with Accutane in a clinical trial
developed musculoskeletal symptoms (including arthralgia) during treatment.
In general, these symptoms were mild to moderate, but occasionally required
discontinuation of the drug. Transient pain in the chest has been reported less
frequently. In the clinical trial, these symptoms generally cleared rapidly
after discontinuation of Accutane, but in some cases persisted (see ADVERSE
REACTIONS: Musculoskeletal). There have been rare postmarketing reports
of rhabdomyolysis, some associated with strenuous physical activity (see Laboratory
Tests: CPK).
· Pediatric patients and their
caregivers should be informed that approximately 29% (104/358) of pediatric
patients treated with Accutane developed back pain. Back pain was severe in
13.5% (14/104) of the cases and occurred at a higher frequency in female than
male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients.
Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of
the musculoskeletal system should be done in patients who present with these
symptoms during or after a course of Accutane. Consideration should be given
to discontinuation of Accutane if any significant abnormality is found.
· Neutropenia and rare cases
of agranulocytosis have been reported. Accutane should be discontinued if clinically
significant decreases in white cell counts occur.
Hypersensitivity
Anaphylactic reactions and other allergic reactions have been
reported. Cutaneous allergic reactions and serious cases of allergic vasculitis,
often with purpura (bruises and red patches) of the extremities and extracutaneous
involvement (including renal) have been reported. Severe allergic reaction necessitates
discontinuation of therapy and appropriate medical management. Carcinogenesis,
Mutagenesis and Impairment of Fertility
In male and female Fischer 344 rats given oral isotretinoin
at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose
of 1.0 mg/kg/day, respectively, after normalization for total body surface area)
for greater than 18 months, there was a dose-related increased incidence of
pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia
was also increased at the higher dosage in both sexes. The relatively high level
of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes
it an equivocal model for study of this tumor; therefore, the relevance of this
tumor to the human population is uncertain.
The Ames test was conducted with isotretinoin in two laboratories.
The results of the tests in one laboratory were negative while in the second
laboratory a weakly positive response (less than 1.6 x background) was noted
in S. typhimurium TA100 when the assay was conducted with metabolic activation.
No dose-response effect was seen and all other strains were negative. Additionally,
other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse
micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay
with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all
negative.
In rats, no adverse effects on gonadal function, fertility,
conception rate, gestation or parturition were observed at oral dosages of isotretinoin
of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose
of 1.0 mg/kg/day, respectively, after normalization for total body surface area).
In dogs, testicular atrophy was noted after treatment with
oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day
(10 or 30 times the recommended clinical dose of 1.0 mg/kg/day, respectively,
after normalization for total body surface area). In general, there was microscopic
evidence for appreciable depression of spermatogenesis but some sperm were observed
in all testes examined and in no instance were completely atrophic tubules seen.
In studies of 66 men, 30 of whom were patients with nodular acne under treatment
with oral isotretinoin, no significant changes were noted in the count or motility
of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years)
receiving Accutane (isotretinoin) therapy for nodular acne, no significant effects
were seen on ejaculate volume, sperm count, total sperm motility, morphology
or seminal plasma fructose.
Pregnancy: Category X. See boxed CONTRAINDICATIONS
AND WARNINGS.
Nursing Mothers
It is not known whether this drug is excreted in human milk.
Because of the potential for adverse effects, nursing mothers should not receive
Accutane.
Pediatric Use
The use of Accutane in pediatric patients less than 12 years
of age has not been studied. The use of Accutane for the treatment of severe
recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be
given careful consideration, especially for those patients where a known metabolic
or structural bone disease exists (see PRECAUTIONS:
General). Use of Accutane in this age group for severe recalcitrant nodular
acne is supported by evidence from a clinical study comparing 103 pediatric
patients (13 to 17 years) to 197 adult patients (³18
years). Results from this study demonstrated that Accutane, at a dose of 1 mg/kg/day
given in two divided doses, was equally effective in treating severe recalcitrant
nodular acne in both pediatric and adult patients.
In studies with Accutane, adverse reactions reported in pediatric
patients were similar to those described in adults except for the increased
incidence of back pain and arthralgia (both of which were sometimes severe)
and myalgia in pediatric patients (see ADVERSE REACTIONS).
In an open-label clinical trial (N=217) of a single course
of therapy with Accutane for severe recalcitrant nodular acne, bone density
measurements at several skeletal sites were not significantly decreased (lumbar
spine change >-4% and total hip change >-5%) or were increased in the
majority of patients. One patient had a decrease in lumbar spine bone mineral
density >4% based on unadjusted data. Sixteen (7.9%) patients had decreases
in lumbar spine bone mineral density >4%, and all the other patients (92%)
did not have significant decreases or had increases (adjusted for body mass
index). Nine patients (4.5%) had a decrease in total hip bone mineral density
>5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in
total hip bone mineral density >5%, and all the other patients (89%) did
not have significant decreases or had increases (adjusted for body mass index).
Follow-up studies performed in 8 of the patients with decreased bone mineral
density for up to 11 months thereafter demonstrated increasing bone density
in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine
bone density measurements below baseline values. Total hip bone mineral densities
remained below baseline (range –1.6% to -7.6%) in 5 of 8 patients (62.5%).
In a separate open-label extension study of 10 patients, ages
13-18 years, who started a second course of Accutane 4 months after the first
course, two patients showed a decrease in mean lumbar spine bone mineral density
up to 3.25% (see WARNINGS: Skeletal: Bone Mineral
Density).
Geriatric Use
Clinical studies of isotretinoin did not include sufficient
numbers of subjects aged 65 years and over to determine whether they respond
differently from younger subjects. Although reported clinical experience has
not identified differences in responses between elderly and younger patients,
effects of aging might be expected to increase some risks associated with isotretinoin
therapy (see WARNINGS and PRECAUTIONS).
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