If your acne is really severe and hasn’t responded to other types of therapy, your dermatologist may turn to isotretinoin, commonly known by its original brand name, Accutane. Isotretinoin is a powerful oral medication and, so far, it’s the only treatment that induces a long-term, drug-free remission of severe acne.

The vast majority of people who have taken isotretinoin bear witness to the dramatic reduction in acne symptoms and a prolonged improvement they’ve experienced even after only one course of 15 to 20 weeks of isotretinoin. Okay, then, why don’t I and all the other dermatologists out there simply install an isotretinoin vending machine in our waiting room?

There are three main reasons why isotretinoin treatment must be closely monitored:

• If taken during pregnancy, isotretinoin is highly likely to cause severe birth defects.

• There are many other possible side effects that can occur with isotretinoin use. They range in seriousness from dry lips to persistent headaches and temporary hearing loss.

• Isotretinoin may be linked to an increased risk of depression and suicide in people who take it.

Before going any further, I must tell you that most dermatologists believe that for those who have severe acne, the benefits of isotretinoin far outweigh the risks if the drug is taken as prescribed and specific cautions are followed.

I explain why we’re of this opinion and I give you details about the drug and precautions you can — and must — take, including the new program established in the United States to regulate access to this drug.

But, as only your doctor can prescribe isotretinoin, he has the definitive word on all aspects of your treatment, so follow instructions and ask questions.

Accutane Or Isotretinoin

Isotretinoin (its chemical name is 13-cis-retinoic acid) is related to both tretinoin (retinoic acid) and retinol (vitamin A). Isotretinoin is derived from vitamin A, which makes it a retinoid. In Canada, the United Kingdom, Australia, and Europe, isotretinoin is available as a topical, as well as an oral, preparation to treat acne.

When isotretinoin is taken orally, it’s classified as a teratogen, which means that it’s a substance that can cause deformities in a fetus. The original brand names for oral isotretinoin were Accutane in the United States and Roaccutane in rest of the world.

Besides, Accutane and Roaccutane, it’s now sold under several generic brand names in the United States, including:

• Amnesteem
• Claravis
• Sotret

For our purposes, I simplify matters and simply call it isotretinoin.

Drug and Its Uses

Isotretinoin is so effective because it has the ability to hit specific targets at the root of acne. Isotretinoin treats acne by:

• Stopping the excess oil production: Isotretinoin dramatically reduces the size and output of your sebaceous glands. It limits the amount of sebum and thus cuts off the acne bacteria’s (technically known as P. acnes) food supply. Stemming the flow of oil explains the many drying side effects that I describe later in here.

• Stabilizing keratinization: Keratinization is the process through which keratinocytes (epidermal cells) produce the protein keratin. When acne occurs, the dead cells that are located in your hair follicles are shed more frequently and in an abnormal fashion.

Isotretinoin helps you to more normally shed away dead skin cells, so that they are less likely to clog your pores. This process prevents comedones (whiteheads and blackheads) from forming.

Doctors usually prescribe isotretinoin after other acne treatments have failed to produce satisfactory results. Isotretinoin should never be the therapy of first choice.

It must be demonstrated that you’ve been unresponsive to other standard therapies — the course of which usually begins with topicals, and moves onto oral antibiotics (or a combination of oral antibiotics and topicals), or antiandrogens in women, all of which produce far fewer side effects than does isotretinoin.

Because of its serious side effects, isotretinoin should be used only for severe, resistant acne. The drug isn’t for everyone. However, when any of the following types of acne exist, isotretinoin may be considered (as the final therapeutic option):

• Severe nodular acne that can’t be cleared up by any other acne treatments including oral antibiotics
• Inflammatory acne with scarring that has failed conventional treatment
• Moderate-to-severe acne with frequent relapsing
• Acne with severe psychological distress

I need to emphasize that those last three reasons to use isotretinoin are considered to be “off-label,” meaning that the U.S. Food and Drug Administration (FDA) hasn’t approved isotretinoin for these conditions. Off-label use doesn’t imply that the drug is being used improperly or illegally.

The decision to prescribe isotretinoin for the final three reasons has been based on many years of clinical experience and a careful consideration of the potential risks and benefits in the use of the drug.

Isotretinoin can cause severe birth defects if taken by a pregnant female or a woman who becomes pregnant while taking the drug — even for a short time. Because the drug stays in the body’s system for a long time, it can cause birth defects for one month after a woman has stopped taking it.

Isotretinoin also carries an increased risk of miscarriage when used during pregnancy or up to one month prior to pregnancy. Studies done in males taking isotretinoin showed no significant effects on their sperm and no long-term damage to a male’s ability to have healthy children. Some of the birth defects include:

• Skull abnormalities
• Heart defects
• Deafness
• Cleft palate
• Central nervous system defects

In the treatment of females of childbearing potential, isotretinoin should be used only for patients with severe, disfiguring, cystic acne. If you have unprotected sex without birth control, miss your period, or become pregnant while you’re taking isotretinoin, call your dermatologist immediately!

Preparing For Treatment

Isotretinoin’s toxicity during pregnancy has long been known, but past efforts to reduce birth defects, including stricter product labeling and a limited pregnancy testing system, failed to resolve the problem. Therefore, in 2005, the FDA established an isotretinoin federal registry program called iPLEDGE.

The program is geared toward reducing the number of birth defects, miscarriages, and abortions associated with the drug. The iPLEDGE program only applies to prescriptions for isotretinoin that are written in the United States.

But the precautionary information is valid no matter where you live, and many of the same procedures are followed throughout the world. The registry keeps tabs on all isotretinoin prescriptions in the United States. Manufacturers, wholesalers, pharmacists, prescribers, and patients are linked through a centralized computer registry.

The registry also connects to the laboratories that perform the required pregnancy testing in this system. Physician and patient identification codes are intended to protect the privacy of patients.

Unfortunately, some dermatologists and other healthcare providers, maybe yours, will stop prescribing isotretinoin rather than take on the time-consuming workload inherent in the iPLEDGE registry.

Note: In this section, I use the term prescriber to refer to the person who writes the isotretinoin prescription, whether it’s your dermatologist or primary care provider.

Procedures all patients must follow

Everybody in the United States who is prescribed the drug, including females who can’t get pregnant and males, must register with iPLEDGE.

The registration procedure requires your prescriber — or a designated person in your prescriber’s office — to connect with the iPLEDGE Web site or phone system to enroll you into the system before being permitted to prescribe isotretinoin.

Reactivation must be done on an annual basis. After you’re registered and been prescribed isotretinoin, your prescriber must confirm to the registry that you are receiving ongoing counseling each month while taking the drug. A monthly review about birth-control requirements is especially crucial for female patients of childbearing potential.

In addition to keeping tabs on all the prescriptions, registering everyone is meant to discourage men from sharing their isotretinoin with a girlfriend, sister, wife, and so on and to discourage women from asking men they know to get isotretinoin for them.

Before starting treatment, your isotretinoin prescriber will order a lot of blood tests. A complete blood count, liver function studies, and triglyceride and cholesterol levels should be determined before treatment begins. That’s because isotretinoin can cause changes in the blood and the liver. Your prescriber will likely continue to order more tests as treatment continues.

Your prescriber will also explain the risks and requirements for safely using the drug, and have you or your parent or guardian sign a consent form that says you understand the risks associated with isotretinoin, including possible birth defects as well as the possibility of depression and suicide. (Pharmacists must also hand out a detailed warning brochure.)

All patients, male or female, are only allowed a 30-day supply of isotretinoin at each office visit. These prescriptions are only valid for seven days after they’re prescribed.

You must be reliable and capable of understanding the prescriber’s instructions on the use of isotretinoin and the risks involved, and be willing to comply with these instructions. Be sure to talk to your doctor about any of the following conditions that you or a family member may have:

• Allergies to foods or medicines
• Anorexia nervosa
• Asthma
• Diabetes
• Heart disease
• Liver disease
• Mental problems
• Osteoporosis

Additionally, tell your doctor if you’re taking phenytoin (Dilantin), because using it in combination with isotretinoin may weaken your bones.

Additional steps females must take

Because isotretinoin is harmful to the fetus and therefore shouldn’t be used during pregnancy, women of childbearing age must commit to additional testing and compliance in order to receive isotretinoin.

Table 1 contains a breakdown of the monthly responsibilities that you, your prescriber, and your pharmacist share within the iPLEDGE program if you’re a woman capable of having children. The discuss these requirements in the following sections (for more information you can check out iPledgeProgram.com and talk to your prescriber).

Individual	Interaction
Your doctor	Confirms that you’ve received contraceptive counseling Enters the two types of contraceptives that you’ve chosen to use Enters your pregnancy test results
You	Answer educational questions before each prescription Enter the two types of contraceptives that you’ve chosen to use
Your pharmacist	Checks with iPLEDGE to get authorization to fill the prescription.

In addition to these steps, you also need to avoid becoming pregnant for at least one month after stopping isotretinoin treatment. And because of isotretinoin’s potentially serious side effects, nursing mothers should unquestionably not use it.

Male patients who are taking isotretinoin should be informed about the risk associated with use during pregnancy, emphasizing that they shouldn’t share the drug with females.

Birth control discussion

You must discuss birth control methods with your prescriber or a healthcare professional with expertise in contraception, such as a gynecologist. Such counseling and patient education are prerequisites to obtaining isotretinoin prescriptions.

Two negative pregnancy tests

Two negative pregnancy tests before you start isotretinoin are necessary. The first test (a screening test) is done when the decision is made to start isotretinoin. The second test (a confirmation test) must be done during the first five days of your menstrual period right before starting isotretinoin.

You won’t get your first prescription for isotretinoin until there is proof that you have had two negative pregnancy tests. The pregnancy tests are performed only at certified laboratories that are CLIA approved.

CLIA stands for Clinical Laboratory Improvement Amendments and was enacted by the United States Congress to ensure the accuracy, reliability, and timeliness of patient test results regardless of where the test was performed.

Ongoing pregnancy tests during treatment

You continue to have a pregnancy test every month during isotretinoin therapy. Along with confirming that appropriately timed initial pregnancy tests performed at a CLIA-approved laboratory are negative prior to authorizing the dispensing of an isotretinoin prescription for a female patient who is capable of becoming pregnant, the iPLEDGE registry requires a new pregnancy test before each refill is authorized.

Use of two separate forms of effective birth control at the same time

You must be using two of these birth controls at least one month before beginning therapy, during therapy, and for one month after isotretinoin treatment has stopped. Effective forms of birth control include:

• Hormonal birth control — including birth control pills, patches, long-term injections (like Depo-Provera), and implants (like Norplant)
• Condoms
• IUDs (or Intra Uterine Devices)
• Diaphragms
• Tubal ligation (having your tubes tied)
• A partner who’s had a vasectomy

The following are unacceptable forms of contraception:

• Progesterone-only minipills that don’t contain estrogen (In fact, if you’re taking this form of birth control, talk to your doctor, as it may not work while you’re taking isotretinoin.)
• IUD Progesterone T
• Female condoms
• Natural family planning (rhythm method) or breastfeeding
• Fertility awareness
• Withdrawal
• Cervical shield

All birth control methods (besides total abstinence) can fail. Discuss the various options with your prescriber or your contraception advisor. In two specific situations, you don’t need to use these birth control methods:

• You commit to being absolutely and consistently abstinent (no sexual intercourse) during and for one month before and one month after your isotretinoin treatment.

• You have had a hysterectomy (your uterus was surgically removed).

If you are capable of becoming pregnant — even if you commit to abstinence — your prescriber may insist that oral contraceptives are one of the two methods used before starting, during, and for one month after isotretinoin treatment is completed.

Knowing What to Expect when You Take Isotretinoin

If I haven’t scared you off yet with all the warnings, here’s the section that tells you how to take isotretinoin, what to look out for, and how to deal with some of its inevitable side effects.

Taking your pills and observing results

Isotretinoin is available as capsules in the following strengths: 10, 20, 30, and 40 milligrams. The recommended dose depends on your body weight. Usually you take a pill with food twice a day for a total of 15 to 20 weeks. (In Europe, patients are often given lower dosages for longer periods of time.)

Initially, your doctor may decide to start you off on a low dose so that you can get used to any side effects and then the dosage can be increased. Often there is an observable improvement over the first month that continues over the course of treatment.

In the vast majority of isotretinoin users, complexions smooth out, marks fade, and acne improves dramatically. Some lesions may still remain after you have stopped treatment, but many individuals notice that their acne continues to improve even in the weeks after treatment has stopped.

Shortly after starting isotretinoin therapy, some people may initially get worse before they get better. Often that’s because they stopped all of the other acne medications that they were using up until then. A minority of isotretinoin users have a more serious flare at the beginning of treatment.

Your dermatologist can manage this by adjusting the dosage or by adding other medications to calm things down. Most people don’t require a second course of treatment; when needed, it should be resumed only after the drug has been stopped for four months.

What not to do when you’re taking isotretinoin

You must avoid certain things while taking isotretinoin, including the following:

• If you’re a woman, don’t even consider having unprotected sex while you’re taking isotretinoin.

• Don’t breastfeed while taking isotretinoin and for one month after stopping.

• Don’t donate blood during treatment or for one month after stopping treatment. If someone who is pregnant gets your donated blood, her baby may develop severe birth defects.

• Treatment with tetracycline and isotretinoin shouldn’t be given at the same time because the combination has been associated with brain swelling (pseudotumor cerebri).

• Vitamin A should be strictly avoided while undertaking therapy with isotretinoin because they’re closely related to one another. The use of both vitamin A and isotretinoin at the same time may lead to added side effects.

• If you’re taking birth control pills, the herbal supplement St. John’s Wort may make the birth control pills work less effectively.

Sizing up side effects

Although they’re common, side effects with isotretinoin are usually tolerable. In general, most folks work through many of the reactions because the drug is so effective that people with severe acne want to continue taking it despite some of the bothersome side effects. Side effects of isotretinoin are dose-related.

That means that the higher the dosage, the greater chance of having side effects. One way around this problem is for your dermatologist to put you on a low dosage for a longer period of time. However, females will then have to continue monitoring pregnancy tests and continue birth control for a longer period of time.

Mild side effects

Isotretinoin is effective, in part, because it can shut down the oil production in the body, but this action accounts for some of its side effects. Because of the great decrease in oil production, even your mucous membranes, such as the inside of your nose, eyelids, and mouth, lose oil and become very dry.

In fact, dryness is the most common side effect of isotretinoin. This reduction of oil can result in some of the less serious side effects, such as:

• Dry lips: Dry, chapped, and sometimes cracked lips are the most common and persistent annoyances from isotretinoin. These irritating problems occur in just about everybody who takes the drug. You can deal with them by gobbing on lip balm. I recommend Vaseline Petroleum Jelly, Chapstick, or Bag Balm.

• Dry eyes: You may find dry eyes to be a problem, particularly if you wear contact lenses. You may need to stop wearing them temporarily, but the frequent use of artificial tears such as Tears Naturale or Visine True Tears may allow you to continue using contacts. Artificial tears are used as one or two drops placed in the affected eye(s), as needed.

• Mild nosebleeds: Nosebleeds occur when the nasal lining dries out. They’re usually short-lived and can be stopped with direct pressure. Nosebleeds can be prevented by coating nasal surfaces with lubricants, such as Vaseline Petroleum Jelly or Aquaphor ointment.

• Dry skin: You may notice peeling of your palms and soles, or scaly skin on the backs of your hands and forearms. Helpful moisturizers such as Eucerin cream, Moisturel, Cutemol, and Am-Lactin, are all available over the counter.

However, reduction in oil isn’t the only annoying problem you face. You may also experience:

• Aches and pains: Musculoskeletal symptoms such as pain or stiffness of large joints or of the lower back occur and are usually very mild and disappear after a month or so. Try Tylenol (acetaminophen) if you experience ongoing pain.

• Increased sensitivity to the sun: I know you’re all wearing sunscreen daily anyway (hint, hint), so apply it more often and use a higher SPF than you might normally.

• Thinning hair: Less common, but still annoying; some people have reported thinning hair during treatment. Rarely has this been a persistent or a permanent problem — the hair generally grows back when the treatment regimen is over.

More serious problems

More serious unwanted events have also been reported and you should stop taking isotretinoin and call your dermatologist if you experience any of the following side effects. Most, if not all, of these side effects disappear after treatment is stopped, however, some have persisted after therapy:

• Changes in mood, depression, or suicidal thoughts or attempts: For more on this topic, see the section “The risk of depression and suicide.”

• Allergic reactions such as an itchy red rash or difficulty breathing: In some people, isotretinoin can cause serious allergic reactions. Stop taking it and get emergency care right away if you develop hives, a swollen face or mouth, or have trouble breathing. Also stop taking isotretinoin and call your prescriber if you develop a fever, rash, or red patches.

• Changes in vision: You may experience decreased night vision. You should be particularly careful when driving at night. Rarely has this persisted following treatment.

• Persistent headaches: A rare side effect of this drug is benign intracranial hypertension, which is an increase in pressure of the fluid surrounding your brain. If you have continual headaches that are present in the morning on waking and wear off through the day, you should be evaluated by your doctor.

• Hearing impairment: This problem has rarely persisted following treatment.

• Skeletal hyperostosis: This condition is typified by excessive bone growth along the sides of the vertebrae of the spine. It is diagnosed by X-ray studies. This problem is limited to those who take a high dosage and long-term therapy with isotretinoin, a dosage much higher than is used to treat acne.

The risk of depression and suicide

Depression is unfortunately a common problem in the age group that needs isotretinoin most frequently — the adolescent group. Acne appears most often between the ages of 12 to 24. The onset of depression also commonly occurs at about the same time.

In the United States, the FDA has been receiving reports of depression and suicide in patients taking isotretinoin and there is concern about a possible link between the drug, psychiatric disorders, and suicide.

Emotional problems in the adolescent population coupled with the stress of having severe acne, makes it difficult to determine whether isotretinoin can trigger depression and suicide or whether successful treatment may thwart such problems. This controversy has made its current use an issue of concern for many dermatologists and patients alike.

The package insert provided with isotretinoin prescriptions includes warnings about mental problems and suicide. Depression, other serious mental problems, suicidal thoughts, suicide attempts, and aggressive, violent behaviors have been reported while patients took the drug or soon after stopping it.

No one knows if isotretinoin caused these behaviors or if they would’ve happened even if the person didn’t take the drug. According to a recent study, isotretinoin doesn’t cause depression. In fact, many patients in this study described themselves as being emotionally better off after being on the medication.

Many dermatologists believe the research supports what they have seen in their patients all along. (If you’re into medicalese, you can find the study by Christina Chia and her fellow researchers in the May 2005 issue of the journal Archives of Dermatology.)

One Canadian study found that 4 percent of patients taking isotretinoin became depressed and remained depressed during treatment with isotretinoin; however, there were no control subjects for comparisons.

Studies of this sort, without controls (persons not taking isotretinoin), can’t provide convincing scientific data about whether a common disorder — depression — is caused by a drug. The FDA currently regards these associations as unproven, but needing further study.

The bottom line, as of 2005, is that it is still unclear whether isotretinoin causes increased risk for depression and possible suicide. Because suicide is a major cause of death in teenagers, particularly in males, it has been difficult to determine a causal relationship between isotretinoin and these events and there is a great need for further study.

If you or your child is taking isotretinoin and is showing signs of moodiness, depression, or psychosis, the drug should be stopped and you should notify your dermatologist immediately so that the situation can be evaluated.

Stop taking the drug and contact your doctor should you see signs of acting on dangerous impulses or seeing or hearing things that are not real.