The drug that clears acne, but was also linked to depression, suicidal thoughts and fetal deformities is still on the market in its generic form
Accutane — the drug that cleared severe acne but was also linked to depression, suicidal thoughts and fetal deformities — is still on the market in its generic form, isotretinoin. How can this be, given that the original drug was discontinued by its manufacturer Hoffmann-La Roche, in part due to lawsuits relating to inflammatory bowel diseases and other issues?
With intense patient screening, compliance protocols and careful monitoring, isotretinoin (eye-soh-tret-in-OH-in) can be effective and the risk of terrible side effects can be minimized. Isotretinoin is not without problems, however, so patients need to weigh the risks and the benefits before taking the drug.
Here are nine things you should know about isotretinoin. They can help you gauge whether it is a drug you want to take yourself or have prescribed for your teen to treat severe acne.
1. Isotretinoin by any other name is still isotretinoin
In 1982, the US Food and Drug Administration (FDA) approved the active ingredient isotretinoin for use in treating severe nodular acne, under the brand name Accutane. Although the name is still widely recognized, Accutane was discontinued in 2009 due to lawsuits over side effects and diminishing market share due to the availability of the many generic versions of the drug.
Currently isotretinoin is available in similar generic versions from six manufacturers under the names Amnesteem, Claravis, Myorisan, Absorica, Amneal isotretinoin and Zenatane. Rachel Nazarian, MD, a board certified dermatologist at Schweiger Dermatology’s Clear Clinic in New York City, explains that all of the generic versions have similar formulas. They also have similar side effects, the same warning of fetal deformity and the same iPLEDGE pregnancy-monitoring requirements as did Accutane. The drugs are prescribed to patients ages 12 and older whose severe acne has not responded to other treatments.
2. Isotretinoin still has a bad rap — for good reason
The American Academy of Dermatology (AAD) acknowledges that isotretinoin has been linked to serious side effects, such as depression, suicidal thoughts and inflammatory bowel disease. But in an updated position statement, issued in 2018, the AAD reported that no direct causal link has been found between isotretinoin and these conditions. More recent studies have shown that isotretinoin is not an independent risk factor for depression. A 2020 study in the Journal of the American Academy of Dermatology concluded that since acne in itself is associated with depression and anxiety, it’s important to treat it, even if that means using isotretinoin.
Also, multiple studies, including a 2019 French study of more than 328,000 people, haven’t found a causal relationship between isotretinoin use and suicide. The French researchers determined that most of the patients on isotretinoin who attempted suicide had a risk-prone profile at the start of treatment. And in a 2020 commentary on suicidal risk with isotretinoin, published in the Journal of the European Academy of Dermatology and Venereology, researchers noted that severe acne often lowers mood and self esteem, so effective treatment can improve emotional health.
Defense attorneys have tried unsuccessfully to cite the use of tretinoin as an excuse for murder. In 2017 lawyers for a 15-year-old Colorado boy who stabbed a young woman to death suggested that isotretinoin was to blame for the boy’s violent behavior. And a 20-year-old Pennsylvania man claimed isotretinoin caused the mental impairment that led him to murder his ex-girlfriend in 2007. In both cases attempts at blaming isotretinoin failed and the assailants were found guilty.
Still, there are things to consider. By 2002 — 20 years after Accutane entered the market, and the year it lost its patent — the FDA became aware through the Adverse Event Reporting System of 173 reports of suicide worldwide associated with Accutane treatment. That same year, the FDA required manufacturer Hoffmann-La Roche to begin submitting quarterly summaries of side effects; and by August 2002, the summaries included roughly 6,000 additional reports of psychiatric adverse events, such as depression and suicidal thoughts. By 2005, 190 suicides had been associated with Accutane use, according to Drugwatch.com, a class-action attorney website.
A 2019 study published in JAMA Dermatology found that between 1997 and 2017, nearly 18,000 psychiatric adverse events were reported with isotretinoin use. Using data from the iPLEDGE program and the FDA Adverse Events Reporting System, the researchers noted that the most frequently reported psychiatric events were depressive disorders, emotional lability and anxiety disorders. There were 368 suicides, a rate that the researchers suggest may be lower than that of the general US population. Again, rates of depression and suicide are elevated among patients with acne at large, but patients taking isotretinoin still appear to be vulnerable to psychiatric issues, the researchers concluded.
Accutane users have also complained of problems with inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, and filed lawsuits against Hoffmann-La Roche, although research has shown that the incidence of these diseases does not appear to increase with isotretinoin use, and may even be reduced.
‘I resisted taking the drug initially because of the negative hype surrounding Accutane and birth deformities at the time. Once I was on the medication, I had to see the images of deformed babies on the papers I signed to get my prescription every month.’
Apart from these issues, isotretinoin carries an FDA category X label (not for use during pregnancy) and a stringent FDA“black box” warning (see the one for Claravis here), citing the drug’s detrimental effects on a developing fetus. Kathy, a 45-year-old mother of two in Manhattan, took Accutane 20 years ago. As she recalls: “I resisted taking the drug initially because of the negative hype surrounding Accutane and birth deformities at the time. Once I was on the medication, I had to see the images of deformed babies on the papers I signed to get my prescription every month.”
Patients taking isotretinoin may also find that their level of triglycerides (a type of fat or lipid in the blood) increases while using the drug. Julie, an 18-year-old from Florida, found that her triglycerides shot up way above normal to 270 mg/dL in the second month of a five-month course of treatment. (The National Heart, Lung, and Blood Institute cites a normal range for triglycerides as 150 mg/dL or lower.) High triglycerides — along with other factors — can increase the risk of heart disease.
Isotretinoin can also cause dry skin and extremely chapped lips in many users (Julie has reported having dry, peeling lips and skin that looks “sunburned” without makeup), as well as hair loss, nosebleeds and headaches. Isotretinoin may affect night vision, so it may not be possible to drive after dark; and it may make the skin more sensitive to sunlight, causing it to become irritated and burn easily. Drinking alcohol while taking the drug may increase the risk of side effects.
In addition, isotretinoin can interact negatively with some medications and vitamin supplements. Taking isotretinoin with corticosteroids can weaken bones; when taken with tetracycline antibiotics, it can increase pressure in the brain. Isotretinoin can interfere with progestin-only birth control pills, making them less effective. The drug — which is derived from vitamin A — should not be taken with vitamin A supplements as this can increase the risk of side effects.
Some side effects and allergic reactions are cause to discontinue taking isotretinoin and/or to call your doctor immediately.
3. Most side effects are not permanent
While the list of side effects may seem staggering, Dr. Nazarian notes that “most patients find their skin dryness resolves within days of their last dose; and most [milder] side effects should completely resolve within two weeks.” Some researchers have expressed concern that since dryness also affects the nasal passages, patients taking isotretinoin may be more vulnerable to COVID-19. Others have suggested that isotretinoin may be protective against COVID-19. Either way, more research is called for and studies are underway.
In clinical trials of Accutane, marked elevations of serum triglycerides were reported in approximately 25% of patients. Most triglyceride levels returned to normal once patients stopped taking the drug, but some persisted after treatment was stopped.
In terms of serious side effects, such as depression and IBD (whose debilitating effects can be permanent), the medical literature to date has found no direct causal link between isotretinoin and these conditions. In fact, a 2018 analysis of 20 studies on the risk of depression with isotretinoin use suggests not only that isotretinoin does not contribute to the development of depression in patients with acne, it improves patients’ preexisting depression symptoms.
Still, dermatologists take these side effects seriously and monitor patients before and during treatment. During an initial consultation, for example, Dr. Nazarian will take a patient’s verbal and written medical history, and, if prescribing the drug, will closely monitor side effects.. Prescribing physicians will also issue baseline blood tests to check triglyceride levels and for other possible abnormalities and may adjust dosages as needed. In some cases, patients have been able to lower their triglycerides by reducing their weight and restricting their dietary fat and alcohol while continuing on isotretinoin.
Some doctors have always ordered monthly blood tests throughout treatment. But more recently a meta-analysis of 26 studies, published in JAMA Dermatology, determined that unless a patient has abnormalities on lab tests or independent risk factors for liver, lipid or other disorders prior to starting isotretinoin, monthly blood tests may not be necessary. The studies revealed that any rise in triglycerides or cholesterol occurred within the first two months of treatment and on average had not changed at the five-month point. So if lipid levels are normal at baseline and after two months of treatment, repeated testing may not be necessary.
4. Isotretinoin is tightly regulated
Birth defects are another serious side effect associated with the use of isotretinoin. As a result, the FDA implemented the iPLEDGE program in 2006 to reduce the risk of fetal exposure to the drug. Today, all patients — including men — must adhere to iPLEDGE program requirements every month before getting a 30-day prescription. Doctors who prescribe isotretinoin and pharmacies who fill prescriptions must also register with iPLEDGE.
As part of the program, all women who are able to get pregnant must have two negative pregnancy tests before starting on isotretinoin and a negative pregnancy test each month, performed by an approved lab. Women must pick up their prescription within seven days of the negative results. During the coronavirus pandemic, women should discuss with their doctors the safest way to go about continuing treatment. This may mean using at-home pregnancy tests, or having video meetings with their doctor by smartphone or computer.
Women must also pledge to use two effective forms of birth control simultaneously during treatment and answer questions online each month about the iPLEDGE program and pregnancy prevention. Because of the risks to a developing fetus, female patients should continue using two forms of birth control for an additional month after treatment to allow for total elimination of the medication from their body.
Despite efforts to reduce fetal exposure to tretinoin, 4,647 pregnancies were reported to the FDA among patients taking tretinoin after the 2006 introduction of iPLEDGE through 2017, according to a 2019 analysis published in JAMA Dermatology. The researchers noted that the number of pregnancy-related adverse events for patients taking isotretinoin has decreased since 2006, but pregancies, abortions and fetal defects continue to be a problem. The iPLEDGE program provides only limited counseling regarding contraception, according to the researchers. They suggest that automatically providing emergency contraception alongside isotretinoin prescriptions may be an option for reducing the number of pregnancies.
Although isotretinoin can certainly harm a fetus, the drug doesn’t affect a patient’s fertility, says Jodi LoGerfo, a nurse practitioner certified in family medicine and dermatology at the Orentreich Medical Group in New York City. Studies show that ovarian reserve, an indicator of fertility, is diminished while a woman takes isotretinoin but rebounds after treatment stops. Research also shows that isotretinoin does not reduce male fertility, and may even have a positive effect on it. Importantly, a fetus is not affected by sperm from isotretinoin-treated men and using the drug does not affect future pregnancies. Kathy, who was on the original Accutane more than 20 years ago, went on to have two completely healthy children with normal pregnancies and births, she says.
5. Despite its potentially worrisome side effects, isotretinoin yields results
About 30% of patients who receive isotretinoin may see their acne worsen within the first month of treatment, which may be prevented by starting out on a low dose. But ultimately, the results are usually dramatic. Studies have shown that oral isotretinoin is the only drug to effectively target the four causes of severe nodular acne, which include inflammation, a buildup of skin cells in the hair follicle, the proliferation of acne bacteria and excess sebum (oil) production. Patients can generally expect to see an 80% to 90% reduction in inflammatory lesions after a 20-week course of treatment.
6. Isotretinoin affects the oil ducts of the skin
Isotretinoin is a naturally occurring compound derived from vitamin A (also known as 13-cis-retinoic acid). It is administered in an oral pill twice a day with a meal. Even though the drug has no direct antibacterial action, it alters what happens within the oil duct that causes acne. As LoGerfo explains, isotretinoin significantly decreases the size of the oil duct; and the typical dose of 10 to 40 mg a day (based on weight) dramatically reduces sebum excretion by almost 90% within 6 weeks. This decrease in oil production causes skin cells to loosen up and shed, so the common acne bacteria, P. acnes, has no place to grow and form a cyst in the hair follicle. Isotretinoin also has anti-inflammatory properties, she says.
Kathy still vividly recalls how terrible she felt about her appearance, which was marred by severe acne. “My acne cysts were so horrible that if I saw someone I knew on the street, I would cross to the other side,” she says. Her dermatologist suggested that Accutane would clear her acne when all other treatments had failed. She admits he was right and adds, “It changed my life for the better, permanently.”
7. One full course of treatment generally takes five months (or longer) to complete
LoGerfo says that fewer than 5% of her patients discontinue use of isotretinoin due to side effects during the five-month course of treatment. But it is common to adjust the dosage, based on a patient’s response. “If a patient is still breaking out months after starting treatment, we may increase their dose. But if a patient is bothered by dryness or other mild side effects, we may decrease the dose so the course of treatment will last longer,” she explains.
Lori, a 16-year-old from New York City, has been on and off isotretinoin for the better part of a year. During her treatment, she has had higher than normal triglycerides, dry, peeling skin and swollen lips (which she later determined to be a reaction to eating spicy foods while on the medication). Lori reduced her dose and even took time off from the drug when her dry skin and swollen lips became unbearable, but she is still using isotretinoin months later.
8. Sometimes another course is necessary
LoGerfo maintains that isotretinoin is reliable in most patients. “I usually start patients at a dose of 20 to 40 mg daily (depending on weight), increasing monthly based on their response.” She says a higher dose results in a more permanent acne clearing. LoGerfo reports about 40% to 60% of her patients remain acne-free after a single course of isotretinoin. About one-third of her patients who relapse after the first round will need only topical therapy consisting of a topical retinoid or topical benzoyl peroxide combination treatment.
‘Generally speaking, a patient treated with isotretinoin will almost never break out to the same degree again.’
“However, if the patient and practitioner agree that they did not achieve the clearing results expected, a second course of treatment can bring about a more permanent acne clearing,” LoGerfo explains. “I often re-treat patients with a second round of isotretinoin because it is reliably effective and we can predict their side effects.” Patients can start on a second round after two months if desired. LoGerfo advises most patients to wait several months to see if more acne clearing continues after ceasing treatment, which sometimes happens.
9. Your health insurance plan may not cover every generic version, and pharmacy supplies may be scarce
Before starting treatment, make sure the brand of isotretinoin you’ve been prescribed is covered by your insurance and carried by a local pharmacy registered with iPLEDGE. Lori’s mother found out firsthand why this is important — and cost-effective. “When the regular pharmacist was out of Lori’s usual version [of isotretinoin], I had to go to a different pharmacy to get it. That pharmacist had to re-prescribe for a version that the store had in stock, which was not covered by insurance.” If you’re having trouble getting a prescription filled, don’t be tempted to buy isotretinoin online. The FDA warns that Internet companies bypass important procedures that ensure that consumers take the medication safely.
BONUS FACT: Only you can decide if the risk is worth the reward
Dermatologists agree that isotretinoin is effective in treating severe, disfiguring acne when no other medication has worked. What’s more, the drug has long-lasting effects, often curing patients permanently. “Generally speaking, a patient treated with isotretinoin will almost never break out to the same degree again,” LoGerfo says.
Dr. Nazarian adds, “Truthfully, when a patient is chosen carefully, labs are monitored and the medication is taken as prescribed, stubborn, scarring acne can be cured and improve a patient’s quality of life.” Both Lori and Kathy saw their acne clear substantially and report a major positive effect on their lives. The jury is still out for Julie, however, who didn’t experience as much acne clearing as she had hoped and is now considering a second course of treatment.