By Steven DiJoseph
To say that Accutane is a controversial drug would be about as much of an understatement as saying King Kong was a monkey. In fact, as the drug approaches 25 years on the market, it just may be the most controversial drug of all time in terms of how many serious medical problems it has been linked to as compared to the relatively limited purpose for which it is prescribed.
The latest probe of the drug is being launched by Health Canada as a result of an unusual number of strokes and heart attacks having been reported in people taking it. There have been 29 cases of patients between 15 and 48 who developed vascular disorders after taking the drug.
Of those, 11 involved strokes, heart attacks, and blood clots, which are not currently included in the drugÃ¢â‚¬â„¢s product information. Many of the people who suffered these medical complications were otherwise young and healthy.
According to a Health Canada report: Ã¢â‚¬Å“ Health-care professionals are encouraged to report any cases of myocardial infarction, cerebrovascular and thromboembolic disorders suspected of being associated with isotretinoin.”
While Health Canada points out that there is no definitive proof that Accutane causes these injuries, the number of reports and the common link to the drug have prompted the agency to take a closer look. The suspicion is there, the causation must be examined, however.
It appears that some of the patients involved had recognized risk factors like obesity and hypertension. Other underlying illnesses must also be ruled out.
In any event, the latest investigation has done nothing to improve AccutaneÃ¢â‚¬â„¢s image .
For years, Accutane has been under siege from numerous medical experts, consumer watchdog groups, and even many officials within the FDA itself because of the many serious Accutane side effects.
One problem associated with the current FDA approval and review process that is quite troublesome, is the dramatic increase in the harm or risk that will be tolerated when weighing the potential benefits of a new prescription drug.
Traditionally, even drugs which promised significant benefits would be subjected to greater testing over longer periods of time when significant side-effects or adverse reactions were possible. If the drug was developed to treat a relatively minor condition, the possibility of dangerous side effects usually spelled the end of the drug in terms of FDA approval for marketing.
Today, however, drugs are routinely given FDA approval without sufficient long-term testing using large study groups and without adequate warnings despite evidence of significant side-effects and adverse reactions. Drugs are also permitted to remain on the market far longer than they should be once significant problems are suspected or even confirmed.
This has repeatedly resulted either in the need for upgraded warnings one or more times after a drug is already on the market or in dangerous drugs being pulled from the market only after causing numerous serious injuries or deaths.
Probably the most alarming situation today, however, is when a drug designed to treat a relatively minor condition is approved by the FDA and permitted to remain on the market despite clear evidence of significant side effects or adverse reactions.
In such cases, the risk versus benefit equation has all but vanished from the pharmaceutical companiesÃ¢â‚¬â„¢ consideration and the FDAÃ¢â‚¬â„¢s standards. Accutane is an example of such a drug.
For all of the positive results it might have achieved, Accutane is still nothing more than an acne drug. This fact alone has caused a wide range of critics of the drug to wonder how it has been permitted to remain on the market at all.
Recent developments with respect to the drug and the manner in which Accutane is regulated and monitored requires a fresh look at the drug and its uncanny ability to survive when other drugs used to treat far more serious conditions with considerably less serious side-effects have been pulled from the market.
Accutane is manufactured by Hoffman-LaRoche Pharmaceuticals. Its active ingredient is known as isotretinoin and it is primarily used to treat nodular acne, a condition that is resistant to other treatments, including antibiotics, and is characterized by the appearance of many nodules or cysts.
These nodules are inflammatory lesions filled with pus and get lodged deep within the skin. The lesions can cause pain, permanent scarring, and negative psychological effects.
Since its approval in 1982, Accutane has been linked to serious potential side-effects including:
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â birth defects when taken by pregnant women
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â psychological problems including possible suicide
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â neurological problems
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â stomach, bone and muscle problems
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â hearing and vision problems
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â problems with fats and cholesterol in the blood
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â ulcerative colitis
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â CrohnÃ¢â‚¬â„¢s disease
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â inflammatory bowel disorder
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â rectal bleeding
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â abdominal pain
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â central nervous system injuries
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â bone and muscle loss
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â cardiovascular injuries
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â liver and kidney damage
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â pancreatitis
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â immune system disorder
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â lupus
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â thyroid disorders
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â various allergic reactions
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Some minor side effects include dry skin, chapped lips, dry eyes, and dry nose that may lead to nosebleeds.
In 1998, the Food and Drug Administration advised doctors who prescribe Accutane to watch their patients for signs of depression. Afterward, Hoffman-LaRoche, the maker of Accutane, notified doctors that the drug Ã¢â‚¬Å“may cause depression, psychosis, and, rarely, suicidal ideation, suicide attempts and suicide.Ã¢â‚¬Â
This was one of the first indications that Accutane was headed for further problems. In January 2001, Roche began mailing doctors, psychiatrists, and pharmacists, information about the recent discovery of links between Accutane and various psychological problems.
By that time, the FDA had already received reports concerning 66 suicides and 1,373 cases of psychiatric problems. The drugÃ¢â‚¬â„¢s information packet had already been updated in 1986 to include information about links between Accutane and depression.
Birth defects are perhaps the most severe side effects to be linked to Accutane.Ã‚Â The list of possible birth defects include: hydrocephaly (enlargement of the fluid-filled spaces of the brain); microcephaly (small head); heart defects; facial deformities; and mental retardation.
The warnings originally released with Accutane in 1982 designated it as Category X, which means that it must be avoided under all circumstances by pregnant women and nursing mothers. Yet in 1983 reports of babies being born with certain defects began to surface.
As a result, in 1988, Roche launched the Pregnancy Prevention Program (PPP) with a kit that included a contraceptive booklet, checklists to help assess whether patients could comply with the drugÃ¢â‚¬â„¢s requirements, and a consent form for patients to sign stating that they were fully aware of the risk of birth defects.
In 2001, Roche and the FDA also developed what is known as the System to Manage Accutane-Related Teratogenicity (SMART), a plan which requires those female Accutane users in their childbearing years, who have not had hysterectomies, to take and submit a pregnancy test every month before receiving a 30-day refill of the medication.
Since AccutaneÃ¢â‚¬â„¢s market approval, there have been 2,000 incidences of pregnancies among users, many of which ended in abortion.Ã‚Â The FDA, however, has calculated that more than 160 babies were born with defects directly attributable to Accutane usage.
It is likely that there were actually more pregnancies that occurred in female Accutane users because there was no system for reporting Accutane-linked pregnancies at the time.
Apparently, however, these precautions and amendments relating to Accutane were not enough to prevent the continuation of some of the most severe side effects associated with the drug.
For some time now, it has been well-publicized that Accutane, a drug used to treat severe acne, can pose a significant risk of birth defects if taken during pregnancy.
Both Accutane and its generic versions, which include the active ingredient known as Isotretonin, are known to cause birth defects when taken by pregnant women.
The FDA and the drugÃ¢â‚¬â„¢s manufacturer, Hoffman-LaRoche, now provide information about this adverse health risk in the labeling and packet information for Accutane.
New information, however, indicates, that despite all the warnings, some women continue to use Accutane while pregnant.
A 2005 report appearing online in Birth Defect Research found that 34 women called a hotline run by the Organization of Teratology Information Services between April 2002 and September 2004 claiming they didnÃ¢â‚¬â„¢t remember hearing the guidelines relating to Accutane usage and pregnancy. (A teratogen is a substance that causes birth defects.)
Surprisingly, eight of the 34 women said that they didnÃ¢â‚¬â„¢t recall being counseled about birth control prior to taking Accutane, and 25 said that they had not taken a second pregnancy test before taking the drug.
In light of these continued problems connected to education about the drug, the FDA introduced a new program with an entirely new set of rules for Accutane.
Up until recently, women who wished to begin treatment with Accutane had to get birth control counseling and have two negative pregnancy tests prior to beginning treatment with the drug.
The new program, called Ã¢â‚¬Å“iPLEDGE,Ã¢â‚¬Â requires that all women of childbearing age take the following steps:
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Sign an informed consent form in their doctorÃ¢â‚¬â„¢s office;
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Personally register with iPLEDGE;
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Take two negative pregnancy tests in a doctorÃ¢â‚¬â„¢s office within seven days of beginning treatment;
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Agree to use two forms of birth control while taking the drug;
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â And get another negative pregnancy test in a doctorÃ¢â‚¬â„¢s office within one week of requesting a refill.
Men are also asked to sign an informed consent form to indicate that they too are aware of the risks but they do not have to personally register with iPLEDGE.
Doctors, pharmacies, and wholesalers are required to register with iPLEDGE.Ã‚Â Doctors must make sure that patients are aware of the drugÃ¢â‚¬â„¢s risks before they sign a consent form and begin the procedures to ensure safety in relation to Accutane usage.
Pharmacies must make sure that they log onto iPLEDGE before filling a prescription for Accutane to make sure that the patient has taken the necessary safety steps.Ã‚Â Finally, wholesalers must agree to only supply Accutane to pharmacies that have registered with iPLEDGE.
For more information about iPLEDGE visit www.ipledgeprogram.com or call (866) 495-0654.
Reports of suicides and birth defects relating to Accutane continued to surface forcing the FDA and Roche to once again review AccutaneÃ¢â‚¬â„¢s warning label.
In May of 2005, a study published in the American Journal of Psychiatry suggested that Accutane can actually change brain functioning.Ã‚Â This is the first study to monitor brain functioning of Accutane patients and the first to show a direct biological link between the drug and depression.
The team of psychiatrists conducting the study found that the group of young adults taking Accutane showed decreased brain functioning of up to 21% in the front part of the brain Ã¢â‚¬â€œ an area known to mediate symptoms of depression.
The authors of the study urged the FDA and Hoffman-La Roche to conduct further research on the drug.Ã‚Â Accutane has now been linked to 266 cases of suicide in the United States including some high-profile cases such as the death of U.S. Congressman Bart StupakÃ¢â‚¬â„¢s son.
In their alert regarding Accutane released in May of 2005, the FDA advised all Accutane patients to discontinue usage of the drug and inform their health care professional immediately if they experienced any of the following symptoms:
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Feelings of sadness or crying spells
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Loss of interest in activities once enjoyed
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Sleeping too much or having trouble sleeping
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Having increased irritability, anger, or aggressivity (i.e. temper outbursts, thoughts of violence)
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Change in appetite or body weight
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Trouble concentrating
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Withdrawal from family or friends
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Loss of energy
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Feelings of worthlessness or inappropriate guilt
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Thoughts of self-harm or suicide
In some situations, discontinuing the drug may not alleviate the problem and psychiatric evaluation or further medical investigation may be necessary.
Currently, litigation involving the following injuries is either in progress or being considered in a number of states:
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Inflammatory Bowel Disease
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Premature Closure of Growth Plates
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Birth Defects
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ulcerative Colitis
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Crohn’s Disease
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Inflammatory Bowel Syndrome
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Rectal Bleeding
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Abdominal Pain
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Central Nervous System Injuries
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Bone and Muscle Loss
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Cardiovascular Injuries
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Liver and Kidney Damage
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Pancreatitis
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Immune System Disorder
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Lupus
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Hearing and Vision Damage
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Thyroid Disorders
Many experts and consumer advocates believe the range of serious health risks (physical and psychological) associated with Accutane should have doomed the drug long ago. The fact that it is nothing more than a treatment for acne (regardless of how serious it may be) makes its survival all the more astounding to its critics.
The basis for the strong opposition to the drug was expressed best in the Public Citizen publication Worst Pills Best Pills (April 2004 Newsletter. The more compelling sections of that article are as follow:
Ã¢â‚¬Å“Public CitizenÃ¢â‚¬â„¢s Health Research Group has been warning the FDA about the risks of birth defects and mental retardation for fetuses exposed to isotretinoin (ACCUTANE) for over 20 years. In 1983 we sent a petition recommending patient package inserts and a black box warning describing the risks of birth defects and life-threatening side effects of the drug. The next year we sent a letter advocating improved pregnancy surveillance and lower dosing regimens. In 1988 we described isotretinoin as an imminent public health hazard to an FDA Advisory Committee and we urged the FDA to remove it from the market unless tight restrictions were implemented and proved effectiveÃ¢â‚¬Â¦The following year we testified and again urged the FDA to initiate Accutane recall from the market unless our previously proposed restrictions were immediately adoptedÃ¢â‚¬Â¦Then, in 2000 we testified and recommended a Patient Medication Guide and again advised removal from the market unless the restrictions were implemented and shown to be effective.
Ã¢â‚¬Å“In 1989, the CDC testified before an FDA Advisory Committee, stating that, Ã¢â‚¬Ëœ[t]he birth of babies with defects caused by fetal exposure to Accutane is unnecessary,Ã¢â‚¬â„¢ and the Ã¢â‚¬Ëœ…FDA decision to allow the marketing of Accutane [is] a failed regulatory experiment.Ã¢â‚¬â„¢ They also declared that a Ã¢â‚¬Ëœ…decision to depend on better contraception alone, without active intervention to reduce the number of users, is a decision to leave the number of affected babies at an unacceptably high level.Ã¢â‚¬â„¢ They suggested that Ã¢â‚¬Ëœ[p]erhaps a formal IND…would be a suitable mechanism…to reduce the frequency of Accutane embryopathy.Ã¢â‚¬â„¢ This echoes Public CitizenÃ¢â‚¬â„¢s recommendation to remove Accutane from the market and reintroduce it only under strict Investigational New Drug (IND) restrictions.
Ã¢â‚¬Å“Since there is currently no reporting requirement for pregnancies exposed to isotretinoin, the actual numbers of affected pregnancies are unknown. There is information from surveys and spontaneous reporting, however, and according to data presented at the 2000 FDA Advisory Committee meeting, there have been 1,995 pregnancies exposed to Accutane between 1982 and 2000. The known outcomes of these pregnancies included 1,214 elective abortions, 383 live births, and 162 infants with birth defects. During the first year of S.M.A.R.T., the System to Manage Accutane Related Teratogenicity, there were 156,800 Ã¢â‚¬ËœuniqueÃ¢â‚¬â„¢ women who were given the drug, and the pregnancy rate was estimated at 0.35%. We can therefore calculate that there would be 548 total pregnancies, which is 4.6 times higher than the 120 pregnancies spontaneously reported. Of 61 pregnancies with known outcomes, 48/61 or 78.7% resulted in elective abortions. Applied to the 548 estimated pregnancies, there would have been 431 elective abortions in that year. Of 61 pregnancies with known outcomes, 7/61 or 11.5% resulted in deliveries. Based on the 548 estimated pregnancies, there would have been 63 deliveries. Using estimates of 25% birth defects and 50% mental retardation, this would result in 16 infants with birth defects and 31 with mental retardation.
Ã¢â‚¬Å“Proposals of S.M.A.R.T. and the new Roche, the drugÃ¢â‚¬â„¢s manufacturer, have failed to seriously address two major issues. The first is the need for at least a 95% reduction in prescribing. The CDC estimated in 1989 that there were no more than 4,000 women of child-bearing age with severe cystic acne. Adjusting for population growth, this number may now be 6,000. Given that there were 156,800 Ã¢â‚¬ËœuniqueÃ¢â‚¬â„¢ women of child-bearing age who got the drug in 2002-2003, this represents a twenty-six fold excess in prescribing over the number of on-label prescriptions. The second problem is the need for mandatory pregnancy test results (not just assurance) before starting therapy and monthly while on therapy as a prerequisite for getting every prescription filled.
Ã¢â‚¬Å“We therefore insist on the withdrawal of isotretinoin from the market. Twenty years of failed voluntary and, more recently, mandatory restrictions have led to a total of more pregnancy exposures because the total number of prescriptions has increased. As we recommended in 1988 and the CDC suggested the next year, a ban on marketing with subsequent availability only under a tightly controlled investigational new drug application (IND) procedure is the only feasible way to significantly reduce prescriptions and pregnancy exposuresÃ¢â‚¬Â¦The S.M.A.R.T program is clearly a failure. Without these proposed IND restrictions, this administration and this advisory committee will continue to put its imprimatur on the reckless use of a drug that each year causes the need for hundreds of abortions and many seriously deformed infants with birth defects and/or mental retardation. It is time to end the more than twenty years of voluntary restrictions that have failed to reduce its prescribing for more than ten times as many women as would be using the drug if it were limited to the approved indications.Ã¢â‚¬Â
Under the circumstances, it would seem that Health CanadaÃ¢â‚¬â„¢s latest investigation will only serve to make this drug even more controversial than it already is.