Is accutane a restricted prescription?

Certain medications listed on the PBS are available only for specific therapeutic indications or to patients meeting specific criteria where the PBAC has deemed that the cost-benefit analysis is favourable only in those indications/patients. These are noted as "restricted benefits" on the Schedule. Medicare Australia places the onus of policing restricted benefits on the prescribers themselves and the pharmacists dispensing (unless the listing is also 'Authority Required'). For example, the COX-2 inhibitor celecoxib is listed on the PBS as a restricted benefit for the symptomatic treatment of osteoarthritis and rheumatoid arthritis. Prescribers using celecoxib for other indications are expected to indicate "non-PBS" on the prescription, and/or the pharmacist dispensing the celecoxib should charge the patient the full cost.

Pharmaceutical Benefits Scheme

The Pharmaceutical Benefits Scheme (PBS) is a program of the Australian Government that provides subsidised prescription drugs to residents of Australia, as well as certain foreign visitors covered by a Reciprocal Health Care Agreement. The PBS seeks to ensure that Australian residents have affordable and reliable access to a wide range of necessary medicines. The PBS has faced increased scrutiny as its cost has increased. The scheme assumes responsibility for the cost of drugs to patients in the community setting rather than while in hospital which is the responsibility of each state and territory. Together with Medicare the PBS is a key component of health care in Australia.

The PBS was established by the Labor Chifley Government, by the "Pharmaceutical Benefits Act 1947" which commenced on 1 July 1948, as part of a wider plan to create a British-style National Health Service. The scheme was an extension of the similar Repatriation Pharmaceutical Benefits Scheme established in 1919 for Australian servicemen and women who had served in the Boer War and World War I.

Though the High Court of Australia ruled that most of Chifley's health care plans were unconstitutional, the PBS was ruled to be constitutional. Initially, PBS covered approximately 140 lifesaving and disease-preventing drugs. Medicines on the PBS list were free to the consumer until 1960, when a 50 cent co-payment was introduced by the Menzies Government.

By 2003 the number of drugs included under the scheme had expanded to 601 general products which were marketed as 2,602 different brands. The scheme was appealing to policy makers because it required no major capital works program and could be implemented immediately without lengthy consultation with the medical profession.

PBS is governed by the "National Health Act 1953" and "National Health (Pharmaceutical Benefits) Regulations 1960 (Cth)". Pharmaceutical benefits under PBS may only be supplied by pharmacists and medical practitioners approved under the Act. Applications to list a drug on the PBS are administered by the Department of Health. Pharmaceutical benefits under the PBS are administered by Medicare Australia (formerly the Health Insurance Commission) under the "Health Insurance Act 1973 (Cth)".

A benefit under PBS is only given on medications which are listed in the Pharmaceutical Benefits Schedule. The medication may be listed for general use as an unrestricted benefit, or for a specific indication as a restricted benefit. When a PBS medication is dispensed by a pharmacist, the patient pays the patient contribution (subject to concessions and safety nets) and Medicare Australia pays the remainder of the agreed cost of the medication to the pharmacist.

The cost of a medication is negotiated between the government, through the Department of Health, and the supplier of the drug. The agreed price becomes the basis of the dispensed price of the medication which is negotiated between the government and the Pharmacy Guild of Australia under the current Community Pharmacy Agreement. The dispensed price includes the wholesaler's markup, pharmacist's markup, and a dispensing fee. Pharmacies purchase PBS-listed drugs from the wholesaler or supplier, and claim the difference between the dispensed price and the patient co-payment contribution from Medicare Australia.

The PBS is separate to its counterpart, the Medical Benefits Schedule, which provides subsidised medical services such as doctors consultations and diagnostic tests.

When purchasing a medication under PBS the maximum price a patient pays is the patient contribution (also called a co-payment or out-of-pocket cost), which in 2016 is A$38.30 for general patients. For PBS medications costing less than $38.30, the patient pays the PBS dispensed price plus an additional $1.17 safety net recording fee plus an optional pharmacy charge of $4.33 or less, provided that the total charge does not exceed $38.30. Concessional patients - i.e., low-income earners, welfare recipients, Health Care Card holders, etc. and those covered under the Repatriation Pharmaceutical Benefits Scheme (RPBS) - pay a patient contribution of $6.20 in 2016. Patient contributions are compulsory and cannot be discounted by pharmacies.

Safety net provisions in PBS reduce patient contributions when singles and families exceed in a calendar year the PBS safety net threshold: when a general patient reaches the general PBS threshold, their co-payment reduces to the concession price for the remainder of that calendar year; while concession patients who reach the concession PBS threshold do not pay anything on PBS medications for the remainder of the year. The PBS safety net is separate from and in addition to the Medicare safety nets.

Changes in patient contributions and the safety net over the years are as follows:

In an effort to limit the cost of PBS by discouraging patients from filling PBS prescriptions earlier than needed, in 2009 the safety net 20-day rule was brought in. Under the rule, a repeat prescription supplied within 20 days of a previous supply of the same medicine will not count towards the PBS safety net threshold. If the patient has already reached the safety net threshold, they will be charged the normal patient contribution instead of the reduced safety net amount.

In an effort to limit the cost of PBS, the Australian Government introduced Brand Premiums on medications where cheaper generic brands were available. The Brand Premium is usually the price difference between the innovator brand and the generic brand. The patient pays the Brand Premium in addition to the normal patient contribution if they decline to purchase the generic brand. The Brand Premium paid does not count toward either safety net threshold and must still be paid even after the threshold is reached.

Pharmacists are allowed to substitute generic brands for prescribed brands if the brands are flagged "a" in the Schedule of Pharmaceutical Benefits, and if consent is obtained from the patient and prescriber. The prescriber's consent is always assumed to be granted unless "brand substitution not permitted" is indicated on the prescription.

On 1 February 1998, another effort to limit the cost of the PBS involved the introduction of Therapeutic Group Premiums (TGPs) on medications that are priced significantly above the cheapest medication in a defined therapeutic sub-group where the drugs are considered to be of similar safety and efficacy. The TGP is the price difference between the premium brand and the benchmark (base) price for drugs in the class. The patient must pay this TGP in addition to the normal patient co-payment contribution if they have been prescribed such a medication. The TGP paid does not count toward the Safety Net threshold.

However, a prescriber may obtain an exemption from the TGP if:

Such an exemption requires an approved PBS Authority prescription from Medicare Australia.

PBS subsidies are available only to Australian residents (who generally must produce a Medicare card) and to certain foreign visitors whose countries have entered into a Reciprocal Health Care Agreement with Australia. These countries are the United Kingdom, Ireland, New Zealand, Malta, Italy, Sweden, the Netherlands, Finland, Norway, Belgium and Slovenia. Eligible foreign visitors must produce a passport to obtain subsidised medications.

The Pharmaceutical Benefits Advisory Committee (PBAC) makes recommendations to the Minister for Health and Ageing regarding drugs which should be made available as pharmaceutical benefits, which are listed on the Schedule of Pharmaceutical Benefits. The Schedule is published monthly since January 2007, (prior to this it was published three times a year).

In considering a medication for listing on the PBS, the PBAC considers factors including:

Decisions on PBS listing are generally made on a health economics perspective, using cost-effectiveness analysis. Cost-effectiveness analysis evaluates the cost and health effects of one technology versus the cost and health effects of another technology, which is usually standard of care. A new technology whose incremental health benefit justifies its additional expense is deemed to be cost-effective and thus reimbursed by PBAC. Drugs that provide little health benefit at considerable additional expense, such as the PDE5 inhibitors (e.g. sildenafil) and certain expensive cancer chemotherapy drugs are not listed on the basis of poor cost-effectiveness. The principles that are applied during the evaluation of drugs for PBS listing are described in the PBAC Guidelines.

Drugs that have unrestricted benefit listing on the PBS are available for general use without being limited to particular indications. Such items are typically those whose use in clinical practice is widely accepted. Examples include methotrexate, prednisone and amoxycillin.

Some PBS medications are restricted and require prior approval from Medicare Australia. These are noted as "authority required benefits" on the Schedule. Again, the PBAC has deemed that the cost-benefit analysis is favourable only under in specific indications/patients under certain circumstances. Authority may be obtained by telephone to Medicare Australia (known as "phone approval") or in writing from an authorised delegate of the Minister for Health. Prescriptions must be written on Authority Prescription Form, and the approval number must be noted on the prescription. Pharmacists cannot dispense the item as a pharmaceutical benefit unless it has been approved by Medicare Australia (indicated by the presence of the approval number).

In obtaining a phone approval, the doctor simply identifies themselves (using their name and provider number), the patient (using their Medicare number), and when asked by the operator, confirms which of the conditions eligible for an authority the patient is suffering from. Medicare normally assumes the doctor's assertion that the condition exists as sufficient. For a written Authority however, evidence of diagnosis and patient eligibility criteria such a pathology test results are usually required.

Some drugs may have Authority Required (Streamlined) status which does not require an explicit approval from Medicare, instead the doctor can use the Authority code found in the published Schedule for a given drug/indication.

In its first year, the PBS cost the Commonwealth Government £149,000 (or $7,600,000 in 2009). The PBS now costs the Commonwealth approximately $6.5 billion a year to operate, despite consumers contributing around $1.3 billion in patient co-payments. According to a report by the Australian Productivity Commission the PBS is expected to cost 2.6% of Australia's GDP by 2045 up from 0.7% in 2005. Further attempts to restrain the growth in costs of the PBS may be needed, however, attempts to increase consumer prices of drugs have always proved politically unpopular. The comparative cost-effectiveness processes of the PBS nonetheless ensure it provides Australian citizens with more equitable access to medicines than in many other developed nations and for many the issue of sustainability of the PBS as a key component of the egalitarian architecture of Australian society is equivalent to asking whether that nation's education system or defence forces are sustainable.

Former federal Treasurer Peter Costello and the Liberal Party attempted to raise the patient co-payment of PBS medicines by up to 30 per cent in the 2002 Federal Budget, however this measure was blocked in the Senate in which various minor parties held the balance of power. However, in June 2004 the main opposition party, the Australian Labor Party, announced that it would allow the PBS co-payment increases to proceed through the Senate.

Grattan Institute Health Program released a report titled "Australia’s bad drug deal" by Dr Stephen Duckett, in which he states that Australia’s Pharmaceutical Benefits Scheme pays at least $1.3 billion a year too much for prescription drugs. New Zealand, which has capped its budget and appointed independent experts to make decisions through the Pharmaceutical Management Agency (Pharmac), pays a sixth as much as the PBS for the same drugs. Public hospitals in two Australian states pay much lower prices than the PBS. In one case,the prices are just a sixth of PBS prices. In one extreme example the report states that "The price of one drug, Olanzapine, is 64 times higher on the PBS than in Western Australian public hospitals". This report proposes three ways Australia can regain its lost leadership in pharmaceutical pricing.

In July 2007 changes to the "National Health Act 1953 (Cth)" divided the PBS formulary into an F1 category (for patented, single brand medicines) and an F2 category (for generic medicines) with reduced reference pricing between them. Academic opinion is divided about the value of these changes and the extent to which they arose from industry lobbying drawing strength from Annex 2C of the AUSFTA.

The biggest cuts on prices of medicines in Australian history occurred from 1 April 2012 under the Gillard Labor government. PBS pricing for low-income consumers remained at $5.80 per script.

17 types of medication will be removed from the PBS, including Panadol Osteo, aspirin, iron/folic supplements, electrolytes, and laxatives. Other medications include medication for reflux, skin allergies, antacids, urine test strips, and Vitamin B12 injections. This proposed plan will save taxpayers approximately $87 million a year.

Although the goal of the program is to prevent pregnancies of women who take the drug, male patients must also participate in anti-pregnancy restrictions, primarily due to fears that male isotretinoin users might share their prescriptions with females without their physicians' knowledge. There has been no link to birth defects from Accutane associated with males using the drug, though male sexual dysfunction has been suggested by one study. As this has not been conclusively proven, this is not acknowledged as a side effect in the official literature accompanying the medication.

IPLEDGE program

The iPLEDGE program is a risk management distribution program mandated by the U.S. Food and Drug Administration (FDA) for isotretinoin, marketed as Absorica, Claravis, Amnesteem, Myorisan, and Zenatane, and sometimes referred to by its former brand name, Accutane. Isotretinoin is a prescription medication that is highly effective in treating severe acne and moderate acne that doesn't respond to other treatments, however carries a high risk of causing severe birth defects if taken during pregnancy ("see Teratogenicity of isoretinoin"). The goals of the iPLEDGE REMS (risk evaluation and mitigation strategy) Program are to prevent fetal exposure to isotretinoin and to inform prescribers, pharmacists, and patients about isotretinoin’s serious risks and safe-use conditions.

The program was designed by the Isotretinoin Product Manufacturers Group (IPMG) and its chosen vendor, Covance, under the direction of the FDA.

As of March 1, 2006, iPLEDGE patients, their doctors and their pharmacists are required by the FDA to register and use a web site in order to receive, prescribe or dispense this medication. The program has reduced exposure of pregnant women to the drug, and has also been criticized for being overly complicated.

Once a doctor decides a patient is a candidate for isotretinoin, they will counsel the patient to ensure the patient understands the drug and the potential side effects. Once the patient signs the necessary paperwork, their doctor will give them a patient ID number and ID card, as well as other program educational materials. After they have been registered in iPLEDGE by their doctor, they will receive their password in the mail after 5–10 business days. Patients are classified either as females of child-bearing potential (FCBPs), females not of child-bearing potential (FnCBPs), or males.

FCBPs are required to pick and use two birth control methods (abstinence included), and must take doctor-administered pregnancy tests in two consecutive months. After the second (confirmatory) negative pregnancy test, the FCBP must also take an online comprehension test to ensure she understands the requirements of the Program. Once those two items are complete, the FCBP is authorized to receive drug at an authorized pharmacy. From the date of the second (confirmatory) negative pregnancy test, an FCBP has seven days to pick up her prescription. FCBPs must see their doctor and take a pregnancy test in each subsequent month in order to get another prescription for the next 30 days.

Males and FnCBPs must see their doctor every month, but don't have to take the pregnancy or comprehension tests. They have 30 days from the date of their office visit to pick up their prescriptions. After that point they have to see their doctor for another 30-day prescription.

Before dispensing isotretinoin, the pharmacist must check the iPLEDGE Program website to ensure the patient is authorized to receive the drug. Isotretinoin may only be dispensed at authorized US pharmacies that are registered with the iPLEDGE Program, and FDA has taken action against Canadian and internet pharmacies which dispense isotretinoin outside of the iPLEDGE Program. Patients who acquire and consume isotretinoin without the care of a prescriber are putting themselves in jeopardy.

The typical course of isotretinoin treatment will last 4–5 months, and is generally considered to be an option when nothing else has worked.

Some dermatologists have praised isotretinoin for its ability to treat severe acne, with current research calling it "a drug of choice" with "immense promise … in reducing dermal irritation and increasing the therapeutic performance, thus resulting in an efficacious and patient-compliant formulation". However, there have also been many reports and studies criticizing the negative side effects of isotretinoin have been published over the years. The author of a 2002 paper from Harvard Law School wrote: "Accutane also has the potential to destroy lives. Accutane is an extremely dangerous teratogen: It can cause severe birth defects when taken during pregnancy. About one quarter of babies born who have been exposed to Accutane during gestation have major congenital deformities. Those babies born without major malformations frequently develop severe learning disabilities. A whole segment of Accutane babies do not even survive pregnancy: 40% are spontaneously miscarried." The author goes on to compare Accutane to Thalidomide.

The iPLEDGE Program was instituted as a replacement for the failed SMART program (System to Manage Accutane Related Teratogenicity). Instituted in April 2002, SMART aimed to eliminate isotretinoin-induced birth defects by preventing pregnant women from being prescribed or exposed to the drug. The program mandated two consecutive negative pregnancy tests, birth defect risk counseling and a pledge to use two forms of contraception when engaging in intercourse for all women of childbearing age seeking an isotretinoin prescription. A voluntary registration program called The Accutane Survey was also established. However, no effort was made to verify the compliance of doctors and pharmacists, only a small percentage of women registered in the survey, and isotretinoin's reputation as an acne wonder drug continued to fuel demand for new prescriptions, an increasing number of which were being written and dispensed for relatively minor cases of acne vulgaris without proper screening, supervision or evidence that less risky medications had first been attempted.

In 2003, a first-year review of SMART compliance conducted by the pharmaceutical industry revealed that the number of pregnant women prescribed isotretinoin actually "increased" by hundreds of documented cases over the previous year, before the program was instituted. Of these cases, the majority of women underwent abortions—either spontaneous or elective—with a handful of children reported to be born with typical isotretinoin-induced birth defects. When surveyed, many pregnant women reported that their physicians had attempted to downplay the risks of isotretinoin or violated the standards in other ways, such as failing to inform women they needed to use two forms of birth control or allowing them to substitute a single, less-accurate urine pregnancy test conducted in the doctor's office for the two laboratory-conducted blood pregnancy tests mandated by SMART. The FDA also concluded that, considering the voluntary nature of the reporting program and lack of mandatory record-keeping, the actual number of pregnant women affected was likely far higher than the reported number.

The report led to SMART being dismissed as "a total failure", with the FDA quickly moving to halt the downward slide with a stricter mandatory registry system to document and verify all isotretinoin prescriptions written or dispensed to childbearing-age women in the United States. This was a feature originally included in the plan for SMART recommended by the original FDA advisory panel and wholeheartedly endorsed by the pharmaceutical manufacturers, but removed due to concerns that political opposition from lobbying groups would delay the program's implementation. Although eventually resolved, the older concerns proved valid in 2003 when the launch of iPLEDGE was held up for three years while objections from women's rights, patient's rights, physician's rights and pro-choice lobbyists were debated in committee.

The iPLEDGE program was put into place a group formed by the companies that manufactured the drug at the time – Roche, Mylan, Barr, and Ranbaxy – called the Isotretinoin Products Manufacturing Group (IPMG); they are responsible for iPLEDGE and they hired Covance to manage it. The program launched on March 1, 2006, at the beginning of the annual meeting of the American Academy of Dermatology.

In the U.S., around 2000 women became pregnant while taking the drug between 1982 and 2000, with most pregnancies ending in abortion or miscarriage. About 160 babies with birth defects were born. After the FDA put the more strict iPLEDGE program in place for the companies marketing the drug in the US, in 2011, 155 pregnancies occurred among 129,544 women of childbearing potential taking isotrentinoin (0.12%).

Criticisms of the iPLEDGE program include the following:

Due to the nature of restricted distribution programs in general, and ETASU REMS programs specifically, stakeholder burden has always been balanced against control and compliance.

When the Program launched in March 2006, there were many complaints about how difficult it was to use the system. Launch and pre-launch difficulties were common with the system jointly built by the drug manufacturers with the assistance of Covance, Inc, and approved by the FDA. Glitches with the website and long hold times were rampant at the time, and became a focus of physician and patient ire. Physicians have continued to be concerned that this very effective drug is made difficult to obtain due to a relatively small proportion of potential birth defects.

Though prescriber and pharmacy populations have become more familiar with the requirements of the iPLEDGE Program over the years, and some of the initial issues with the system have subsided, the nature of the restrictive distribution program continues to cause inconvenience, added expenses, and interruptions in the course of treatment. For example, if there is a problem with the data a patient or prescriber enters, the patient may be locked out of the system, unable to obtain the drug, for that 30-day cycle. Additionally, if a patient misses her 7-day prescription pick-up window, the patient must return to the prescriber for another pregnancy test before being able to get the drug again. This return visit to the doctor, of course, can be inconvenient and costly. To minimize the number of necessary visits to the doctor, a patient would want to schedule their appointment near the end of a 30-day period, but then must pick up the medicine quickly to avoid being blocked out of the system and running out of the medication. In 2008, dermatologist Robert Greenburg said "For a program to be so inflexible that it doesn't take into consideration the holiday or a patient's extenuating circumstances is such an impediment. It happens often that the 30-day window runs into the weekend when offices are closed. This [iPLEDGE] isn't the way things are done in the real world." "Why is iPLEDGE so complicated? Clearly, it's for political reasons," said Greenberg, citing political opposition to abortion and his impression that morality has guided the policy development more than medical science and evidence of effectiveness.

Some patients feel that the requirements to take monthly pregnancy tests and enter information about contraceptive choices constitute an unreasonable instrusion, and feel that's too high a price to pay to gain access to this drug. Additionally, maintenance of a pregnancy registry is part of the Program, though participation in the registry is voluntary for those patients who might've become pregnant.

Requirements of the program also mandate, per FDA requirements, monthly pregnancy tests for women who may become pregnant.

The website does include a privacy statement, which discusses what information is collected, how it is used, and where questions can be directed.

The iPLEDGE Program requires the participation of both males and FnCBPs, and this has been a subject of criticism over the course of the program's lifetime. Dermatologist Ned Ryan said "They [the FDA and drug manufacturers] want a wide net, understandably. But this is completely over the top."

Participation is required to ensure that these two groups understand the basic requirements, as sharing of medication with women who can get pregnant is a real concern.

Though they must be part of the iPLEDGE Program, requirements for males and FnCBPs are more lenient than those for FCBPs. Males and FnCBPs do not need to take either pregnancy or comprehension tests on a monthly basis, and their prescription window is 30 days from the date of the office visit, rather than seven days as it is with FCBPs.

Some criticisms of the iPLEDGE website include that the website does not clearly identify who administers the site, despite being a mandatory program that requires the submission of private information about medical patients. The terms of use and legal disclaimer section of the site do not clearly identify the legal entity running the program or describe how the private information of the patients is secured. The terms of use for the site is phrased as a contract between "you" and "the sponsors of the Site" (which it defines as synonymous with "iPLEDGE"), without clearly saying who "the sponsors of the Site" includes.

The program was mandated by the FDA despite criticism from practicing medical doctors that its cumbersome nature and strict deadlines can make the drug unavailable to deserving patients. In practice, the website has presented many problems to physicians; once information is entered, it can be difficult or impossible to change or correct it. If there is an error, the patient can be locked out for 30 days without being able to receive the medication. Problems are common and take days to correct. Technical assistance by phone is available via a toll free number, but trying to correct problems using the phone system can be difficult and time-consuming. Cathy Boeck, a past president of the Dermatology Nurses Association, said "Nurses are having the same frustrations as doctors regarding difficulties of getting the drug to patients and patients' complaints. It has a huge impact on resources if someone is waiting on hold with iPLEDGE and is also taking calls from patients who are upset and frustrated. That’s what we’ve heard from members."

Isotretinoin is a teratogen; there is about a 20–35% risk for congenital defects in infants exposed to the drug "in utero", and about 30–60% of children exposed to isotretinoin prenatally have been reported to show neurocognitive impairment. Because of this, there are strict controls on prescribing isotretinoin to women who may become pregnant and women who become pregnant while taking isotretinoin are strongly advised to terminate their pregnancies.

Isotretinoin

Isotretinoin, also known as 13-"cis"-retinoic acid (and colloquially referred to by its former brand name Accutane or Roaccutane), is a medication primarily used to treat severe acne. Rarely, it is also used to prevent certain skin cancers (squamous-cell carcinoma), and in the treatment of other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body. Its isomer, tretinoin, is also an acne drug.

Isotretinoin is primarily used as a treatment for severe acne. The most common adverse effects are a transient worsening of acne (lasting 1–4 months), dry lips (cheilitis), dry and fragile skin, and an increased susceptibility to sunburn. Uncommon and rare side effects include muscle aches and pains (myalgias), and headaches. Isotretinoin is known to cause birth defects due to in-utero exposure because of the molecule's close resemblance to retinoic acid, a natural vitamin A derivative which controls normal embryonic development. It is also associated with psychiatric side effects, most commonly depression but also, more rarely, psychosis and unusual behaviours. Other rare side effects include hyperostosis, and premature epiphyseal closure, have been reported to be persistent.

In the United States, a special procedure is required to obtain the pharmaceutical. In most other countries, a consent form is required which explains these risks. Women taking isotretinoin must not get pregnant during and for 1 month after the discontinuation of isotretinoin therapy. Sexual abstinence or effective contraception is mandatory during this period. Barrier methods by themselves (e.g., condoms) are not considered adequate due to the unacceptable failure rates of approximately 3%. Women who become pregnant while taking isotretinoin therapy are generally counseled to have an abortion.

Isotretinoin was first marketed as Accutane by Hoffmann-La Roche. It sold well for many years, but in 2009, Roche decided to remove Accutane from the US market after juries had awarded millions of dollars in damages to former Accutane users over inflammatory bowel disease claims. The American College of Gastroenterologists has released a position paper stating that people with inflammatory bowel disease should not be precluded from having their acne treated with isotretinoin. It then became generic and as of 2017 was marketed under many brand names worldwide.
Isotretinoin is used primarily for severe cystic acne and acne that has not responded to other treatments. Many dermatologists also support its use for treatment of lesser degrees of acne that prove resistant to other treatments, or that produce physical or psychological scarring. Isotretinoin is not indicated for treatment of prepubertal acne and is not recommended in children less than 12 years of age.

It is also somewhat effective for hidradenitis suppurativa and some cases of severe rosacea. It can also be used to help treat harlequin ichthyosis, lamellar ichthyosis and is used in xeroderma pigmentosum cases to relieve keratoses. Isotretinoin has been used to treat the extremely rare condition fibrodysplasia ossificans progressiva. It is also used for treatment of neuroblastoma, a form of nerve cancer.

Isotretinoin therapy has furthermore proven effective against genital warts in experimental use, but is rarely used for this indication as there are more effective treatments. Isotretinoin may represent an efficacious and safe alternative systemic form of therapy for recalcitrant condylomata acuminata (RCA) of the cervix. In most countries this therapy is currently unapproved and only used if other therapies failed.

In most countries, isotretinoin can only be prescribed by dermatologists or specialist physicians; some countries also allow limited prescription by general practitioners and family doctors. In the United Kingdom and Australia, isotretinoin may be prescribed only by or under the supervision of a consultant dermatologist. Because severe cystic acne has the potential to cause permanent scarring over a short period, restrictions on its more immediate availability have proved contentious. In New Zealand, isotretinoin can be prescribed by any doctor but subsidised only when prescribed by a vocationally-registered general practitioner, dermatologist or nurse practitioner.

In the United States, since March 2006 the dispensing of isotretinoin is run through a website called iPLEDGE. The FDA required the companies marketing the drug in the US, which at the time that iPLEDGE was launched were Roche, Mylan, Barr, and Ranbaxy, to put this website in place as a risk evaluation and mitigation strategy. These companies formed a group called the Isotretinoin Products Manufacturing Group, and it hired Covance to run the website. Prescribers, pharmacists, and all people to whom the drug is prescribed need to register on the site and log information into it. Women with child-bearing potential must commit to using two forms of effective contraception simultaneously for the duration of isotretinoin therapy and for a month immediately preceding and a month immediately following therapy. Additionally they must have two negative pregnancy tests 30 days apart and have negative pregnancy tests before each prescription is written.

Increasingly higher dosages will result in higher toxicity, resembling vitamin A toxicity. Adverse effects include:

Isotretinoin may stop long bone growth in young people who are still growing. Premature epiphyseal closure can occur in people with acne receiving recommended doses of Accutane.

Isotretinoin is known to cause meibomian gland dysfunction which causes persistent keratoconjunctivitis sicca (dry eye). Problems with the meibomian and salivary glands are likely due to the non-selective apoptosis of the cells of the exocrine glands. Decreased night vision has been reported to persist in some people after discontinuation of isotretinoin therapy.

The most common side effects are mucocutaneous: dry lips, skin and nose. Other common mucocutaneous side effects are inflammation and chapping of the lips (cheilitis), redness of the skin (erythema), rashes, peeling, eczema (dermatitis), itching (pruritus) and nose bleeds (epistaxis). Absence of dryness of the lips is considered an indication of non-compliance with treatment (not taking the drug as advised), as it occurs in almost all people who take it.

Regular use of lip balm and moisturizer is recommended throughout a course of treatment to reduce these problems. The dose may need to be decreased to reduce the severity of these side effects. The skin becomes more fragile—especially to frictional forces—and may not heal as quickly as normal. Wound healing is delayed. For this reason elective surgery, waxing of hair, tattooing, tattoo removal, piercings, dermabrasion, exfoliation, etc., are not recommended. Treatment of acne scars is generally deferred until 12 months after completion of a course of isotretinoin.

Acne usually flares up 2–3 weeks into the treatment and is usually mild and tolerable. Occasionally this flare-up is severe, necessitating oral antiobiotics such as erythromycin. A short course of oral prednisolone may be required. Some dermatologists favour a few weeks of pre-treatment with oral antibiotics before commencing isotretinoin to reduce the chance of a severe flare. A "stepped" course may also be used to reduce the chance of this initial flare, by which the initial dose is low (e.g. 0.5 mg/kg) and subsequently increased throughout the course.

Isotretinoin use can rarely lead to a more severe form of acne, acne fulminans.

Isotretinoin is a teratogen highly likely to cause birth defects if taken by women during pregnancy or even a short time before conception. A few of the more common birth defects this drug can cause are hearing and visual impairment, missing or malformed earlobes, facial dysmorphism, and abnormalities in brain function. Isotretinoin is classified as FDA Pregnancy Category X and ADEC Category X, and use is contraindicated in pregnancy.

The manufacturer recommends pregnancy be ruled out two weeks prior to commencement of isotretinoin, and women should use two simultaneous forms of effective contraception at least one month prior to commencement, during, and for at least one month following isotretinoin therapy.

In the U.S., around 2000 women became pregnant while taking the drug between 1982 and 2000, with most pregnancies ending in abortion or miscarriage. About 160 babies with birth defects were born. After the FDA put the more strict iPLEDGE program in place for the companies marketing the drug in the US, in 2011, 155 pregnancies occurred among 129,544 women of childbearing potential taking isotrentinoin (0.12%).

People taking isotretinoin are not permitted to donate blood during and for at least one month after discontinuation of therapy due to its teratogenicity.

Rare psychological side effects may include depression, worsening of pre-existing depression, aggressive tendencies, irritable mood and anxiety. Very rare effects include abnormal behaviour, psychosis, suicidal ideation, suicide attempts and suicide. In a total of 5577 adverse reactions reported to the UK's MHRA up to 31 March 2017, the plurality (1207, or 22%) concerned psychiatric effects. There were 85 reports of suicidal ideation, 56 of completed suicide and 43 of suicide attempts.

The association between isotretinoin use and psychopathology has been controversial. Beginning in 1983, isolated case reports emerged suggesting mood change, particularly depression, occurring during or soon after isotretinoin use. A number of studies have been conducted since then of the drug's effect on depression, psychosis, suicidal thoughts and other psychological effects.

Isotretinoin is the only non-psychiatric drug on the FDA's top 10 list of drugs associated with depression and is also within the top 10 for suicide attempts. A black box warning for suicide, depression and psychosis has been present on isotretinoin's packaging in the United States since 2005.

In 2012, a systematic review covering all articles in the literature related to isotretinoin, depression and suicide, as well as articles related to class effect, dose response, and biologic plausibility found that the literature reviewed was consistent with an association of isotretinoin administration and depression and with suicide in a subgroup of vulnerable individuals. Following this systematic review, in a 2014 review a group of Australian dermatologists and psychiatrists collaborated on a set of recommendations for safe prescribing of isotretinoin. However, whether isotretinoin use is causally associated with mental illness remains controversial.

Evidence for depression being causally associated with isotretinoin use includes 41 reports of positive challenge/dechallenge/rechallenge with isotretinoin, involving administering isotretinoin, withdrawing the drug and then re-administering it. The majority of these cases had no psychiatric history. There is also a temporal relationship between development of depression and initiation of isotretinoin treatment, with most cases developing after 1–2 months of treatment. Further, higher doses of isotretinoin increases the risk of developing depression, with 25% of people showing depression on a dose of 3 mg/kg/day as compared with 3–4% at normal doses. Studies have uncovered several biological processes which may credibly explain the affective changes induced by isotretinoin.

Isotretinoin has also been linked to psychosis. Many of the side effects of isotretinoin mimic hypervitaminosis A, which has been associated with psychotic symptoms. The dopamine hypothesis of schizophrenia and psychosis suggests that an increase in dopaminergic stimulation or sensitivity in the limbic system causes psychotic symptoms.

It has been suggested that dysregulation of retinoid receptors by retinoids such as isotretinoin may cause schizophrenia. The evidence for this is threefold - Transcriptional activation of the dopamine D2 receptor, in addition to serotonin and glutamate receptors, is regulated by retinoic acid, schizophrenia and the retinoid cascade have been linked to the same gene loci and retinoid dysfunction causes congenital anomalies identical to those observed in people with schizophrenia. Further, the expression of dopamine receptors has indeed been shown to be regulated by retinoic acid.

Isotretinoin has a number of muscoloskeletal effects. Myalgia (muscular pain) and arthralgia (joint pain) are rare side effects. Retinoids, such as high dose etretinate, are well known to cause bone changes, the most common type of which is hyperostotic changes (excessive bone growth), especially in growing children and adolescents. Other problems include premature epiphyseal closure and calcification of tendons and ligaments. The bones of the spine and feet are most commonly affected. Risk factors for skeletal effects include older age, greater dosage and longer course of treatment. Most bone changes cause no symptoms and may only be noticed using X-ray imaging.

Isotretinoin may cause non-specific gastrointestinal symptoms including nausea, diarrhea and abdominal pain. The drug is associated with inflammatory bowel disease (IBD)—ulcerative colitis, but not Crohn's disease. There are also reports of people developing irritable bowel syndrome (IBS) and worsening of existing IBS.

Isotretinoin and other retinoids are well known to affect the eyes. Dry eyes are very common during treatment and is caused by isotretinoin's apoptotic effect on the meibomian glands. Some people develop contact lens intolerance as a result. In some people, these changes are long-lasting or irreversible and represent Meibomian Gland Dysfunction (MGD). Other common effects on the eyes include inflammation of the eyelid (blepharitis), red eye caused by conjunctivitis and irritation of the eye. More rare ocular side effects include blurred vision, decreased night vision (which may be permanent), colour blindness, development of corneal opacities, inflammation of the cornea (keratitis), swelling of the optic disk (papilloedema, associated with IIH), photophobia and other visual disturbances.

Isotretinoin is also associated with sexual side effects, namely erectile dysfunction and reduced libido. In October 2017, the UK MHRA issued a Drug Safety Update to physicians in response to reports of these problems. This was in response to an EU review, published in August 2017, which states that a plausible physiological explanation of these side effects "may be a reduction in plasma testosterone". The review also stated that "the product information should be updated to include ‘sexual dysfunction including erectile dysfunction and decreased libido’ as an undesirable effect with an unknown frequency". There have also been reports of spermatogenesis disorders, such as oligospermia. 27 cases of sexual dysfunction report either negative dechallenge or positive dechallenge.

Isotretinoin's exact mechanism of action is unknown, but several studies have shown that isotretinoin induces apoptosis (programmatic cell death) in various cells in the body. Cell death may be instigated in the meibomian glands, hypothalamic cells, hippocampus cells and—important for treatment of acne—in sebaceous gland cells. Isotretinoin has a low affinity for retinoic acid receptors (RAR) and retinoid X receptors (RXR), but may be converted intracellularly to metabolites that act as agonists of RAR and RXR nuclear receptors.

One study suggests the drug amplifies production of neutrophil gelatinase-associated lipocalin (NGAL) in the skin, which has been shown to reduce sebum production by inducing apoptosis in sebaceous gland cells, while exhibiting an antimicrobial effect on "Propionibacterium acnes". The drug decreases the size and sebum output of the sebaceous glands. Isotretinoin is the only available acne drug that affects all four major pathogenic processes in acne, which distinguishes it from alternative treatments (such as antibiotics) and accounts for its efficacy in severe, nodulocystic cases. The effect of Isotretinoin on sebum production can be temporary, or remission of the disease can be "complete and prolonged."

Isotretinoin has been speculated to down-regulate the enzyme telomerase and hTERT, inhibiting "cellular immortalization and tumorigenesis." In a 2007 study, Isotretinoin was proven to inhibit the action of the metalloprotease MMP-9 (gelatinase) in sebum without any influence in the action of TIMP1 and TIMP2 (the tissue inhibitors of metalloproteases). It is already known that metalloproteases play an important role in the pathogenesis of acne.

A possible biological basis for the case reports of depression involves decreased metabolism in the orbitofrontal cortex (OFC) of the frontal lobe. It has also been found that decreased OFC metabolism was correlated with headaches. People reporting headache as a side effect often report comorbid neuropsychiatric symptoms, especially depression; a statistically significant relationship between headache and depression has been established. It is suggested that people sensitive to isotretinoin-induced CNS effects may also be susceptible to other psychiatric side effects such as depression.

Studies in mice and rats have found that retinoids, including isotretinoin, bind to dopaminergic receptors in the central nervous system. Isotretinoin may affect dopaminergic neurotransmission by disrupting the structure of dopamine receptors and decreasing dopaminergic activity. The dopaminergic system is implicated in numerous psychological disorders, including depression. Isotretinoin is also thought to affect the serotonergic system - it increases expression of 5-HT receptors in the pre-synaptic neuron, which inhibit serotonin secretion. Isotretinoin also directly and indirectly increases the translation of the serotonin transporter protein (SERT), leading to increased reuptake and consequently reduced synaptic availability of serotonin.

Inhibition of hippocampal neurogenesis may also play a role in the development of isotretinoin-induced depression. A further effect of isotretinoin on the brain involves retinoic acid function in the hypothalamus, the hormone regulatory centre of the brain and part of the hypothalamus-pituitary-adrenal axis, a key part of the body's stress response. Other brain regions regulated by retinoic acid and potentially disrupted by isotretinoin include the frontal cortex and the striatum.

Oral Isotretinoin is best absorbed when taken with a high-fat meal, because it has a high level of lipophilicity. The efficacy of isotretinoin doubles when taken after a high-fat meal compared to when taken without food. Due to Isotretinoin's molecular relationship to Vitamin A, it should not be taken with Vitamin A supplements due to the danger of toxicity through cumulative overdosing. Accutane also negatively interacts with tetracycline, another class of acne drug, and with micro-dosed ('mini-pill') progesterone preparations, norethisterone/ethinylestradiol ('OrthoNovum 7/7/7'), St. John's Wort, phenytoin, and systemic corticosteroids.

Isotretinoin is primarily (99.9%) bound to plasma proteins, mostly albumin. Three metabolites of Isotretinoin are detectable in human plasma after oral administration: 4-"oxo"-isotretinoin, retinoid acid (tretinoin), and 4-"oxo"-retinoic acid (4-"oxo"-tretinoin). Isotretinoin also oxidizes, irreversibly, to 4-"oxo"-isotretinoin—which forms its geometric isomer 4-"oxo"-tretinoin. After an orally-administered, 80 mg dose of liquid suspension C-isotretinoin, C-activity in blood declines with a half-life of 90 hours. The metabolites of isotretinoin and its conjugates are then excreted in the subject's urine and faeces in relatively equal amounts. After a single, 80 mg oral dose of Isotretinoin to 74 healthy adult subjects under fed conditions, the mean ±SD elimination half-life (t) of isotretinoin and 4-"oxo"-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in people with cystic acne.

The compound 13-cis retinoic acid was first studied in the 1960s at Roche Laboratories in Switzerland by Werner Bollag as a treatment for skin cancer. Experiments completed in 1971 showed that the compound was likely to be ineffective for cancer and, surprisingly, that it could be useful to treat acne. However, they also showed that the compound was likely to cause birth defects, so in light of the events around thalidomide, Roche abandoned the product. In 1975, Gary Peck and Frank Yoder independently rediscovered the drug's use as a treatment of cystic acne while studying it as a treatment for lamellar ichthyosis, and published that work. Roche resumed work on the drug. In clinical trials, subjects were carefully screened to avoid including women who were or might become pregnant. Roche's New Drug Application for isotretinoin for the treatment of acne included data showing that the drug caused birth defects in rabbits. The FDA approved the application in 1982.

Scientists involved in the clinical trials published articles warning of birth defects at the same time the drug was launched in the US, but nonetheless isotretinoin was taken up quickly and widely, both among dermatologists and general practitioners. Cases of birth defects showed up in the first year, leading the FDA to begin publishing case reports and to Roche sending warning letters to doctors and placing warning stickers on drug bottles, and including stronger warnings on the label. Lawsuits against Roche started to be filed. In 1983 the FDA's advisory committee was convened and recommended stronger measures, which the FDA took and were that time unprecedented: warning blood banks not to accept blood from people taking the drug, and adding a warning to the label advising women to start taking contraceptives a month before starting the drug. However use of the drug continued to grow, as did the number of babies born with birth defects. In 1985 the label was updated to include a boxed warning. In early 1988 the FDA called for another advisory committee, and FDA employees prepared an internal memo estimating that around 1,000 babies had been born with birth defects due isotretinoin, that up to around 1,000 miscarriages had been caused, and that between 5,000 and 7,000 women had had abortions due to isotretinoin. The memo was leaked to the New York Times a few days before the meeting, leading to a storm of media attention. In the committee meeting, dermatologists and Roche each argued to keep the drug on the market but to increase education efforts; pediatricians and the CDC argued to withdraw the drug from the market. The committee recommended to restrict physicians who could prescribe the drug and to require a second opinion before it could be prescribed. The FDA, believing it did not have authority under the law to restrict who had the right to prescribe the drug, kept the drug on the market but took further unprecedented measures: it required to Roche to make warnings yet more visible and graphic, provide doctors with informed consent forms to be used when prescribing the drug, and to conduct follow up studies to test whether the measures were reducing exposure of pregnant women to the drug. Roche implemented those measures, and offered to pay for contraception counseling and pregnancy testing for women prescribed the drug - the program was called the "Pregnancy Prevention Program".

A CDC report published in 2000 showed problems with the Pregnancy Prevention Program and showed that the increase in prescriptions was from off-label use, and prompted Roche to revamp its program, renaming it the "Targeted Pregnancy Prevention Program" and adding label changes like requirements for two pregnancy tests, two kinds of contraception, and for doctors to provide pharmacists with prescriptions directly; providing additional educational materials, and providing free pregnancy tests. The FDA had another advisory meeting in late 2000 that again debated how to prevent pregnant women from being exposed to the drug; dermatologists testified about the remarkable efficacy of the drug, the psychological impact of acne, and demanded autonomy to prescribe the drug; others argued that the drug be withdrawn or much stricter measures be taken. In 2001 the FDA announced a new regulatory scheme called SMART (the System to Manage Accutane Related Teratogenicity) that required Roche to provide defined training materials to doctors, and for doctors to sign and return a letter to Roche acknowledging that they had reviewed the training materials, for Roche to then send stickers to doctors, which doctors would have to place on prescriptions they give people after they have confirmed a negative pregnancy test; prescriptions could only be written for 30 days and could not be renewed, thus requiring a new pregnancy test for each prescription.

In February 2002, Roche's patents for isotretinoin expired, and there are now many other companies selling cheaper generic versions of the drug. On June 29, 2009, Roche Pharmaceuticals, the original creator and distributor of isotretinoin, officially discontinued both the manufacture and distribution of their Accutane brand in the United States due to what the company described as business reasons related to low market share (below 5%), coupled with the high cost of defending personal-injury lawsuits brought by some people who took the drug. Generic isotretinoin will remain available in the United States through various manufacturers. Roche USA continues to defend Accutane and claims to have treated over 13 million people since its introduction in 1982. F. Hoffmann-La Roche Ltd. apparently will continue to manufacture and distribute Roaccutane outside of the United States.

Among others, actor James Marshall sued Roche over allegedly Accutane-related disease that resulted in removal of his colon. The jury, however, decided that James Marshall had a pre-existing bowel disease.

Several trials over inflammatory bowel disease claims have been held in the United States thus far, with many of them resulting in multimillion-dollar judgments against the makers of isotretinoin.

As of 2017 isotretinoin was marketed under many brand names worldwide: A-Cnotren, Absorica, Accuran, Accutane, Accutin, Acne Free, Acnecutan, Acnegen, Acnemin, Acneone, Acneral, Acnestar, Acnetane, Acnetin A, Acnetrait, Acnetrex, Acnogen, Acnotin, Acnotren, Acretin, Actaven, Acugen, Acutret, Acutrex, Ai Si Jie, Aisoskin, Aknal, Aknefug Iso, Aknenormin, Aknesil, Aknetrent, Amnesteem, Atlacne, Atretin, Axotret, Casius, Ciscutan, Claravis, Contracné, Curacne, Curacné, Curakne, Curatane, Cuticilin, Decutan, Dercutane, Effederm, Epuris, Eudyna, Farmacne, Flexresan, Flitrion, I-Ret, Inerta, Inflader, Inotrin, Isac, Isdiben, Isoacne, Isobest, Isocural, Isoderm, Isoface, IsoGalen, Isogeril, Isolve, Isoprotil, Isoriac, Isosupra, Isosupra Lidose, Isotane, Isotina, Isotinon, Isotren, Isotret, Isotretinoin, Isotretinoina, Isotretinoína, Isotretinoine, Isotretinoïne, Isotrétinoïne, Isotretinoinum, Isotrex, Isotrin, Isotroin, Izotek, Izotziaja, Lisacne, Locatret, Mayesta, Myorisan, Neotrex, Netlook, Nimegen, Noitron, Noroseptan, Novacne, Oralne, Oraret, Oratane, Piplex, Policano, Procuta, Reducar, Retin A, Roaccutan, Roaccutane, Roacnetan, Roacta, Roacutan, Rocne, Rocta, Sotret, Stiefotrex, Tai Er Si, Teweisi, Tretin, Tretinac, Tretinex, Tretvita, Tufacne, Zenatane, Zerocutan, Zonatian ME, and Zoretanin.

As of 2017 it was marketed as a topical combination drug with erythromycin under the brand names Isotrex Eritromicina, Isotrexin, and Munderm.

While excessive bone growth has been raised a possible side effect, a 2006 review found little evidence for this.